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2022 - Book - PrecisionMedicineInDiabetes Precision Medicine in DiabeteS
2022 - Book - PrecisionMedicineInDiabetes Precision Medicine in DiabeteS
Medicine in
Diabetes
A Multidisciplinary Approach
to an Emerging Paradigm
Rita Basu
Editor
123
Precision Medicine in Diabetes
Rita Basu
Editor
Precision Medicine
in Diabetes
A Multidisciplinary Approach
to an Emerging Paradigm
Editor
Rita Basu
Division of Endocrinology
University of Virginia
Charlottesville, VA, USA
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Foreword
v
vi Foreword
with weight loss. Ultimately, we hope to understand nutrition and exercise better so
that those treatments can be tailored to individuals, leading to better outcomes.
Finally, technology has led to dramatic improvements in the management of type
1 diabetes with the ability to use glucose sensors in a closed-loop system with insu-
lin pumps, leading to less glucose variability and a substantial reduction in the risk
of hypoglycemia while achieving better control.
Thus, precision medicine has come of age for both type 1 and type 2 diabetes and
will surely lead to better outcomes. This book summarizes the current state of
knowledge, and understanding of these advances will help us refine our research to
deliver better and more precise therapies and manage the millions of people living
with diabetes.
Vivian Fonseca, MD
Professor of Medicine and Pharmacology
Assistant Dean for Clinical Research
Tullis Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University Health Sciences Center
New Orleans, LA, USA
Preface
President Barack Obama, in his State of the Union address on January 20, 2015, had
announced “Tonight, I’m launching a new Precision Medicine Initiative to bring us
closer to curing diseases like cancer and diabetes — and to give all of us access to
the personalized information we need to keep ourselves and our families healthier.”
Following the announcement, the National Institute of Health’s director Dr. Francis
Collins advocated, “What is needed now is a broad research program to encourage
creative approaches to precision medicine, test them rigorously, and ultimately use
them to build the evidence base needed to guide clinical practice.”
The concept of precision or personalized medicine is not new. Precision medi-
cine, like its precursor, evidence-based medicine, aims at diagnostic specificity. In
terms of precision diabetes management, one aims at identifying the underlying
pattern of dysglycemia, determining whether the cause is genetic, physiologic,
behavioral, and/or pharmacologic; identifying concurrent comorbidities; and match-
ing appropriate management strategies by proper initiation, adjustment, and assess-
ment of clinical response to avoid metabolic and other complications.
I had the honor of organizing a symposium related to precision diabetes manage-
ment at the American Diabetes Association scientific sessions in June 2018, after
which the idea of bringing together world-renowned physician scientists working in
diabetes to write a book about this topic came to mind.
However, as I began to give shape to this idea in early 2020, our lives changed
forever with a pandemic that one had previously only read about in medical text-
books and journals but had not faced. I am grateful to my colleagues for continuing
their patient care through the COVID-19 crisis and still finding time to write the
chapters presented to you.
For many of us working in the field of diabetes, there are often personal stories
to share why we chose this career. I began my journey in diabetes research back in
the mid-1990s and soon realized that if we want to make change happen, then there
is a need to conduct translational research and advance science so that newer and
better management strategies can be brought to patients. We hope that this collec-
tion of topics encourages you to consider precision diabetes approaches when pro-
viding care to your patients.
vii
viii Preface
ix
x Contents
Index�������������������������������������������������������������������������������������������������������������������� 323
Contributors
xi
xii Contributors
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong
Kong, Hong Kong, China
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong,
Hong Kong, China
Lalo Magni Department of Civil and Architecture Engineering, University of
Pavia, Pavia, Italy
Roger S. Mazze AGP Clinical Academy, Portsmouth, UK
John M. Miles Divisions of Endocrinology, Metabolism and Genetics, University
of Kansas School of Medicine, Kansas City, KS, USA
Francisco J. Pasquel Division of Endocrinology, Department of Medicine, Emory
University School of Medicine, Atlanta, GA, USA
Goran Petrovski Cornell University/Sidra Medicine, Doha, Qatar
Michal Rein Department of Computer Science and Applied Mathematics and
Department of Molecular Cell Biology, Weizmann Institute of Science,
Rehovot, Israel
School of Public Health, Faculty of Social Welfare and Health Sciences, University
of Haifa, Haifa, Israel
Michael Roden Department of Endocrinology and Diabetology, Medical Faculty
and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf,
Düsseldorf, Germany
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for
Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany
German Center for Diabetes Research, Partner Düsseldorf, München-
Neuherberg, Germany
Peter Rossing Steno Diabetes Center Copenhagen, Herlev, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Stacey A. Sakowski Department of Neurology, University of Michigan, Ann
Arbor, MI, USA
Vera B. Schrauwen-Hinderling Institute for Clinical Diabetology, German
Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine-
University, Düsseldorf, Germany
German Center for Diabetes Research, Partner Düsseldorf, München-
Neuherberg, Germany
Department of Radiology and Nuclear Medicine/Nutrition and Movement Sciences,
NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht
University Medical Center, Maastricht, The Netherlands
xiv Contributors
xv
xvi Introduction
cardiovascular risk reduction can be achieved through judicious use of these medi-
cations in conjunction with lipid-specific agents.
Michael Roden, Oana Patricia Zaharia, and Vera B. Schrauwen–Hinderling write
Chap. 4, “Imaging in Precision Medicine for Diabetes,” covering the various imag-
ing tools that can assist in identifying specific abnormal factors in physiological
structures that can delineate subgroups of patients for better treatment options.
These tools can show specific structural, functional, or molecular abnormalities in
groups otherwise classified under the broad umbrella of type 1 diabetes or type 2
diabetes, and provide the basis for optimal preventive or therapeutic measures. For
example, different techniques including bioimpedance, hydrostatic weighing, air
displacement plethysmography, densitometry (DXA), computed tomography (CT),
and magnetic resonance imaging (MRI) can perform an assessment of whole body
adiposity, but MRI usually shows the best results.
Ronald C.W. Ma and Juliana C.N. Chan author Chap. 5, “Implementation of
Precision Medicine Approaches for Type 1 and 2 Diabetes.” The authors cover
recent advances in genetics of type 1 diabetes, type 2 diabetes and its associated
complications, which have greatly facilitated the potential implementation of preci-
sion medicine in diabetes. Personalized approaches to diagnose, prevent, treat, and
predict diabetes complications are potential areas to incorporate genomic or other
information. However, the implementation of these approaches requires a multi-
pronged approach in biomarker discovery, validation, clinician education and
patient empowerment, as well as regulatory support and reimbursement.
Development of precision medicine in diabetes represents an important opportunity
to improve outcomes and “modernize” diabetes management despite some initial
challenges.
Chapter 6, “Precision Medicine for Monogenic Diabetes,” by Andrea On Yan
Luk and Lee-Ling Lim, covers the methods to diagnose monogenic diabetes, chal-
lenges faced, and possible solution to improve case finding. The chapter also
addresses common forms of monogenic diabetes including maturity onset diabetes
of the young and neonatal diabetes. With monogenic diabetes contributing to 1–3%
of diabetes in young people, molecular diagnosis of this condition fully demon-
strates the feasibility of precision medicine because it will influence the choice of
pharmacotherapy, direct relevant investigation, and prompt screening of at-risk fam-
ily members. Because of similar clinical symptoms, monogenic diabetes can fre-
quently be misdiagnosed as type 1 diabetes or type 2 diabetes, and over 80% of
cases remain unrecognized in clinical practice. Misdiagnosis is mainly due to the
lack of initiating genetic testing, the high cost of testing, and a lack of awareness
among general physicians.
M. Luiza Caramori and Peter Rossing write Chap. 7, “Diabetic Kidney Disease:
Precision Medicine for Identification, Prevention and Treatment.” About 10% of the
world’s population has diabetes, so as a result, diabetes and its complications are a
very extensive public health problem. Increased mortality and morbidity are associ-
ated with diabetes in large part due to end-stage kidney disease (ESKD) in the USA
(47% of new cases) and other developed countries. Type 2 diabetes (T2D) is the
major cause of ESKD rather than type 1 diabetes (T1D). However, worldwide, the
Introduction xvii
derived from the most important risk factors of overweight and obesity for type 2
diabetes (DM2). Because type 2 is a chronic and progressive disease, “diabesity” is
increasing rapidly and is now a public health crisis. Although modest weight loss
can improve patients’ glucose control, sustained weight loss through lifestyle
changes is difficult. Therefore, bariatric surgery has become the most effective and
efficient therapy for sustained weight loss and an alternative for patients with “dia-
besity.” Although much evidence has shown that bariatric surgery is associated with
30–95% remission rates of DM2, reasons for remission are not understood fully.
Many pre- and post-operative variables are involved, including caloric restriction
resulting in massive weight loss, gastrointestinal peptides, bile acids, and microbi-
omes. Additionally, remission is not always long-term, depending on the individual
and these variables.
Chapter 12, “Precision Nutrition for Type 2 Diabetes,” by Orly Ben-Yacov and
Michal Rein, teaches that precision nutrition aims to affect health outcomes by tai-
loring dietary recommendations to individuals or population subgroups based on
their unique characteristics to effectively promote dietary health. Many recent
advances in technologies, such as genomics, metabolomics, and microbiome, and
the development of mobile applications and wearable devices offer opportunities
for prevention and management of type 2 diabetes mellitus (T2DM). Genetic vari-
ants have been identified by nutrigenomics studies related to intake and metabolism
of specific nutrients. Potentially modified by diet, individualized fingerprints of
food and nutrient consumption and newly uncovered metabolic pathways have been
identified by metabolomics. Interpersonal variability of host metabolism and glyce-
mic status and personal postprandial responses are affected by gut microbiome
composition and function. Plus, real-time assessment of dietary intake and meta-
bolic state can be detected by mobile applications and wearable devices, which can
improve glycemic control and diabetes management. Although the field is rapidly
evolving, there are still several challenges impeding the clinical translation of scien-
tific evidence. So, more research is definitely needed before precision nutrition
approaches become widely used for prevention and management of T2DM in clini-
cal and public health settings.
Jane Yardley and Normand G Boulé give us Chap. 13, “Precision Exercise and
Physical Activity for Diabetes.” We know exercise and physical activity improve
overall health, but in the management of both type 1 and type 2 diabetes, they are
important, in part, due to their ability to decrease risk factors associated with diabe-
tes-related complications. But, just as with any other treatment, a great deal of inter-
and intra-individual variation exists in responses to different activity doses (type,
timing, intensity, frequency, and duration). This chapter shares the factors that may
influence both short- and long-term adaptation to exercise and physical activity in
individuals with both type 1 and type 2 diabetes so that the right treatment for the
right person at the right time can be designed as an appropriate exercise/physical
activity prescription.
Chapter 14, entitled “Diabetes Technology for Precision Therapy in Children,
Adults and Pregnancy,” is written by Roger S.Mazze, Alice Pik Shan Kong, Goran
Petrovski, and Rita Basu. Using case study materials, this chapter reviews the
Introduction xix
Introduction
D. Chen
Monash School of Medicine, Monash University, Melbourne, VIC, Australia
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
J. Fulcher
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
Austin and Repatriation General Hospital, Melbourne, VIC, Australia
E. S. Scott
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
Royal North Shore Hospital, Sydney, NSW, Australia
A. J. Jenkins (*)
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Department of Endocrinology, St. Vincent’s Hospital, Melbourne, VIC, Australia
e-mail: [email protected]
The hallmark of diabetes is elevated blood glucose levels, which are used to diag-
nose diabetes, usually by fasting or random blood glucose levels, an oral glucose
tolerance test (OGTT), and/or HbA1c, and to monitor its treatment, usually by serial
HbA1c levels and sometimes by self-monitoring of capillary blood or interstitial
fluid glucose levels [13, 14]. Yet, the metabolic derangement prior to and during the
course of Type 2 diabetes is far more widespread, as summarized in Fig. 1.1.
Diabetes is associated with abnormalities in glucose, lipid, and protein metabo-
lism, changes in insulin secretion and sensitivity, and alterations in the immune sys-
tem, microbiome, genetics, and epigenetics. It is also associated with increased
inflammation, oxidative stress, and advanced glycation end-products (AGEs), as
well as abnormalities in β-cell function, hemostasis, fibrinolysis, cell signaling, tis-
sue repair, fibrosis, calcification, angiogenesis, and vascular tone [10, 15–17]. These
factors and processes contribute to the pathogenesis of diabetes and its acute and
chronic complications. Some of these processes are at least partly modulated by
glycemia and insulin and may also be therapeutic targets. Diet and drugs may modu-
late these processes directly or as pleiotropic effects. It must also be recognized that
the metabolic milieu of a person with diabetes may vary substantially over time, with
aging; changes in glycemia; weight; diet; kidney, liver, or cardiac function; chronic
complication status; intercurrent illnesses; changes in lifestyle; and treatments.
There are many genetic and environmental factors that modulate diabetes onset,
progression or regression, and response to therapeutics. The person with diabetes
can now use an array of devices to collect information, such as their heart rate and
1 Precision Medicine Approaches for Management of Type 2 Diabetes 3
Environmental factors
- Nutrition
- Physical activity
Normal glucose - Gut microbiome
Genetic factors - Smoking
metabolism - Lipids
- Blood pressure
- Drugs
- Early life in utero
Effects of prediabetes
- ↓ Insulin sensitivity
- Glycemic variablity
Genetic & - Vascular dysfunction
environmental Prediabetes - Inflammation
factors (as above) - Oxidative stress
- Altered microbiome
- Altered microRNAs
- Altered epigenetics
Effects of diabetes
Genetic & environmental
Effects of prediabetes plus:
factors (as above) - ↓ Insulin secretion
Type 2 diabetes
- AGE formation
Traditional risk factors without complications - Fibrosis, calcification
(i.e, glucose, lipids, blood - Cell apoptosis
pressure, smoking) - Angiogenesisaa
rhythm, blood pressure, physical activity, food intake, sleep quality, oxygenation,
and blood and interstitial fluid glucose levels. It is likely that these data will be
increasingly integrated into medical records, complementing other clinical and lab-
oratory data. In this era of molecular biology and advanced biochemistry, such as
lipidomics, proteomics, metabolomics, and the capacity to collect and analyze large
and complex data sets, new knowledge is emerging, including related to diabetes,
that can inform precision medicine. To realize its full potential, there must be more
clinical research, advanced accurate and affordable laboratory and computational
facilities, and informed participants, including patients, their multidisciplinary
healthcare providers, the healthcare system, payers (government or private health
insurance), and society.
4 D. Chen et al.
Many genetic factors have been associated with the risk of Type 2 diabetes, the
level of glycemic control, its chronic complications [18–25], and responsiveness to
therapies, including nutrition [26–34] and drugs [35, 36]. Some gene chip assays are
already available for clinical use, such as for common gene variants that predispose
to drug intolerances [37, 38], but having a gene that predisposes one to drug intoler-
ance does not mean that one will be drug intolerant nor that one will be drug tolerant
if one does not have the gene. As diabetes and its complications are complex disor-
ders, there are likely multiple genetic factors at play, which may also differ by eth-
nicity; hence, the use of genetics in diabetes is currently a clinical research tool. In
the UK Biobank [39], a GWAS analyses, identified 208 independent SNPs mapping
to 69 loci to be associated with Type 2 diabetes. There were age subgroup-specific
genetics and causal determinants, supporting the hypothesis that the pathogenesis of
Type 2 diabetes changes with age. This increases the challenge for personalized
medicine and to the prediction of Type 2 diabetes at different life stages. In less
common cases, about 1–5% of people with Type 1 or Type 2 diabetes, a single gene
defect is responsible for diabetes—called monogenic diabetes; hence, the clinical
use of genetic tests, where available, is useful and enables the practice of precision
medicine in diabetes [40]. Some polygenic risk scores have shown utility in predict-
ing diabetes complication risk [41–45]. Other chapters in this book discuss in more
detail the genetics of diabetes, including monogenic diabetes.
Acquired factors may alter if and how genes are expressed; this is the field of
epigenetics, the study of changes in modification of gene expression rather than of
the genetic code itself. Biomarkers in epigenetics include DNA methylation,
mRNAs, and microRNAs. MicroRNAs are small non-coding RNAs that modulate
gene and mRNA expression and are involved in cell-to-cell communication [46,
47]. Their altered expression has been associated with diabetes and its chronic com-
plications [48–58]. Another molecular factor at the interface of genetics and
acquired factors is telomeres, protective caps at chromosome ends, which usually
shorten with each cell division. As we recently reviewed in diabetes [59], shorter
telomeres in circulating white blood cells have been associated with increased risk
of diabetes and its chronic complications, and telomere length is often inversely
correlated with traditional cardiometabolic risk factors, such as obesity, hyperten-
sion, smoking, and dyslipidemia. In adults with Type 2 diabetes from the Hong
Kong Diabetes Register, we showed that shorter relative leukocyte telomere length
independently predicted cardiovascular disease and all-cause mortality [60, 61].
Both genetics and environmental factors, including diet, exercise, and medications,
impact telomere length and their shortening rate, with drugs commonly used in
diabetes, such as metformin, HMG-CoA reductase inhibitors, fenofibrate, and
angiotensin converting enzyme (ACE) inhibitors being telomere protective [59, 62,
63]. While there are an increasing number of basic science and clinical studies with
positive associations between diabetes and its complications and genetic and epi-
genetic markers, no such tests are used clinically, apart from monogenic diabetes
tests. In addition to a strong evidence base and the dissemination and acceptance of
knowledge, an affordable, user-friendly, and practical means of generating and
implementing optimal treatments is essential. Advanced computer programs will be
1 Precision Medicine Approaches for Management of Type 2 Diabetes 5
required. For simpler data, usually based on traditional risk factors, complication
status, and sometimes imaging, such as retinal images or coronary artery calcifica-
tion, useful risk equations/calculators are already available, such as for Type 2 dia-
betes itself [64, 65], sight-threatening diabetic retinopathy [66, 67], diabetic kidney
disease [68, 69], and cardiovascular disease (CVD) [70], often presented as web-
sites or apps. Artificial intelligence (AI) for the diagnosis of diabetic retinopathy is
already being implemented, but further refinements are desirable [71, 72].
While we await further knowledge and translational tools to enhance our ability
to tailor lifestyle and therapies to the individual with diabetes, we can already prac-
tice some precision medicine for people with diabetes with current resources based
on traditional risk factors. Patient preferences, medico-legal considerations, and
local resources, such as the ability and preparedness to self-administer injectable
drugs and out-of-pocket drug costs, should be considered.
As there are numerous abnormalities in the metabolic milieu of diabetes (Fig. 1.1)
and many risk factors for complications, multiple treatments are needed to achieve
metabolic control and reduce adverse outcomes. Once Type 2 diabetes is present,
there are recommended targets for HbA1c, blood pressure, lipids, albuminuria,
BMI, and smoking, and also for vaccinations and complication screening. Table 1.1
summarizes some national/international guidelines. In spite of such guidelines and
Table 1.1 Risk factor targets for diabetes patients from major bodies
RACGP/Diabetes
ADA [155] ESC/EASD [266] IDF [267] Australia [14]
HbA1c <7% (53 <7.0% (53 mmol/mol) <7% (53 mmol/mol) ≤7% (53
mmol/mol) mmol/mol)
SBP <140 <130 mmHg ≤130–140 mmHg ≤140 mmHg
mmHga
DBP <90 mmHga <80 mmHg ≤80 mmHg ≤90 mmHg
LDL-C –b Moderate CV risk: <2.6 mmol/L <2.0 mmol/L
<2.6 mmol/L Established CVD or <1.8 mmol/L if
High CV risk: high CV risk: established CVD
<1.8 mmol/L and <1.8 mmol/L
≥50% reduction
Very high CV risk:
<1.4 mmol/L and
≥50% reduction
BMI <25 kg/m2c – – <25 kg/m2
[78]
WHR – – – –
Waist – – – ♂ < 94 cm
circumference ♀ < 80 cm
a
Target lower by 10 mmHg may be appropriate in individuals at higher CV risk (existing CVD or
10-year ASCVD risk ≥15%)
b
Prescription of lipid-lowering medications dependent on patient’s age and CV risk (as detailed in
Fig. 1.2)
c
<23 kg/m2 for Asian American individuals
6 D. Chen et al.
Pre-diabetes
Fig. 1.2 Evidence-based clinical practice points for adults with pre-diabetes and diabetes
1 Precision Medicine Approaches for Management of Type 2 Diabetes 7
Diabetes with CVD Diabetes with heart failure Diabetes with microvascular
complications complications
See Table 1.7
See Table 1.6 See Table 1.8
the proven benefit of optimizing multiple risk factors in diabetes [73], the majority
of people with diabetes do not meet recommended treatment targets [74, 75].
Multiple risk factors, even at low severity levels, can place people with diabetes at
moderate-to-high risk of complications.
While precision medicine for diabetes will improve, the current evidence base
already enables clinicians to personalize diabetes care based on their patients’ age,
diabetes type, duration, and complication status. In this chapter, we summarize evi-
dence for proven therapies in Type 2 diabetes and its chronic complications. We
provide flowcharts, tables, mnemonics, and relevant websites to outline major man-
agement points. Other book chapters herein expand some areas.
Progression from normal glucose tolerance to Type 2 diabetes is relatively slow, and
even when diabetes is present, it can be asymptomatic or symptoms misattributed
[76, 77]. National diabetes associations generally recommend testing for Type 2
8 D. Chen et al.
diabetes in all asymptomatic adults aged ≥45 years (or younger for high-risk ethnic
groups) and overweight adults with one or more diabetes risk factors [78]. The
American Diabetes Association (ADA)-endorsed guidelines “Standards of Medical
Care in Diabetes,” which are updated at least annually [13, 78], provide detailed
guidance regarding screening and diagnosis (including in the pediatric
population).
A range of lifestyle modifications, with an emphasis on weight loss through diet
and exercise, medications, and bariatric surgery (discussed in another chapter) can
reduce risk of Type 2 diabetes. As shown by the Diabetes Prevention Program (DPP)
over 3 years and its ongoing follow-up study (DPPOS), both lifestyle interventions
and metformin can reduce progression from pre-diabetes to Type 2 diabetes [79,
80]. The T4DM trial showed that in high BMI middle-aged or elderly men with pre-
diabetes or recent-onset Type 2 diabetes and low testosterone levels, testosterone
replacement therapy reduced Type 2 diabetes [81]. Technology-mediated interven-
tions, such as Internet-based programs, phone calls, and mobile applications, can
deliver lifestyle intervention programs on a much larger scale, and a systematic
review found that such interventions improved weight loss and glycemia [82]. A
systematic review and meta-analysis of over 49,000 subjects in 43 studies [83] eval-
uated the sustainability of lifestyle modifications or drugs for Type 2 diabetes pre-
vention. At the end of the intervention phase, the relative risk (RR) reduction for
Type 2 diabetes was 39% for lifestyle and 36% for drugs. Following washout or
follow-up (mean 7.2 years), the RR reduction was 28% for lifestyle modification,
while there was no sustained RR reduction after drug cessation. Bariatric surgery, of
various types, discussed in another chapter, is an effective option to prevent and
reverse Type 2 diabetes, with both weight-dependent and weight-independent
effects [84–86].
Table 1.2 Mnemonic for clinical factors to address in diabetes care: GLOBES STRIVED
G Glucose S Screening
L Lipids and lipid drugs TR Treatment to target
O Obesity I Inflammation/infections
B BP and BP drugs V Vaccination
E Emotions E Education
S Smoking D Devices
Most people with Type 2 diabetes have multiple vascular risk factors [75]. Substantial
reductions of CVD events, sight-threatening retinopathy, end-stage kidney disease,
and all-cause mortality of 46–59% have been demonstrated with intensified multi-
factorial intervention [73]. We now overview recommendations for all people with
diabetes (summarized in Fig. 1.2), including those free of clinically evident compli-
cations, and then highlight additional recommendations for those with chronic com-
plications. The evidence for various therapeutics for the primary and secondary
prevention of CVD and microvascular complications are summarized in Tables 1.3,
1.4, 1.5, 1.6, 1.7, and 1.8.
Lifestyle
Many aspects of daily life are key to diabetes care: physical activity and sedentary
time, nutrition, adiposity, smoking status, mental well-being, and self-monitoring of
risk factors such as glucose and blood pressure. Exercise and reduced sedentary
time benefits, appetite, weight, blood pressure (BP), lipids, (mainly increasing
HDL), glycemia, insulin resistance, mental well-being, cardiorespiratory fitness,
cardiovascular risk, bone density, and balance.
Exercise Adults with Type 2 diabetes are recommended to undertake ≥150 min-
utes of moderate-vigorous exercise and 2–3 sessions of resistance training (on non-
consecutive days) every week [78]. While the Look AHEAD trial did not show
cardiovascular event or mortality benefits with intensive lifestyle intervention in
Type 2 diabetes, there were minimal group differences in weight, waist c ircumference,
physical fitness, and HbA1c after the first year [88]. Longer-term studies may be
more informative.
Nutrition A number of diets have shown benefits in Type 2 diabetes. The Dietary
Approaches to Stop Hypertension (DASH) diet, comprising foods low in sodium
and rich in potassium, magnesium, and calcium, significantly reduced fasting blood
glucose, HbA1c, LDL-cholesterol, and BP in people with Type 2 diabetes [89]. In a
10 D. Chen et al.
evidence
Smoking Nicotine replacement Yes [297] (II) Yes [297] (II) Yes [298] (I) Yes [298] (I)
therapy, varenicline,
bupropion
(continued)
11
Table 1.4 (continued)
12
[131–133] (II)
The levels of evidence (placed in brackets) have been determined using the National Health and Medical Research Council levels of evidence
“No” suggests negative results in ≥1 large RCTs
Lifestyle modifications are recommended first line for all of these risk factors
a
Currently no renal indication for statins or fenofibrates
b
A RCT showed candesartan non-significantly reduced risk of retinopathy progression and significantly increased regression on active treatment, though a
Cochrane review found that lowering BP did not slow retinopathy progression
c
Currently no indication for antihypertensive agents in the primary prevention of diabetic nephropathy
13
14 D. Chen et al.
Table 1.6 Clinical practice points for management of diabetes with cardiovascular disease
Diabetes with CVD complications
Refer to cardiologist
Fairly fast SA2A2B: fish oil, fibrate, statin, antiplatelets (dual), ACEi/ARB, aldosterone
antagonist, beta-blocker
Glucose Consider relaxing HbA1c target to mitigate risk of hypoglycemia (e.g.,
patients on insulin or sulfonylureas, patients with history of hypoglycemia)
[110, 312]
Consider cardioprotective glucose-lowering agents (e.g., SGLT2 inhibitors,
GLP-1 analogues) [268, 280]
Fish oil Current evidence does not support use nor cessation of fish oils. Systematic
review showed nil reduction in CV events, but reduced CVD mortality [313]
Consider highly purified fish oils (on statin background) if high triglycerides
[314]
Fibrate Fenofibrate if patient has dyslipidemia (elevated triglycerides, low HDL-C)
[291, 292]
Statin High-dose statin therapy (e.g., atorvastatin 40–80 mg nocte, rosuvastatin
20–40 mg daily) [150]
Consider combination therapy with ezetimibe [315] 10 mg daily if LDL-C
>1.6 mmol/L or PCSK9 inhibitor [295] if not reaching targets
Antiplatelets Aspirin 75–162 mg daily (reduces major vascular events by 25%) [237]
(dual) Use clopidogrel if patient is allergic to aspirin
ACS: aspirin + ticagrelor 90 mg bd [316] (or clopidogrel 75 mg daily [317])
for up to a year
ACS treated with coronary stent: aspirin + ticagrelor 90 mg bd [316]/
prasugrel 10 mg daily [318] (or clopidogrel 75 mg daily) for 12 months
(minimum duration of DAPT depends on stent type – consult cardiologist
for early cessation)
2016 ACC/AHA guidelines recommend prasugrel for ACS patients not at
high risk of bleeding and with no history of cerebrovascular events and
ticagrelor in other ACS patients [319]
Seek input from cardiology team
ACEi/ARB Long-term therapy is recommended, including in normotensive individuals
[320, 321]
Aim for BP <130/80 mmHg if achievable
If BP not achieved with monotherapy, add CBB or thiazide [259]
Monitor potassium, especially with CKD, or on ACEi/ARB or aldosterone
antagonist
Aldosterone Recommended in post-MI patients with LVEF ≤40% [322]
antagonist Equal CV benefits of spironolactone (lower cost) and eplerenone (fewer side
effects) [323]
Beta blocker Long-term therapy is recommended, unless contraindicated [324]
ACS acute coronary syndrome, DAPT dual antiplatelet therapy, HFrEF heart failure with reduced
ejection fraction
RCT of which 50% of subjects had Type 2 diabetes, the Mediterranean diet, charac-
terized by abundant olive oil, fruits, vegetables, nuts, and cereals, significantly low-
ered the risk of a major cardiovascular event by 31% [90].
1 Precision Medicine Approaches for Management of Type 2 Diabetes 15
Table 1.7 Clinical practice points for management of diabetes with symptomatic HFrEF
Diabetes with symptomatic HFrEF
Refer to cardiologist
BANDAID2: beta-blocker, ACEi/ARB, nitrate-hydralazine, diuretic, aldosterone antagonist,
ivabradine, device (AICD, CRT), and digoxin
Most patients will also benefit from fish oils, statins, and antiplatelet medications (e.g., aspirin)
Glucose Consider relaxing HbA1c target to mitigate risk of hypoglycemia (e.g.,
in patients on insulin or sulfonylureas, patients with history of
hypoglycemia) [110]
Consider SGLT2 inhibitors (i.e., empagliflozin, canagliflozin), or
GLP-1 analogues with proven CVD benefits if SGLT2 inhibitors are
contraindicated or not tolerated [268, 280, 325]
Beta-blocker Recommended for all patients [326]
Ensure that the patient is clinically stable and euvolemic before
commencing
ACEi/ARB Recommended for all patients [327, 328]
ARNI recommended as replacement for ACEi/ARB (with at least
36-hour washout window) in patients with LVEF ≤40% despite
maximal ACEi/ARB and beta-blocker dosage [249]
Nitrate-hydralazine Recommended if an ACEi/ARB is contraindicated or if there are no
other therapeutic options [329, 330]
Diuretic Recommended to achieve euvolemia in fluid-overloaded patients [331]
Aldosterone antagonist Recommended for all patients [332]
Avoid/use cautiously in patients with stage 4–5 CKD or K >5 mmol/K
Ivabradine Consider in patients with LVEF ≤35% who are receiving appropriate
therapy with sinus rhythm and HR ≥70 bpm despite maximum
beta-blocker dosage [333]
AICD Recommended in NYHA II-III HFrEF patients at least 1 month
post-MI with LVEF ≤35% and a prognosis of ≥12 months [334]
CRT Recommended in patients with LVEF ≤35%, sinus rhythm, and QRS
duration ≥150 ms
Consider in patients with LVEF ≤35%, sinus rhythm, and QRS
duration 130–149 ms [335]
Digoxin Consider in patients with sinus rhythm and moderate-severe symptoms
(NYHA class III-IV) despite maximum ACEi/ARB dosage (reduces
hospitalizations for recurrent heart failure but has not been shown to
clearly reduce all-cause mortality) [336]
ARNI angiotensin receptor-neprilysin inhibitor, AICD automatic implantable cardioverter-
defibrillator, CRT cardiac resynchronization therapy, NYHA New York Heart Association, LVEF
left ventricular ejection fraction, LBBB left bundle branch block
Table 1.8 Clinical practice points for management of diabetes with microvascular complications
Diabetic retinopathy
Screening
Annual comprehensive dilated exam by an ophthalmologist or optometrist
More frequent for progressive or sight-threatening retinopathy
Treatment
Optimizing glycemia slows retinopathy progression in short-duration diabetes, but there is
little benefit in older patients [102, 132, 133]
Consider avoiding semaglutide in patients with retinopathy due to association with early
retinopathy worsening related to rapid and substantial HbA1c reduction [337]
A Cochrane review found that better BP control did not slow retinopathy progression,
despite some trial evidence of ACEi/ARB therapy benefit [303, 304]
While not the primary trial endpoint, fenofibrate may slow retinopathy progression in Type
2 diabetes with some retinopathy, independent of traditional lipid levels [180, 181, 338]
Several RCTs of fenofibrate with a diabetic retinopathy endpoint are underway, e.g.,
LENS trial (https://clinicaltrials.gov/ct2/show/NCT03439345)
In late-stage retinopathy, anti-VEGF injections, intraocular steroids, laser therapy, or
vitrectomy can reduce risk of vision loss [339]
An ophthalmologist can advise regarding treatment choice and delivery
Referral
Refer to ophthalmologist if:
Sudden onset or slowly progressive vision loss, or increased “floaters”
Any level of diabetic macular edema, severe non-proliferative or proliferative diabetic
retinopathy
Diabetic nephropathy
Screening
Monitor renal function, electrolytes, Ca, PO4, and Hb every 6 months at eGFR of 45–60
and every 3 months at eGFR <45
Annual bone density scan, parathyroid hormone, and vitamin D levels at eGFR <60
Treatment
Smoking cessation, a healthy weight and diet (protein intake of <0.8 g/kg/day in non-
dialysis patients) [177], better glycemia [99, 131], and ACEi/ARB therapy [306, 340] can
slow nephropathy progression
Consider a SGLT2 inhibitor in albuminuric CKD [341]
Effects are unclear in patients with eGFR <30 mL/min/1.73 m2
If SGLT2 inhibitors are not tolerated or contraindicated, consider GLP-1 analogues with
CVD benefit [135]
No lipid-lowering drugs have regulatory approval for nephropathy, although fenofibrate
was renoprotective in FIELD and ACCORD Lipid trials in spite of an apparent rise (≈12–
20%) in serum creatinine [182, 183, 342, 343]
Statins can reduce albuminuria, but not eGFR, serum creatinine, and blood urea nitrogen
[300]
For late-stage renal disease, a nephrologist can guide use (or non-use) of renal replacement
therapy (dialysis or transplant)
Referral
Refer to nephrologist if:
Doubt about cause of nephropathy
Rapid decline in renal function
GFR <30 ml/min/1.73m2
1 Precision Medicine Approaches for Management of Type 2 Diabetes 17
A 12-week pilot study found similar glycemic and weight improvements with a 5:2
diet (2 days of severe energy restriction (1670–2500 kJ/day) and 5 days of habitual
eating) and moderate continuous energy restriction (5000–6500 kJ/day) [93]. While
no long-term studies have been reported, this study provides promising evidence that
a 5:2 diet may be a suitable alternative for those who prefer intermittent fasting.
We will now discuss in order the elements of our GLOBES STRIVED mne-
monic. We then briefly comment on aspirin usage in people with diabetes.
Glycemia
There are several aspects of glucose control that should be addressed in diabetes
care, including the mean glucose level, usually assessed by HbA1c levels, time in
the recommended target glucose range and above and below it (if continuous glu-
cose monitoring (CGM) is used), hypoglycemia, and glucose variability. A stan-
dardized Average Glucose Profile (AGP) report summarizing the CGM profile has
been developed, and CGM-related targets for people with Type 2 diabetes recom-
mended [94]. Glucose variability (discussed more below) may be assessed by vari-
ability in interstitial fluid glucose levels (by CGM) or serial blood glucose or HbA1c
levels. All aspects of glucose control, including hyperglycemia, hypoglycemia, and
higher glucose variability, have been linked with increased risk of micro- and mac-
rovascular complications and with mortality [95–98]. Given the slow development
of the chronic complications of diabetes, years will need to pass until robust
18 D. Chen et al.
drugs such as SGLT2 inhibitors [125] and GLP 1 analogues [125], and insulin, opti-
mal insulin dosing times, and medication adherence [126]. The use of CGM can
assist with patient education and guide clinicians regarding GV. Electronic medical
records and pathology reports could automate the calculation of HbA1c variability.
VADT found benefits in younger patients but harm in older patients [133]. Trial dif-
ferences may relate to differences in participant ages, diabetes duration, HbA1c
starting points and targets, their rate of achievement, and in drugs used and their
pleiotropic effects.
Recently, several large RCTs have demonstrated exciting major clinical benefits
with SGLT-2 inhibitors and GLP-1 analogues, reducing CVD events, heart failure,
diabetic kidney disease, and mortality, with much benefit independent of their
HbA1c reductions (summarized in Table 1.3). These trials are already changing
guidelines and clinical practice, often becoming first- or second-line glucose control
drugs in advantaged regions [13, 134].
There are now regularly (at least annually) updated guidelines on how to personal-
ize glucose-lowering medications [134, 135]. Given the dynamic nature of available
drugs, for example, with the increasing longer-acting injectable GLP-1 agonists
[136–140], and results of newly completed clinical trials, we recommend readers
review the regularly updated guidelines on websites such as by the ADA [141] and
the Australian Diabetes Society [134, 135, 142] for guidance. Along with the
patient’s age, diabetes duration, complications, kidney function, pregnancy status,
and other medications, treatment options will also be influenced by national drug
approval, local drug availability, affordability, and patient preference (e.g., inject-
able or non-injectable drugs). Formulations combining drug classes to reduce pill
burden and subsidies to minimize drug costs may promote patient adherence.
Cardiovascular disease The initial low-dose statin lowers LDL-C levels by about
50%, and each doubling of the dose usually lowers LDL-C by an additional 6%
[149]. The primary and secondary cardioprotective effects of statins in people with
Type 2 diabetes are well established. In the Cholesterol Treatment Trialists’
Collaboration (CTTC) meta-analysis of 14 trials (18,686 subjects), statins reduced
cardiovascular events by 25%, all-cause mortality by 9%, and CV death by 13% for
every 1 mmol/L reduction in LDL-C levels [150], comparable to results of the
CTTC’s meta-analysis of statin trials in the general population [151]. Unless contra-
indicated or not tolerated, statins are the recommended first-line lipid-lowering
therapy for the secondary prevention of CVD. For primary prevention in people
with diabetes, a CVD risk calculator [152–154] can be used to derive risk levels and
guide statin therapy. Some national diabetes care guidelines, such as the those by
the ADA, do not recommend the routine assessment of subclinical coronary artery
disease in asymptomatic people, such as by coronary artery calcification (CAC) or
CT coronary angiography as it will not change management or outcomes, providing
there is judicious attention to risk factor management as per guidelines [155]. In
some cases, a non-evidence-based specialist consensus exists for consideration of
screening for people who have “atypical” symptoms which might be angina vari-
ants, other markers of atherosclerosis, ischemic ECG changes, or in people wishing
to start strenuous physical activity in the absence of regular exercise. Such testing
may include exercise testing, CAC or CT angiography, nuclear imaging, or pharma-
cologic stress echocardiography. It is recognized that some patients and some clini-
cians are more likely to initiate and to adhere to proven effective therapies, such as
statins if they are aware of a clinically silent atheroma burden [147]. Referral to a
cardiologist for advice regarding the most appropriate and cost-effective investiga-
tion and management may be appropriate.
Statins and new-onset diabetes (NOD) Statins can increase the risk of Type 2 dia-
betes by 9–12% [141, 166–168]. As this usually occurs in people with pre-diabetes
or other risk factors for diabetes and/or CVD, the risk benefit ratio is seen as favor-
able. Underlying mechanisms may relate to impaired insulin secretion and increased
peripheral insulin resistance [169]. Some risk may be mediated by the lower LDL
levels [170].
A subset of people with diabetes may be statin intolerant. We have reviewed its
diagnosis and provided a management algorithm [171]. Other LDL-C-lowering
drugs which can be used for statin-intolerant subjects or added to a statin in those
not meeting their LDL-C target are a once daily tablet of ezetimibe; less well-
tolerated bile acid binding resins, usually taken 2–3 times a day with food, which
reduce lipid absorption from the gut; bempedoic acid; and injectable PCSK9 inhibi-
tors [172]. Combinations such as of a statin, ezetrol, and bempedoic acid may be
used to lower LDL-C adequately [173, 174].
Ezetimibe acts by inhibiting the cholesterol transport protein Nieman Pick
C1-like 1 protein in small intestine enterocytes, lowering LDL-C by about 20% if
used alone and when added to a statin [174]. In the IMPROVE-IT trial, including
5000 adults with diabetes and acute coronary syndrome, the addition of ezetimibe
to a statin reduced the composite cardiovascular primary endpoint by 14% versus
2% in subjects without diabetes [175].
Resins lower LDL-C levels by 10–30% by binding cholesterol-rich bile acids in
the gut and removing them via the fecal route, which necessitates synthesis of more
bile acids. They also improve glucose control in diabetes. Tolerability is often low
due to gastrointestinal side effects, the inconvenience of multiple daily doses, and
the potential need to separate its dosing from other oral medications due to its
impairment of absorption of some drugs [174].
Bempedoic acid is the first drug in a new class of lipid-lowering agents, the
adenosine triphosphate-citrate lyase (ACL) inhibitors, which act two steps upstream
of HMG-CoA reductase to inhibit cholesterol production. In a meta-analysis (11
trials, n = 4391 general population subjects), bempedoic acid significantly reduced
LDL-C (median −22.9, 95% CI −27.3 to −18.5%), CRP (median −24.7, 95% CI
−32.1 to −17.3%), composite cardiovascular events (RR 0.75, 95% CI 0.56–0.99),
and rates of new-onset or worsening diabetes (RR 0.65, 95% CI 0.44–0.96). Hence,
this drug is not associated with higher rates of NOD or worsening metabolic control
[176]. As yet, there are no Type 2 diabetes-specific drug trial results.
PCSK9 inhibitors Proprotein Convertase Subtilisin-kexin type 9 (PCSK9) is a pro-
protein convertase involved in the degradation of hepatic LDL receptors; hence,
PCSK9 inhibitors inhibit LDL-receptor recycling, which increases LDL clearance.
There are currently two fully human monoclonal antibodies (evolocumab and ali-
rocumab) that inhibit PCSK9 approved for clinical use. These drugs are usually
24 D. Chen et al.
given by subcutaneous injection every 2 weeks and can lower LDL-C levels by 60%
and be used in conjunction with a statin [177]. In the Further Cardiovascular
Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk
(FOURIER) trial in the general population, evolocumab added to a statin signifi-
cantly lowered LDL-C by 59% and reduced the risk of a composite cardiovascular
endpoint (HR 0.86, 95% CI 0.79–0.92, p < 0.001), with similar benefits in people
with versus without diabetes (of which 97.2% had Type 2 diabetes). A meta-analysis
of PCSK9 inhibitors suggested that more potent PCSK9 inhibitors and longer-term
use may be associated with increased risk of NOD and worsening glycemia [178].
Detailed analyses of glycemia, long-term follow-up, and further PCSK9 trials in
diabetes are merited. Local injection site reactions and drug cost may limit drug use.
Triglyceride-Lowering Drugs
In addition to lifestyle measures, statin therapy is indicated for people with a prior
CVD event (secondary prevention) and high CVD risk adults (primary prevention),
usually assessed by a cardiovascular risk calculator, with treatment to evidence-
based lipid targets. If moderate-to-high-dose statin therapy does not achieve ade-
quate LDL-C levels, the usual next step would be to add ezetimibe. If additional
LDL-C lowering is desirable (or nil or only low-dose statin therapy can be toler-
ated), then other lowering drugs such as bempedoic acid or PCSK9 inhibitors can be
used. While not FDA approved for use in the USA, fenofibrate has been approved
1 Precision Medicine Approaches for Management of Type 2 Diabetes 25
for use in Australia and some other (mainly low- and middle-income) countries for
protection against progression of diabetic retinopathy in people with Type 2 diabe-
tes and existent retinopathy, independent of lipid levels. For people with Type 2
diabetes with high triglycerides and low HDL-cholesterol levels, fenofibrate (either
alone or on statin background) can reduce cardiovascular events. For people with
diabetes and severe hypertriglyceridemia (fasting triglycerides over 6.5 mmol/l),
fibrate therapy is appropriate to reduce the risk of acute pancreatitis. If a statin is
being prescribed, fenofibrate is the only fibrate approved for statin-fibrate combina-
tion therapy due to the lower risk of rhabdomyolysis [185]. As for glucose and BP
control, people with diabetes may require and benefit from combination therapy of
lipid-lowering agents.
Obesity
Being overweight or obese is commonly associated with Type 2 diabetes, and its
coexistence usually increases risk factors such as dyslipidemia and hypertension.
An initial weight loss of 5–10% of body weight for overweight or obese patients is
recommended [187]. In obese patients with Type 2 diabetes, a very-low-
carbohydrate, high-unsaturated fat, low-saturated fat diet produced greater improve-
ments in lipids, glycemia, and diabetes medication reductions compared to a
high-carbohydrate, low-fat diet [188]. In addition to lifestyle changes, doctors
should aim to prescribe glucose-lowering drugs that promote weight loss (e.g., met-
formin, SGLT-2 inhibitors, GLP-1 analogues) or are weight neutral (e.g., DPP-4
inhibitors), as well as pharmacological therapies (e.g., orlistat) if the benefits of
weight loss outweigh medication risks. In morbidly obese diabetic patients with
multiple comorbidities, bariatric/metabolic surgery improves glucose control and
may even reverse Type 2 diabetes [189]. Benefits on diabetes prevention and regres-
sion have been shown with bariatric surgery at less severe levels of obesity (BMI
30–35 kg/m2) and even in those with a BMI <30 kg/m2 [190, 191], but more studies
with longer follow-up, standardized definitions of diabetes remission and consider-
ation of the type of bariatric surgery, duration of dysglycemia, and ethnicity are
desirable. There are various types of bariatric surgery, which are discussed in detail
in another book chapter herein.
Blood Pressure
Individualizing BP Targets
Lifestyle changes
Dietary changes (i.e. DASH diet, low salt & high
potassium diet), moderate alcohol intake, increase physical
activity, weight loss
Medical therapy
Take antihypertensives at bedtime
1. ACEi or ARB (not both)
2. Thiazide diuretics
3. Calcium channel blocker
4. Aldosterone antagonist
5. Beta blocker
Commence 2 agents if BP ≥160/100mmHg
Individualise BP target
BP self-monitoring at home
Aim BP <140/90 mmHg for most patients
Aim BP <130/80 in high CVD risk patients
Emotion
Approximately 25% of people with Type 2 diabetes will experience depression, and
40–45% will experience diabetes distress [201]. Suboptimal mental health is associ-
ated with poorer self-care and higher HbA1c levels [202]. Short survey tools (e.g.,
PAID and DDS-2) are recommended to screen for diabetes distress. For patients
experiencing psychological problems, a diabetes educator, psychologist, or psychi-
atrist can be helpful.
28 D. Chen et al.
Smoking
Smoking cessation reduces mortality risk by one third over only a few years [203].
Smokers are more likely to develop Type 2 diabetes, and people with Type 2 dia-
betes are likely to stop smoking if they receive the appropriate counseling and
support [204]. In the motivated patient, combining pharmacological therapy (e.g.,
nicotine patches) with counseling is more effective than either therapy alone
[205]. E-cigarette or “vaping” is not recommended as an aid to smoking cessation,
although a 2016 meta-analysis of 18 observational studies showed that e-cigarette
users had a 28% lower odds ratio of stopping smoking compared to non-
users [206].
Screening
All people with Type 2 diabetes should undergo regular screening, usually annu-
ally, for complications and risk factors (Fig. 1.2). Identified risk factors should
be reassessed after several months of therapy. This screening also applies to
youth with Type 2 diabetes, as they are at a particularly high risk of complica-
tions (even higher than those with comparable duration of Type 1 diabetes)
[207], likely related to risk factors such as obesity, hypertension, and
dyslipidemia.
People with Type 2 diabetes should also undergo appropriate screening for
cancers as they are at the same or increased risk of cancers, except for prostate
cancer, than their non-diabetic peers [208, 209]. Some anticancer immunothera-
pies or chemotherapy regimens can also induce diabetes or worsen glucose con-
trol [210].
TReating to Target
Many people with diabetes do not meet recommended risk factor targets, with mul-
tiple factors likely being contributory, including clinical inertia by the care team
[211] and patient non-adherence. Clinical inertia may be mitigated by educational
or learning interventions and by empowered patients. Clinician diligence, a regular
review of targets met, and audits may be helpful. Electronic decision support tools
can assist with identifying subjects not at target and suggesting therapeutic steps
[211]. Patient non-adherence may arise due to complexity of treatment regimens,
perceived or real drug side effects or risks, inability to afford medications, and men-
tal health issues.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 29
Inflammation/Infections
People with diabetes, particularly with suboptimal glucose control, are at increased
risk of infection. Common infections include urinary tract infections, which can be
asymptomatic, fungal infections of the skin and genitourinary tract, and periodontal
disease. Periodontal disease has been associated with increased risk of CVD, micro-
vascular complications, and death [212, 213].
As recently observed in the COVID-19 pandemic, people with diabetes are also
at increased risk of adverse outcomes such as requiring hospitalization, ventilation,
and death [214–216].
Vaccinations
Due to their increased risk of infection, people with Type 2 diabetes should have all age-
appropriate vaccinations such as against influenza, pneumococcal pneumonia, tetanus,
and COVID-19, and others as appropriate to age, sex, occupation, environment, and travel.
Education
Devices
An increasing array of devices may assist diabetes care. Some people with diabetes
may choose to use food, weight, and physical activity trackers or smartphone apps.
Body weight, body composition scales, and a BP cuff for at-home use may be
30 D. Chen et al.
Glucose Monitoring
fluid and blood glucose levels is about 10% and can be much higher [223]. Interstitial
fluid glucose levels usually lag about 10 minutes behind changes in blood glucose
levels, with about 6 minutes being physiological and the rest device-related. All sen-
sors tend to perform better on and after Day 2 of use, due to initial tissue reactions
around the inserted sensor [224].
Disadvantages include the need to be “attached” to a device continuously, and
the abundance of glucose data, which some may find distressing, particularly if they
spend substantial time out of their desired glucose range. Some people are upset and
lack trust in the system due to differences between interstitial fluid and blood glu-
cose levels. Common problems include skin irritation, which may be reduced by
barrier creams, sensor failures and dislodgement, and high financial costs if subsi-
dies are not available [230].
Publications and experience report feasibility, safety, acceptable accuracy, and
informative use of CGM or FGM in special circumstances such as fasting (for
weight loss or religious reasons), pregnancy, extreme sports, hemodialysis, and
within inpatients and intensive care unit settings.
Interstitial fluid glucose monitoring can facilitate patient education, motivation,
monitoring, decisions regarding glucose control regimens, and also clinical research.
Treatment targets based on interstitial fluid glucose monitoring There are interna-
tional consensus recommendations for standardized reporting of CGM and FGM
data, including mean glucose, SD and CV of glucose levels, GV, an estimated HbA1c
and time (%) in target range (3.9–10 mmol/l), time above 10 and above 13.9 mmol/l,
and time below 3.9 and below 3.0 mmol/l. This is usually presented as a color-coded
bar graph. A daily graph of each glucose trace from midnight to midnight is recom-
mended as an overlay plot with a line for median glucose levels and shaded areas for
25–75th and 10–90th percentiles. Recommended times in each glucose range are
suggested. For non-high-risk adults with Type 2 diabetes, the recommended time in
target range (TIR) is over 70%. Recommended time above 10 and above 13.9 mmol/l
is less than 25% and 5%, respectively, and time below 3.9 and below 3.0 mmol/l is
less than 4% and 1%, respectively. Recommended glucose CV is less than 36%. For
high-risk adults with Type 2 diabetes, avoidance of low glucose levels and less TIR
are suggested. High-risk adults may include people with CVD, multiple comorbidi-
ties, limited life expectancy, impaired cognition, frailty, or those living in assisted
care facilities. For this group, general recommendations are above 50% for TIR;
time above 10 mmol/l and above 13.9 mmol/l are less than 50% and 10%, respec-
tively; and time below 3.9 mmol/l less than 1%, with no time below 3.0 mmol/l. As
yet, there are no recommendations for pregnant women with Type 2 diabetes due to
limited evidence, but such data will likely become available [94].Of course, the
treating clinician should always personalize targets. TIR has been shown to correlate
with HbA1c levels, in spite of the different time frames. It has been calculated that
an increase in TIR by 10% correlates with a HbA1c reduction by 0.9% [231]. It is
recommended that decisions regarding clinical care be based on at least 2 weeks of
CGM (or FGM) data with data available for at least 70% of the time [94].
32 D. Chen et al.
Glucose benefits Relative to Type 1 diabetes, the benefits of CGM and FGM use
on HbA1c levels and TIR are more modest in Type 2 diabetes. Meta-analyses sug-
gest modest (0.35% or less) or no statistically significant impact on HbA1c in Type
2 diabetes [232–234].TIR is usually improved with CGM or FGM use, and in some
studies, low glucose time and hypoglycemia are reduced [232–234]. Wearer accept-
ability is generally good, but there is potential for selection bias in trials and user
bias in clinical practice. Further research is merited to guide user choice and optimal
frequency of use.
Antiplatelet Agents
While recommended for secondary CVD protection, aspirin is not routinely recom-
mended for primary prevention in diabetes, but there may be a role in those at high
risk. An Antithrombotic Treatment Trialists’ meta-analysis concluded that aspirin
was reasonable in high-CVD-risk (5-year risk >5%) patients who are not at increased
bleeding risk. There was a clear recommendation against aspirin in those at low
CVD risk (5-year risk <2.5%) [237]. However, the ASCENDRCT (5480 people
≥40 years old with Type 2 diabetes and no clinically evident CVD) showed daily
100 mg enteric-coated aspirin reduced vascular events by 12% but increased major
(mostly GI) bleeding by 29%, with no effect on all-cause mortality or cancer [238].
Results were broadly consistent across CVD risk levels [238]. It is important to
consider that the impact of an MI or stroke may be very different to that of a
GI bleed.
While there are many features in common for the care of people with Type 2 diabe-
tes with and without complications, there are also differences, such as more aggres-
sive treatment targets for secondary prevention and benefits of additional therapies.
Some drugs used in complication-free people with diabetes may require dosage
adjustment or cessation in the presence of complications, such as CKD.
With 60% of deaths in people with diabetes being due to CVD, clinicians should
implement proven secondary prevention therapies. Fairly fast SA2A2B (fish oil,
fibrate, statin, dual-antiplatelet therapy, ACEi, aldosterone antagonist, beta-blocker)
is an evidence-based mnemonic for the secondary prevention of CVD in the general
1 Precision Medicine Approaches for Management of Type 2 Diabetes 33
population [239]. As there are other related chapters in this book, we list some key
practice points for the management of CVD and heart failure (Tables 1.6 and 1.7).
As there are other relevant chapters in this book, we summarize proven prevention
treatments in Table 1.5 and list some key practice points for the management of
existent microvascular complications in Table 1.8.
34 D. Chen et al.
Conclusions
We already have the evidence base to practice personalized medicine in people with
Type 2 diabetes, and we hope that the mnemonics, tables, and figures in this book
chapter are useful guides for the busy clinician. A holistic multidisciplinary team
approach to patient-centered care is ideal, but this can be challenging given the large
number of people with diabetes and increasing complexity of care. Given the rapid
evolution of new clinical evidence, drugs, and devices, ongoing education of the
diabetes care team and of the person with diabetes is key. More electronic decision
support tools and AI, ideally integrated with electronic medical records, will likely
become available to assist in optimizing the choice of therapies for the person with
diabetes. The approach will need to be modified as new proven therapies become
available and the person’s health status changes. While care should always be per-
sonalized to the person living with Type 2 diabetes, there will be constraints related
to the resources of the patient and the local healthcare system. Clinical inertia must
be prevented and overcome when it occurs. Advocacy at individual, local, and
global levels is also important to ensure more equitable access to quality diabetes
care for all people with or at risk of Type 2 diabetes.
References
1. National Health and Medical Research Council. Clinical utility of personalised medi-
cine: Information for health professionals 2011. Available from: https://www.nhmrc.gov.
au/_files_nhmrc/publications/attachments/ps0001_clinical_utility_personalised_medicine_
feb_2011.pdf.
2. Li X, Oprea-Ilies GM, Krishnamurti U. New developments in breast cancer and their impact
on daily practice in pathology. Arch Pathol Lab Med. 2017;141(4):490–8.
3. International Diabetes Federation. IDF diabetes atlas. 9th ed. Brussels: International Diabetes
Federation; 2019.
4. Chowdhury TA, Shaho S, Moolla A. Complications of diabetes: progress, but significant
challenges ahead. Ann Transl Med. 2014;2(12):120.
5. Most RS, Sinnock P. The epidemiology of lower extremity amputations in diabetic individu-
als. Diabetes Care. 1983;6(1):87–91.
6. National Eye Institute. Health education leads to more eye exams in group at risk for vision
loss 1999. Available from: https://nei.nih.gov/news/pressreleases/morexam.
7. Ghaderian SB, Hayati F, Shayanpour S, Beladi Mousavi SS. Diabetes and end-stage renal
disease; a review article on new concepts. J Renal Inj Prev. 2015;4(2):28–33.
8. Weissgerber TL, Mudd LM. Preeclampsia and diabetes. Curr Diab Rep. 2015;15(3):9.
9. Leslie MS, Briggs LA. Preeclampsia and the risk of future vascular disease and mortality: a
review. J Midwifery Womens Health. 2016;61(3):315–24.
10. Golden TN, Simmons RA. Immune dysfunction in developmental programming of type 2
diabetes mellitus. Nat Rev Endocrinol. 2021;17(4):235–45.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 35
11. Kurbasic A, Fraser A, Mogren I, Hallmans G, Franks PW, Rich-Edwards JW, et al. Maternal
hypertensive disorders of pregnancy and offspring risk of hypertension: a population-based
cohort and sibling study. Am J Hypertens. 2019;32(4):331–4.
12. Rughani A, Friedman JE, Tryggestad JB. Type 2 diabetes in youth: the role of early life expo-
sures. Curr Diab Rep. 2020;20(9):45.
13. American Diabetes Association. Classification and diagnosis of diabetes: standards of medi-
cal care in diabetes2021. Diabetes Care. 2021;44(Suppl 1):S15–33.
14. The Royal Australian College of General Practitioners. Management of type 2 dia-
betes: A handbook for general practice. East Melbourne, Vic: RACGP, 2020. ISBN:
978-0-86906-577-8 (web).
15. Jenkins AJ, Best JD, Klein RL, Lyons TJ. Lipoproteins, glycoxidation and diabetic angiopa-
thy. Diabetes Metab Res Rev. 2004;20(5):349–68.
16. Salamone D, Rivellese AA, Vetrani C. The relationship between gut microbiota, short-chain
fatty acids and type 2 diabetes mellitus: the possible role of dietary fibre. Acta Diabetol.
2021;58(9):1131–8.
17. Yehualashet AS, Yikna BB. Microbial ecosystem in diabetes mellitus: consideration of the
gastrointestinal system. Diabetes Metab Syndr Obes. 2021;14:1841–54.
18. Abuhendi N, Qush A, Naji F, Abunada H, Al Buainain R, Shi Z, et al. Genetic polymorphisms
associated with type 2 diabetes in the Arab world: a systematic review and meta-analysis.
Diabetes Res Clin Pract. 2019;151:198–208.
19. Doumatey AP, Ekoru K, Adeyemo A, Rotimi CN. Genetic basis of obesity and type 2 diabetes
in Africans: impact on precision medicine. Curr Diab Rep. 2019;19(10):105.
20. Guan M, Keaton JM, Dimitrov L, Hicks PJ, Xu J, Palmer ND, et al. Genome-wide asso-
ciation study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in
African Americans. Hum Genomics. 2019;13(1):21.
21. Jia X, Yang Y, Chen Y, Xia Z, Zhang W, Feng Y, et al. Multivariate analysis of genome-wide
data to identify potential pleiotropic genes for type 2 diabetes, obesity and coronary artery
disease using metacca. Int J Cardiol. 2019;283:144–50.
22. Jonas W, Schurmann A. Genetic and epigenetic factors determining NAFLD risk. Mol Metab.
2020;50:101111.
23. Sayed S, Nabi A. Diabetes and genetics: a relationship between genetic risk alleles, clinical
phenotypes and therapeutic approaches. Adv Exp Med Biol. 2021;1307:457–98.
24. Witka BZ, Oktaviani DJ, Marcellino M, Barliana MI, Abdulah R. Type 2 diabetes-associated
genetic polymorphisms as potential disease predictors. Diabetes Metab Syndr Obes.
2019;12:2689–706.
25. Zhang Y, Li S, Cao Z, Cheng Y, Xu C, Yang H, et al. A network analysis framework of genetic
and nongenetic risks for type 2 diabetes. Rev Endocr Metab Disord. 2021;22(2):461–9.
26. Aronica L, Volek J, Poff A, D'Agostino DP. Genetic variants for personalised management of
very low carbohydrate ketogenic diets. BMJ Nutr Prev Health. 2020;3(2):363–73.
27. Berry SE, Valdes AM, Drew DA, Asnicar F, Mazidi M, Wolf J, et al. Human postprandial
responses to food and potential for precision nutrition. Nat Med. 2020;26(6):964–73.
28. Chen Y, Zhou T, Sun D, Li X, Ma H, Liang Z, et al. Distinct genetic subtypes of adiposity and
glycemic changes in response to weight-loss diet intervention: the POUNDS LOST trial. Eur
J Nutr. 2021;60(1):249–58.
29. Correa TAF, Quintanilha BJ, Norde MM, Pinhel MAS, Nonino CB, Rogero MM. Nutritional
genomics, inflammation and obesity. Arch Endocrinol Metab. 2020;64(3):205–22.
30. Franzago M, Santurbano D, Vitacolonna E, Stuppia L. Genes and diet in the prevention of
chronic diseases in future generations. Int J Mol Sci. 2020;21(7):2633.
31. Li X, Zhou T, Ma H, Heianza Y, Champagne CM, Williamson DA, et al. Genetic variation
in lean body mass, changes of appetite and weight loss in response to diet interventions: the
POUNDS LOST trial. Diabetes Obes Metab. 2020;22(12):2305–15.
32. Malekizadeh A, Rahbaran M, Afshari M, Abbasi D, Aghaei Meybodi HR, Hasanzad
M. Association of common genetic variants of KCNJ11 gene with the risk of type 2 diabetes
mellitus. Nucleosides Nucleotides Nucleic Acids. 2021;40(5):530–41.
36 D. Chen et al.
33. Shahcheraghi SH, Aljabali AAA, Al Zoubi MS, Mishra V, Charbe NB, Haggag YA, et al.
Overview of key molecular and pharmacological targets for diabetes and associated diseases.
Life Sci. 2021;278:119632.
34. Spracklen CN, Sim X. Progress in defining the genetic contribution to type 2 diabetes in
individuals of East Asian ancestry. Curr Diab Rep. 2021;21(6):17.
35. Frazier-Wood AC, Ordovas JM, Straka RJ, Hixson JE, Borecki IB, Tiwari HK, et al. The
PPAR-alpha gene is associated with triglyceride, low-density cholesterol and inflamma-
tion marker response to fenofibrate intervention: the GOLDN study. Pharmacogenomics
J. 2013;13(4):312–7.
36. Morieri ML, Shah HS, Sjaarda J, Lenzini PA, Campbell H, Motsinger-Reif AA, et al. PPARa
polymorphism influences the cardiovascular benefit of fenofibrate in type 2 diabetes: findings
from ACCORD-LIPID. Diabetes. 2020;69(4):771–83.
37. Sivashanmugarajah A, Fulcher J, Sullivan D, Elam M, Jenkins A, Keech A. Author reply.
Intern Med J. 2020;50(4):507–8.
38. Suthers G, Somogyi AA. Pharmacogenetics of statin intolerance. Intern Med
J. 2020;50(4):506–7.
39. Noordam R, Lall K, Smit RA, Laisk T, Estonian Biobank Research, Loos RJ, et al. Stratification
of type 2 diabetes mellitus by age of diagnosis in the UK biobank reveals subgroup-specific
genetic associations and causal risk profiles. Diabetes. 2021;70(8):1816–25.
40. Zhang H, Colclough K, Gloyn AL, Pollin TI. Monogenic diabetes: a gateway to precision
medicine in diabetes. J Clin Invest. 2021;131(3):e142244.
41. Bebu I, Schade D, Braffett B, Kosiborod M, Lopes-Virella M, Soliman EZ, et al. Risk fac-
tors for first and subsequent CVD events in type 1 diabetes: the DCCT/EDIC study. Diabetes
Care. 2020;43(4):867–74.
42. Forrest IS, Chaudhary K, Paranjpe I, Vy HMT, Marquez-Luna C, Rocheleau G, et al.
Genome-wide polygenic risk score for retinopathy of type 2 diabetes. Hum Mol Genet.
2021;30(10):952–60.
43. Jiang G, Luk AO, Tam CHT, Lau ES, Ozaki R, Chow EYK, et al. Obesity, clinical, and
genetic predictors for glycemic progression in Chinese patients with type 2 diabetes: a cohort
study using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank. PLoS Med.
2020;17(7):e1003209.
44. Tam CHT, Lim CKP, Luk AOY, Ng ACW, Lee HM, Jiang G, et al. Development of genome-
wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclini-
cal atherosclerosis, and diabetes cardiovascular complications among East Asians. Genome
Med. 2021;13(1):29.
45. Vujkovic M, Keaton JM, Lynch JA, Miller DR, Zhou J, Tcheandjieu C, et al. Discovery of
318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million par-
ticipants in a multi-ancestry meta-analysis. Nat Genet. 2020;52(7):680–91.
46. O’Brien J, Hayder H, Zayed Y, Peng C. Overview of microRNA biogenesis, mechanisms of
actions, and circulation. Front Endocrinol (Lausanne). 2018;9:402.
47. Su X, Nie M, Zhang G, Wang B. MicroRNA in cardio-metabolic disorders. Clin Chim Acta.
2021;518:134–41.
48. Akbari Kordkheyli V, Amir Mishan M, Khonakdar Tarsi A, Mahrooz A, Rezaei Kanavi
M, Hafezi-Moghadam A, et al. MicroRNAs may provide new strategies in the treat-
ment and diagnosis of diabetic retinopathy: importance of VEGF. Iran J Basic Med Sci.
2021;24(3):267–79.
49. Bielska A, Niemira M, Kretowski A. Recent highlights of research on miRNAs as early
potential biomarkers for cardiovascular complications of type 2 diabetes mellitus. Int J Mol
Sci. 2021;22(6):3153.
50. Fujita Y, Murakami T, Nakamura A. Recent advances in biomarkers and regenerative medi-
cine for diabetic neuropathy. Int J Mol Sci. 2021;22(5):2301.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 37
51. Jakubik D, Fitas A, Eyileten C, Jarosz-Popek J, Nowak A, Czajka P, et al. MicroRNAs and
long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy:
emerging biomarkers and potential therapeutics. Cardiovasc Diabetol. 2021;20(1):55.
52. Joglekar MV, Januszewski AS, Jenkins AJ, Hardikar AA. Circulating microRNA biomarkers
of diabetic retinopathy. Diabetes. 2016;65(1):22–4.
53. Kaidonis G, Gillies MC, Abhary S, Liu E, Essex RW, Chang JH, et al. A single-nucleotide
polymorphism in the microRNA-146a gene is associated with diabetic nephropathy and sight-
threatening diabetic retinopathy in Caucasian patients. Acta Diabetol. 2016;53(4):643–50.
54. Mathur P, Rani V. Micrornas: a critical regulator and a promising therapeutic and diagnostic
molecule for diabetic cardiomyopathy. Curr Gene Ther. 2021;21(4):313–26.
55. Rai AK, Lee B, Gomez R, Rajendran D, Khan M, Garikipati VNS. Current status and poten-
tial therapeutic strategies for using non-coding RNA to treat diabetic cardiomyopathy. Front
Physiol. 2020;11:612722.
56. Ren H, Wang Q. Non-coding RNA and diabetic kidney disease. DNA Cell Biol.
2021;40(4):553–67.
57. Verduci L, Tarcitano E, Strano S, Yarden Y, Blandino G. CircRNAs: role in human diseases
and potential use as biomarkers. Cell Death Dis. 2021;12(5):468.
58. Zhou H, Ni WJ, Meng XM, Tang LQ. MicroRNAs as regulators of immune and inflamma-
tory responses: potential therapeutic targets in diabetic nephropathy. Front Cell Dev Biol.
2020;8:618536.
59. Cheng F, Carroll L, Joglekar MV, Januszewski AS, Wong KK, Hardikar AA, et al. Diabetes,
metabolic disease, and telomere length. Lancet Diabetes Endocrinol. 2021;9(2):117–26.
60. Cheng F, Luk AO, Wu H, Lim CKP, Carroll L, Tam CHT, et al. Shortened relative leukocyte
telomere length is associated with all-cause mortality in type 2 diabetes- analysis from the
Hong Kong Diabetes Register. Diabetes Res Clin Pract. 2021;173:108649.
61. Cheng F, Luk AO, Tam CHT, Fan B, Wu H, Yang A, et al. Shortened relative leukocyte telomere
length is associated with prevalent and incident cardiovascular complications in type 2 diabe-
tes: analysis from the Hong Kong Diabetes Register. Diabetes Care. 2020;43(9):2257–65.
62. Libertini G, Corbi G, Cellurale M, Ferrara N. Age-related dysfunctions: evidence and relation-
ship with some risk factors and protective drugs. Biochemistry (Mosc). 2019;84(12):1442–50.
63. Sutanto SSI, McLennan SV, Keech AC, Twigg SM. Shortening of telomere length by
metabolic factors in diabetes: protective effects of fenofibrate. J Cell Commun Signal.
2019;13(4):523–30.
64. American Diabetes Association. Type 2 diabetes risk test. Available from: https://www.diabe-
tes.org/risk-test.
65. Diabetes Australia. Are you at risk? Available from: https://www.diabetesaustralia.com.au/
about-diabetes/are-you-at-risk-type-2/.
66. Aspelund T, Thornorisdottir O, Olafsdottir E, Gudmundsdottir A, Einarsdottir AB, Mehlsen
J, et al. Individual risk assessment and information technology to optimise screening fre-
quency for diabetic retinopathy. Diabetologia. 2011;54(10):2525–32.
67. Lund SH, Aspelund T, Kirby P, Russell G, Einarsson S, Palsson O, et al. Individualised
risk assessment for diabetic retinopathy and optimisation of screening intervals: a scientific
approach to reducing healthcare costs. Br J Ophthalmol. 2016;100(5):683–7.
68. Ali I, Donne RL, Kalra PA. A validation study of the kidney failure risk equation in advanced
chronic kidney disease according to disease aetiology with evaluation of discrimination, cali-
bration and clinical utility. BMC Nephrol. 2021;22(1):194.
69. Australian Chronic Disease Prevention Alliance. Australian absolute cardiovascular disease
risk calculator. Available from: https://www.cvdcheck.org.au/.
70. Choi Y, Yang Y, Hwang BH, Lee EY, Yoon KH, Chang K, et al. Practical cardiovascular risk
calculator for asymptomatic patients with type 2 diabetes mellitus: precise-DM risk score.
Clin Cardiol. 2020;43(9):1040–7.
71. Grzybowski A, Brona P, Lim G, Ruamviboonsuk P, Tan GSW, Abramoff M, et al. Artificial
intelligence for diabetic retinopathy screening: a review. Eye (Lond). 2020;34(3):451–60.
38 D. Chen et al.
72. Quinn N, Brazionis L, Zhu B, Ryan C, D'Aloisio R, Lilian Tang H, et al. Facilitating diabetic
retinopathy screening using automated retinal image analysis in underresourced settings.
Diabet Med. 2021;38(9):e14582.
73. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention
on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580–91.
74. Atkinson-Briggs S, Jenkins A, Keech A, Ryan C, Brazionis L, on behalf of the Centre of
Research Excellence in Diabetic Retinopathy Study Group. Nurse-led vascular risk assess-
ment in a regional Victorian Indigenous primary care diabetes clinic: An integrated Diabetes
Education and Eye disease Screening [iDEES] study. Journal of Advanced Nursing in press.
Accepted Dec 2021.
75. Australian Institute of Health and Welfare. Cardiovascular disease, diabetes and chronic
kidney disease: Australian facts mortality 2014 [cited 2018 25 January]. Available from:
https://www.aihw.gov.au/reports/heart-stroke-vasculardisease/cardiovascular-diabetes-
chronic-kidney-mortality/contents/table-of-contents.
76. Royal Australian College of General Practitioners. Guidelines for preventive activities in gen-
eral practice. 9th ed. East Melbourne: Royal Australian College of General Practitioners; 2016.
77. Beagley J, Guariguata L, Weil C, Motala AA. Global estimates of undiagnosed diabetes in
adults. Diabetes Res Clin Pract. 2014;103(2):150–60.
78. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of
medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S13–S28. https://doi.
org/10.2337/dc19-S002. PMID: 30559228.
79. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl
J Med. 2002;346(6):393–403.
80. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention
or metformin on diabetes development and microvascular complications over 15-year fol-
low-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol.
2015;3(11):866–75.
81. Wittert G, Bracken K, Robledo KP, Grossmann M, Yeap BB, Handelsman DJ, et al.
Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle
programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial.
Lancet Diabetes Endocrinol. 2021;9(1):32–45.
82. Bian RR, Piatt GA, Sen A, Plegue MA, De Michele ML, Hafez D, et al. The effect of
technology-mediated diabetes prevention interventions on weight: a meta-analysis. J Med
Internet Res. 2017;19(3):e76.
83. Haw JS, Galaviz KI, Straus AN, Kowalski AJ, Magee MJ, Weber MB, et al. Long-term sus-
tainability of diabetes prevention approaches: a systematic review and meta-analysis of ran-
domized clinical trials. JAMA Intern Med. 2017;177(12):1808–17.
84. Affinati AH, Esfandiari NH, Oral EA, Kraftson AT. Bariatric surgery in the treatment of type
2 diabetes. Curr Diab Rep. 2019;19(12):156.
85. Cummings DE, Cohen RV. Bariatric/metabolic surgery to treat type 2 diabetes in patients
with a BMI<35 kg/m2. Diabetes Care. 2016;39(6):924–33.
86. Koliaki C, Liatis S, le Roux CW, Kokkinos A. The role of bariatric surgery to treat diabetes:
current challenges and perspectives. BMC Endocr Disord. 2017;17(1):50.
87. Jenkins A, Januszewski AS, O'Neal D. Addressing vascular risk factors in diabetes.
Endocrinol Today. 2015;4(4):35–8.
88. Look ARG, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, et al. Cardiovascular effects
of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–54.
89. Azadbakht L, Fard NR, Karimi M, Baghaei MH, Surkan PJ, Rahimi M, et al. Effects of the
dietary approaches to stop hypertension (DASH) eating plan on cardiovascular risks among
type 2 diabetic patients: a randomized crossover clinical trial. Diabetes Care. 2011;34(1):55–7.
90. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary prevention of
cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or
nuts. N Engl J Med. 2018;378(25):e34.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 39
91. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-
led weight management for remission of type 2 diabetes (DIRECT): an open-label, cluster-
randomised trial. Lancet. 2018;391(10120):541–51.
92. Newcastle University. Reversing type 2 diabetes. Available from: https://www.ncl.ac.uk/
magres/research/diabetes/reversal/#publicinformation.
93. Carter S, Clifton PM, Keogh JB. The effects of intermittent compared to continuous energy
restriction on glycaemic control in type 2 diabetes; a pragmatic pilot trial. Diabetes Res Clin
Pract. 2016;122:106–12.
94. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical targets for
continuous glucose monitoring data interpretation: recommendations from the International
Consensus on Iime in Range. Diabetes Care. 2019;42(8):1593–603.
95. Foreman YD, van Doorn W, Schaper NC, van Greevenbroek MMJ, van der Kallen CJH,
Henry RMA, et al. Greater daily glucose variability and lower time in range assessed with
continuous glucose monitoring are associated with greater aortic stiffness: the Maastricht
study. Diabetologia. 2021;64(8):1880–92.
96. Handa T, Nakamura A, Miya A, Nomoto H, Kameda H, Cho KY, et al. The association
between hypoglycemia and glycemic variability in elderly patients with type 2 diabetes: a
prospective observational study. Diabetol Metab Syndr. 2021;13(1):37.
97. Scott ES, Januszewski AS, O'Connell R, Fulcher G, Scott R, Kesaniemi A, et al. Long-term
glycemic variability and vascular complications in type 2 diabetes: post hoc analysis of the
FIELD study. J Clin Endocrinol Metab. 2020;105(10):dgaa361.
98. Zhang J, Yang J, Liu L, Li L, Cui J, Wu S, et al. Significant abnormal glycemic variability
increased the risk for arrhythmias in elderly type 2 diabetic patients. BMC Endocr Disord.
2021;21(1):83.
99. Zoungas S, Arima H, Gerstein HC, Holman RR, Woodward M, Reaven P, et al. Effects of
intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-
analysis of individual participant data from randomised controlled trials. Lancet Diabetes
Endocrinol. 2017;5(6):431–7.
100. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, et al. Effect of
intensive control of glucose on cardiovascular outcomes and death in patients with diabetes
mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373(9677):1765–72.
101. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA, et al. Hemoglobin
A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with
type 2 diabetes mellitus: a guidance statement update from the American college of physi-
cians. Ann Intern Med. 2018;168(8):569–76.
102. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME,
Byington RP, Goff DC Jr, Bigger JT, et al. Effects of intensive glucose lowering in type 2
diabetes. N Engl J Med. 2008;358(24):2545–59.
103. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose
control and vascular complications in veterans with type 2 diabetes. N Engl J Med.
2009;360(2):129–39.
104. Group AC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood
glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med.
2008;358(24):2560–72.
105. Andersen A, Jorgensen PG, Knop FK, Vilsboll T. Hypoglycemia and cardiac arrhythmias in
diabetes. Ther Adv Endocrinol Metab. 2020;11:2042018820911803.
106. Heller SR. Abnormalities of the electrocardiogram during hypoglycemia: the cause of the
dead in bed syndrome? Int J Clin Pract Suppl. 2002;129:27–32.
107. Gogitidze Joy N, Hedrington MS, Briscoe VJ, Tate DB, Ertl AC, Davis SN. Effects of acute
hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with
type 1 diabetes and healthy individuals. Diabetes Care. 2010;33(7):1529–35.
108. Yun JS, Park YM, Han K, Cha SA, Ahn YB, Ko SH. Association between BMI and risk of
severe hypoglycemia in type 2 diabetes. Diabetes Metab. 2019;45(1):19–25.
40 D. Chen et al.
109. Cheung NW, Conn JJ, d'Emden MC, Gunton JE, Jenkins AJ, Ross GP, et al. Position state-
ment of the Australian Diabetes Society: individualisation of glycated haemoglobin targets
for adults with diabetes mellitus. Med J Aust. 2009;191(6):339–44.
110. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EA, et al. Intensive gly-
cemic control and the prevention of cardiovascular events: implications of the ACCORD,
ADVANCE, and VA diabetes trials: a position statement of the American Diabetes
Association and a scientific statement of the American College of Cardiology Foundation
and the American Heart Association. Diabetes Care. 2009;32(1):187–92.
111. Huang DL, Abrass IB, Young BA. Medication safety and chronic kidney disease in older
adults prescribed metformin: a cross-sectional analysis. BMC Nephrol. 2014;15:86.
112. Manski-Nankervis JA, Thuraisingam S, Sluggett JK, Kilov G, Furler J, O'Neal D, et al.
Prescribing of diabetes medications to people with type 2 diabetes and chronic kidney dis-
ease: a national cross-sectional study. BMC Fam Pract. 2019;20(1):29.
113. Tuot DS, Lin F, Shlipak MG, Grubbs V, Hsu CY, Yee J, et al. Potential impact of pre-
scribing metformin according to EGFR rather than serum creatinine. Diabetes Care.
2015;38(11):2059–67.
114. Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron B, Stanifer J, Mock CK, et al.
Metformin use in patients with historical contraindications or precautions. VA evidence-
based synthesis program reports. Washington, DC: Department of Veterans Affairs; 2016.
115. Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al.
Clinical outcomes of metformin use in populations with chronic kidney disease, con-
gestive heart failure, or chronic liver disease: a systematic review. Ann Intern Med.
2017;166(3):191–200.
116. Gosmanov AR, Gemoets DE, Kaminsky LS, Kovesdy CP, Gosmanova EO. Efficacy of met-
formin monotherapy in US veterans with type 2 diabetes and preexisting chronic kidney
disease stage 3. Diabetes Obes Metab. 2021;23(8):1879–85.
117. DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: current
perspectives on causes and risk. Metabolism. 2016;65(2):20–9.
118. Bonora BM, Avogaro A, Fadini GP. Euglycemic ketoacidosis. Curr Diab Rep. 2020;20(7):25.
119. Goldenberg RM, Berard LD, Cheng AYY, Gilbert JD, Verma S, Woo VC, et al. SGLT2
inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for preven-
tion and diagnosis. Clin Ther. 2016;38(12):2654–64. e2651.
120. Modi A, Agrawal A, Morgan F. Euglycemic diabetic ketoacidosis: a review. Curr Diabetes
Rev. 2017;13(3):315–21.
121. Hirakawa Y, Arima H, Zoungas S, Ninomiya T, Cooper M, Hamet P, et al. Impact of visit-
to-visit glycemic variability on the risks of macrovascular and microvascular events and all-
cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care. 2014;37(8):2359–65.
122. Su G, Mi SH, Li Z, Tao H, Yang HX, Zheng H. Prognostic value of early in-hospital gly-
cemic excursion in elderly patients with acute myocardial infarction. Cardiovasc Diabetol.
2013;12:33.
123. Nalysnyk L, Hernandez-Medina M, Krishnarajah G. Glycaemic variability and complica-
tions in patients with diabetes mellitus: evidence from a systematic review of the literature.
Diabetes Obes Metab. 2010;12(4):288–98.
124. Costantino S, Paneni F, Battista R, Castello L, Capretti G, Chiandotto S, et al. Impact of
glycemic variability on chromatin remodeling, oxidative stress, and endothelial dysfunction
in patients with type 2 diabetes and with target HbA1c levels. Diabetes. 2017;66(9):2472–82.
125. Henry RR, Rosenstock J, Edelman S, Mudaliar S, Chalamandaris AG, Kasichayanula S, et al.
Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a random-
ized, double-blind, placebo-controlled pilot study. Diabetes Care. 2015;38(3):412–9.
126. Suh S, Kim JH. Glycemic variability: how do we measure it and why is it important? Diabetes
Metab J. 2015;39(4):273–82.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 41
127. Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, et al. SGLT2 inhibitors
for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and
meta-analysis. Lancet Diabetes Endocrinol. 2019;7(11):845–54.
128. Toyama T, Neuen BL, Jun M, Ohkuma T, Neal B, Jardine MJ, et al. Effect of SGLT2 inhibi-
tors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus
and chronic kidney disease: a systematic review and meta-analysis. Diabetes Obes Metab.
2019;21(5):1237–50.
129. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibi-
tors for primary and secondary prevention of cardiovascular and renal outcomes in type 2
diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet.
2019;393(10166):31–9.
130. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, et al. Follow-up
of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med.
2015;372(23):2197–206.
131. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sul-
phonylureas or insulin compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53.
132. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive
treatment of hyperglycemia on microvascular outcomes in type 2 diabetes: an analysis of the
accord randomised trial. Lancet. 2010;376(9739):419–30.
133. Azad N, Agrawal L, Emanuele NV, Klein R, Bahn GD, Reaven P, et al. Association of blood
glucose control and pancreatic reserve with diabetic retinopathy in the Veterans Affairs
Diabetes Trial (VADT). Diabetologia. 2014;57(6):1124–31.
134. Australian Diabetes Society. A new blood glucose management algorithm for type 2 diabetes:
a position statement of the Australian Diabetes Society 2016. Available from: https://t2d.
diabetessociety.com.au/documents/92f4CL73.pdf.
135. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards
of medical care in diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S111–24.
136. Chun JH, Butts A. Long-acting GLP-1ras: an overview of efficacy, safety, and their role in
type 2 diabetes management. JAAPA. 2020;33(S8 Suppl 1):3–18.
137. Cornell S. A review of GLP-1 receptor agonists in type 2 diabetes: a focus on the mechanism
of action of once-weekly agents. J Clin Pharm Ther. 2020;45(Suppl 1):17–27.
138. Jain AB, Ali A, Gorgojo Martinez JJ, Hramiak I, Kavia K, Madsbad S, et al. Switching
between GLP-1 receptor agonists in clinical practice: expert consensus and practical guid-
ance. Int J Clin Pract. 2021;75(2):e13731.
139. Ma J, Zhang B, Hou J, Peng Y. Efficacy and safety of once weekly dulaglutide in East Asian
patients with type 2 diabetes: subgroup analysis by potential influential factors. Diabetes
Ther. 2021;12(1):211–22.
140. Mirabelli M, Chiefari E, Tocci V, Caroleo P, Giuliano S, Greco E, et al. Clinical effectiveness
and safety of once-weekly glp-1 receptor agonist dulaglutide as add-on to metformin or met-
formin plus insulin secretagogues in obesity and type 2 diabetes. J Clin Med. 2021;10(5):985.
141. Guber K, Pemmasani G, Malik A, Aronow WS, Yandrapalli S, Frishman WH. Statins and
higher diabetes mellitus risk: incidence, proposed mechanisms and clinical implications.
Cardiol Rev. 2021;29(6):314–22.
142. American Diabetes Association. American Diabetes Association. Available from: https://
www.diabetes.org/.
143. Atchison E, Barkmeier A. The role of systemic risk factors in diabetic retinopathy. Curr
Ophthalmol Rep. 2016;4(2):84–9.
144. Cai Z, Yang Y, Zhang J. A systematic review and meta-analysis of the serum lipid profile in
prediction of diabetic neuropathy. Sci Rep. 2021;11(1):499.
145. Eid S, Sas KM, Abcouwer SF, Feldman EL, Gardner TW, Pennathur S, et al. New insights into
the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia.
2019;62(9):1539–49.
42 D. Chen et al.
146. Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D, Devereux RB, et al. LDL cho-
lesterol as a strong predictor of coronary heart disease in diabetic individuals with insu-
lin resistance and low LDL: the Strong Heart Study. Arterioscler Thromb Vasc Biol.
2000;20(3):830–5.
147. Jenkins AJ, Scott ES, Fulcher J, Kilov G, Januszewski AS. Management of diabetes mellitus.
In: Toth PP, Cannon CP, editors. Comprehensive cardiovascular medicine in the primary care
setting. 2nd ed. Totowa: Humana Press; 2018.
148. Sobrin L, Chong YH, Fan Q, Gan A, Stanwyck LK, Kaidonis G, et al. Genetically deter-
mined plasma lipid levels and risk of diabetic retinopathy: a Mendelian randomization study.
Diabetes. 2017;66(12):3130–41.
149. Leitersdorf E. Cholesterol absorption inhibition: filling an unmet need in lipid-lowering man-
agement. Eur Heart J Suppl. 2001;3(suppl E):E17–23.
150. Cholesterol Treatment Trialists Collaboration, Kearney PM, Blackwell L, Collins R, Keech
A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in
14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117–25.
151. Cholesterol Treatment Trialists Collaboration, Fulcher J, O'Connell R, Voysey M, Emberson
J, Blackwell L, et al. Efficacy and safety of LDL-lowering therapy among men and women:
meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet.
2015;385(9976):1397–405.
152. University of Oxford. UKPDS risk engine. Available from: https://www.dtu.ox.ac.uk/risken-
gine/download.php.
153. ClinRisk. Qrisk®3-2017 risk calculator 2017. Available from: https://qrisk.org/three/
index.php.
154. American College of Cardiology. ASCVD risk estimator plus. Available from: http://tools.
acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/.
155. American Diabetes Association. Cardiovascular disease and risk management: standards of
medical care in diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S125–50.
156. Kang EY, Chen TH, Garg SJ, Sun CC, Kang JH, Wu WC, et al. Association of statin
therapy with prevention of vision-threatening diabetic retinopathy. JAMA Ophthalmol.
2019;137(4):363–71.
157. Kawasaki R, Konta T, Nishida K. Lipid-lowering medication is associated with decreased
risk of diabetic retinopathy and the need for treatment in patients with type 2 diabetes: a
real-world observational analysis of a health claims database. Diabetes Obes Metab.
2018;20(10):2351–60.
158. Mozetic V, Pacheco RL, Latorraca COC, Riera R. Statins and/or fibrates for diabetic reti-
nopathy: a systematic review and meta-analysis. Diabetol Metab Syndr. 2019;11:92.
159. Murakami T, Kato S, Shigeeda T, Itoh H, Komuro I, Takeuchi M, et al. Intensive treat-to-
target statin therapy and severity of diabetic retinopathy complicated by hypercholesterolae-
mia. Eye (Lond). 2021;35(8):2221–8.
160. Pranata R, Vania R, Victor AA. Statin reduces the incidence of diabetic retinopathy and
its need for intervention: a systematic review and meta-analysis. Eur J Ophthalmol.
2020;31(3):1216–24. https://doi.org/10.1177/1120672120922444.
161. Vail D, Callaway NF, Ludwig CA, Saroj N, Moshfeghi DM. Lipid-lowering medications are
associated with lower risk of retinopathy and ophthalmic interventions among United States
patients with diabetes. Am J Ophthalmol. 2019;207:378–84.
162. Qin X, Dong H, Fang K, Lu F. The effect of statins on renal outcomes in patients with
diabetic kidney disease: a systematic review and meta-analysis. Diabetes Metab Res Rev.
2017;33(6) https://doi.org/10.1002/dmrr.2901.
163. Cholesterol Treatment Trialists’ (CTT) Collaboration, Herrington WG, Emberson J,
Mihaylova B, Blackwell L, Reith C, et al. Impact of renal function on the effects of LDL
cholesterol lowering with statin-based regimens: a meta-analysis of individual participant
data from 28 randomised trials. Lancet Diabetes Endocrinol. 2016;4(10):829–39.
164. Pergolizzi JV Jr, Magnusson P, LeQuang JA, Razmi R, Zampogna G, Taylor R Jr. Statins and
neuropathic pain: a narrative review. Pain Ther. 2020;9(1):97–111.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 43
165. Wang M, Li M, Xie Y. The association between statins exposure and peripheral neuropathy
risk: a meta-analysis. J Clin Pharm Ther. 2021;46(4):1046–54.
166. Keni R, Sekhar A, Gourishetti K, Nayak PG, Kinra M, Kumar N, et al. Role of statins in
new-onset diabetes mellitus: the underlying cause, mechanisms involved, and strategies to
combat. Curr Drug Targets. 2021;22(10):1121–8.
167. Masson W, Lobo M, Lavalle-Cobo A, Masson G, Molinero G. Effect of bempedoic acid on
new onset or worsening diabetes: a meta-analysis. Diabetes Res Clin Pract. 2020;168:108369.
168. Szili-Torok T, Bakker SJL, Tietge UJF. Statin use is prospectively associated with new-onset
diabetes after transplantation in renal transplant recipients. Diabetes Care. 2020;43(8):1945–7.
169. Anyanwagu U, Idris I, Donnelly R. Drug-induced diabetes mellitus: evidence for statins and
other drugs affecting glucose metabolism. Clin Pharmacol Ther. 2016;99(4):390–400.
170. Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, et al.
PCSK9 genetic variants and risk of type 2 diabetes: a Mendelian randomisation study. Lancet
Diabetes Endocrinol. 2017;5(2):97–105.
171. Sivashanmugarajah A, Fulcher J, Sullivan D, Elam M, Jenkins A, Keech A. Suggested clini-
cal approach for the diagnosis and management of ‘statin intolerance’ with an emphasis on
muscle-related side-effects. Intern Med J. 2019;49(9):1081–91.
172. Beshir SA, Hussain N, Elnor AA, Said ASA. Umbrella review on non-statin lipid-
lowering therapy. J Cardiovasc Pharmacol Ther. 2021;26(5):437–52. https://doi.
org/10.1177/10742484211002943.
173. Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, et al. Bempedoic acid
plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD
risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020;27(6):593–603.
174. Feingold KR. Cholesterol lowering drugs. In: Feingold KR, Anawalt B, Boyce A, Chrousos
G, de Herder WW, Dhatariya K, et al., editors. Endotext. South Dartmouth: MDText.
com; 2021.
175. Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalan R, Spinar J, et al. Benefit of
adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with
versus without diabetes mellitus: results from IMPROVE-IT (improved reduction of out-
comes: Vytorin efficacy international trial). Circulation. 2018;137(15):1571–82.
176. Wang X, Zhang Y, Tan H, Wang P, Zha X, Chong W, et al. Efficacy and safety of bempedoic
acid for prevention of cardiovascular events and diabetes: a systematic review and meta-
analysis. Cardiovasc Diabetol. 2020;19(1):128.
177. Robinson JG et al. ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab
in reducing lipids and cardiovasuclar events. New Engl J Med. 2015;372(16):1489–99. PMID
25773378.
178. de Carvalho LSF, Campos AM, Sposito AC. Proprotein convertase subtilisin/kexin type 9
(PCSK9) inhibitors and incident type 2 diabetes: a systematic review and meta-analysis with
over 96,000 patient-years. Diabetes Care. 2018;41(2):364–7.
179. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term feno-
fibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the
FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–61.
180. ACCORD Study Group, ACCORD-Eye Study Group, Chew EY, Ambrosius WT, Davis MD,
Danis RP, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N
Engl J Med. 2010;363(3):233–44.
181. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Moffitt MS, et al. Effect of feno-
fibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised
controlled trial. Lancet. 2007;370(9600):1687–97.
182. Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, et al. Effects of fenofi-
brate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention
and Event Lowering in Diabetes (FIELD) study. Diabetologia. 2011;54(2):280–90.
183. Bonds DE, Craven TE, Buse J, Crouse JR, Cuddihy R, Elam M, et al. Fenofibrate-associated
changes in renal function and relationship to clinical outcomes among individuals with type
44 D. Chen et al.
203. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in
patients with coronary heart disease: a systematic review. JAMA. 2003;290(1):86–97.
204. Wilkes S, Evans A. A cross-sectional study comparing the motivation for smoking cessation
in apparently healthy patients who smoke to those who smoke and have ischaemic heart dis-
ease, hypertension or diabetes. Fam Pract. 1999;16(6):608–10.
205. West R. Tobacco smoking: health impact, prevalence, correlates and interventions. Psychol
Health. 2017;32(8):1018–36.
206. Kalkhoran S, Glantz SA. E-cigarettes and smoking cessation in real-world and clinical set-
tings: a systematic review and meta-analysis. Lancet Respir Med. 2016;4(2):116–28.
207. Dabelea D, Stafford JM, Mayer-Davis EJ, D’Agostino R Jr, Dolan L, Imperatore G, et al.
Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence
with complications during teenage years and young adulthood. JAMA. 2017;317(8):825–35.
208. Feng X, Song M, Preston MA, Ma W, Hu Y, Pernar CH, et al. The association of diabe-
tes with risk of prostate cancer defined by clinical and molecular features. Br J Cancer.
2020;123(4):657–65.
209. Suh S, Kim KW. Diabetes and cancer: cancer should be screened in routine diabetes assess-
ment. Diabetes Metab J. 2019;43(6):733–43.
210. Marchand L, Disse E, Dalle S, Reffet S, Vouillarmet J, Fabien N, et al. The multifaceted nature
of diabetes mellitus induced by checkpoint inhibitors. Acta Diabetol. 2019;56(12):1239–45.
211. Gabbay RA, Kendall D, Beebe C, Cuddeback J, Hobbs T, Khan ND, et al. Addressing thera-
peutic inertia in 2020 and beyond: a 3-year initiative of the American Diabetes Association.
Clin Diabetes. 2020;38(4):371–81.
212. Nguyen ATM, Akhter R, Garde S, Scott C, Twigg SM, Colagiuri S, et al. The association
of periodontal disease with the complications of diabetes mellitus. A systematic review.
Diabetes Res Clin Pract. 2020;165:108244.
213. Paul O, Arora P, Mayer M, Chatterjee S. Inflammation in periodontal disease: possible link to
vascular disease. Front Physiol. 2020;11:609614.
214. Hwang Y, Khasag A, Jia W, Jenkins A, Huang CN, Yabe D, et al. Diabetes and COVID-19:
IDF perspective in the Western Pacific region. Diabetes Res Clin Pract. 2020;166:108278.
215. Scott ES, Jenkins AJ, Fulcher GR. Challenges of diabetes management during the COVID-19
pandemic. Med J Aust. 2020;213(2):56–57 e51.
216. Prattichizzo F, de Candia P, Nicolucci A, Ceriello A. Elevated HbA1c levels in pre-COVID-19
infection increases the risk of mortality: a systematic review and meta-analysis. Diabetes
Metab Res Rev. 2021;38:e3476.
217. Chrvala CA, Sherr D, Lipman RD. Diabetes self-management education for adults with
type 2 diabetes mellitus: a systematic review of the effect on glycemic control. Patient Educ
Couns. 2016;99(6):926–43.
218. Gunawan F, Ng HY, Gilfillan C, Anpalahan M. Ambulatory blood pressure monitoring in
type 2 diabetes mellitus: a cross-sectional study. Curr Hypertens Rev. 2019;15(2):135–43.
219. Najafi MT, Khaloo P, Alemi H, Jaafarinia A, Blaha MJ, Mirbolouk M, et al. Ambulatory
blood pressure monitoring and diabetes complications: targeting morning blood pressure
surge and nocturnal dipping. Medicine (Baltimore). 2018;97(38):e12185.
220. Schwartz FL, Marling CR. Use of automated bolus calculators for diabetes management. Eur
Endocrinol. 2013;9(2):92–5.
221. Sussman A, Taylor EJ, Patel M, Ward J, Alva S, Lawrence A, et al. Performance of a glucose
meter with a built-in automated bolus calculator versus manual bolus calculation in insulin-
using subjects. J Diabetes Sci Technol. 2012;6(2):339–44.
222. Cappon G, Vettoretti M, Sparacino G, Facchinetti A. Continuous glucose monitoring sen-
sors for diabetes management: a review of technologies and applications. Diabetes Metab
J. 2019;43(4):383–97.
46 D. Chen et al.
223. Freckmann G, Pleus S, Grady M, Setford S, Levy B. Measures of accuracy for continu-
ous glucose monitoring and blood glucose monitoring devices. J Diabetes Sci Technol.
2019;13(3):575–83.
224. Mian Z, Hermayer KL, Jenkins A. Continuous glucose monitoring: review of an innovation
in diabetes management. Am J Med Sci. 2019;358(5):332–9.
225. Taylor PJ, Thompson CH, Brinkworth GD. Effectiveness and acceptability of continuous
glucose monitoring for type 2 diabetes management: a narrative review. J Diabetes Investig.
2018;9(4):713–25.
226. Vigersky R, Shrivastav M. Role of continuous glucose monitoring for type 2 in diabetes
management and research. J Diabetes Complicat. 2017;31(1):280–7.
227. Manski-Nankervis J, Yates CJ, Blackberry I, Furler J, Ginnivan L, Cohen N, et al. Impact of
insulin initiation on glycaemic variability and glucose profiles in a primary healthcare type
2 diabetes cohort: analysis of continuous glucose monitoring data from the initiation study.
Diabet Med. 2016;33(6):803–11.
228. Basu A, Veettil S, Dyer R, Peyser T, Basu R. Direct evidence of acetaminophen interfer-
ence with subcutaneous glucose sensing in humans: a pilot study. Diabetes Technol Ther.
2016;18(Suppl 2):S243–7.
229. Basu A, Slama MQ, Nicholson WT, Langman L, Peyser T, Carter R, et al. Continuous glu-
cose monitor interference with commonly prescribed medications: a pilot study. J Diabetes
Sci Technol. 2017;11(5):936–41.
230. Tanenbaum ML, Hanes SJ, Miller KM, Naranjo D, Bensen R, Hood KK. Diabetes device use
in adults with type 1 diabetes: barriers to uptake and potential intervention targets. Diabetes
Care. 2017;40(2):181–7.
231. Vigersky RA, McMahon C. The relationship of hemoglobin A1c to time-in-range in patients
with diabetes. Diabetes Technol Ther. 2019;21(2):81–5.
232. Ida S, Kaneko R, Murata K. Utility of real-time and retrospective continuous glucose moni-
toring in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled
trials. J Diabetes Res. 2019;2019:4684815.
233. Janapala RN, Jayaraj JS, Fathima N, Kashif T, Usman N, Dasari A, et al. Continuous glucose
monitoring versus self-monitoring of blood glucose in type 2 diabetes mellitus: a systematic
review with meta-analysis. Cureus. 2019;11(9):e5634.
234. Park C, Le QA. The effectiveness of continuous glucose monitoring in patients with type
2 diabetes: a systematic review of literature and meta-analysis. Diabetes Technol Ther.
2018;20(9):613–21.
235. Shokrekhodaei M, Quinones S. Review of non-invasive glucose sensing techniques: optical,
electrical and breath acetone. Sensors (Basel). 2020;20(5):1251.
236. Teymourian H, Moonla C, Tehrani F, Vargas E, Aghavali R, Barfidokht A, et al. Microneedle-
based detection of ketone bodies along with glucose and lactate: toward real-time con-
tinuous interstitial fluid monitoring of diabetic ketosis and ketoacidosis. Anal Chem.
2020;92(2):2291–300.
237. Antithrombotic Trialists Collaboration, Baigent C, Blackwell L, Collins R, Emberson
J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular disease:
collaborative meta-analysis of individual participant data from randomised trials. Lancet.
2009;373(9678):1849–60.
238. Group ASC, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, et al. Effects
of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med.
2018;379(16):1529–39.
239. Chin J, Fulcher J, Jenkins A, Keech A. Is it time to repair a fairly fast SAAB convertible?
Testing an evidence-based mnemonic for the secondary prevention of cardiovascular disease.
Heart Lung Circ. 2015;24(5):480–7.
240. Raza S, Blackstone EH, Houghtaling PL, Rajeswaran J, Riaz H, Bakaeen FG, et al.
Influence of diabetes on long-term coronary artery bypass graft patency. J Am Coll Cardiol.
2017;70(5):515–24.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 47
259. Bakris GL, Weir MR, Study of Hypertension and the Efficacy of Lotrel in Diabetes (SHIELD)
Investigators. Achieving goal blood pressure in patients with type 2 diabetes: conventional
versus fixed-dose combination approaches. J Clin Hypertens (Greenwich). 2003;5(3):202–9.
260. Omboni S, Gazzola T, Carabelli G, Parati G. Clinical usefulness and cost effectiveness of
home blood pressure telemonitoring: meta-analysis of randomized controlled studies. J
Hypertens. 2013;31(3):455–67; discussion 467–458.
261. Snoek FJ, Bremmer MA, Hermanns N. Constructs of depression and distress in diabetes:
time for an appraisal. Lancet Diabetes Endocrinol. 2015;3(6):450–60.
262. Hutchinson A, McIntosh A, Peters J, O'Keeffe C, Khunti K, Baker R, et al. Effectiveness of
screening and monitoring tests for diabetic retinopathy—a systematic review. Diabet Med.
2000;17(7):495–506.
263. Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening tests for peripheral neuropathy
in the diabetes clinic. Diabetes Care. 2001;24(2):250–6.
264. Franz MJ, MacLeod J, Evert A, Brown C, Gradwell E, Handu D, et al. Academy of nutrition
and dietetics nutrition practice guideline for type 1 and type 2 diabetes in adults: systematic
review of evidence for medical nutrition therapy effectiveness and recommendations for inte-
gration into the nutrition care process. J Acad Nutr Diet. 2017;117(10):1659–79.
265. Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, et al. Exercise
and type 2 diabetes: the American College of Sports Medicine and the American Diabetes
Association: joint position statement executive summary. Diabetes Care. 2010;33(12):2692–6.
266. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC guide-
lines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with
the EASD. Eur Heart J. 2020;41(2):255–323.
267. Aschner P. New IDF clinical practice recommendations for managing type 2 diabetes in pri-
mary care. Diabetes Res Clin Pract. 2017;132:169–70.
268. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, car-
diovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
269. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin
and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.
270. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and car-
diovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.
271. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al.
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med.
2019;380(24):2295–306.
272. Butler J, Zannad F, Fitchett D, Zinman B, Koitka-Weber A, von Eynatten M, et al.
Empagliflozin improves kidney outcomes in patients with or without heart failure. Circ Heart
Fail. 2019;12(6):e005875.
273. Inzucchi SE, Fitchett D, Jurisic-Erzen D, Woo V, Hantel S, Janista C, et al. Are the cardiovas-
cular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy?
Diabetes Obes Metab. 2020;22(4):631–9.
274. Levin A, Perkovic V, Wheeler DC, Hantel S, George JT, von Eynatten M, et al. Empagliflozin
and cardiovascular and kidney outcomes across KDIGO risk categories: post hoc analysis of
a randomized, double-blind, placebo-controlled, multinational trial. Clin J Am Soc Nephrol.
2020;15(10):1433–44.
275. Monteiro P, Bergenstal RM, Toural E, Inzucchi SE, Zinman B, Hantel S, et al. Efficacy and
safety of empagliflozin in older patients in the EMPA-REG outcome(r) trial. Age Ageing.
2019;48(6):859–66.
276. Roy A, Maiti A, Sinha A, Baidya A, Basu AK, Sarkar D, et al. Kidney disease in type 2 diabe-
tes mellitus and benefits of sodium-glucose cotransporter 2 inhibitors: a consensus statement.
Diabetes Ther. 2020;11(12):2791–827.
277. Williams DM, Nawaz A, Evans M. Renal outcomes in type 2 diabetes: a review of cardiovas-
cular and renal outcome trials. Diabetes Ther. 2020;11(2):369–86.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 49
278. van Ruiten CC, van der Aart-van der Beek AB, Ijzerman RG, Nieuwdorp M, Hoogenberg
K, van Raalte DH, et al. Effect of exenatide twice daily and dapagliflozin, alone and in
combination, on markers of kidney function in obese patients with type 2 diabetes: a pre-
specified secondary analysis of a randomized controlled clinical trial. Diabetes Obes Metab.
2021;23(8):1851–8.
279. Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular,
mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabe-
tes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes
Endocrinol. 2019;7(10):776–85.
280. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide
and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.
281. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and car-
diovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.
282. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide
and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised
placebo-controlled trial. Lancet. 2019;394(10193):121–30.
283. Hernandez AF, Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, et al.
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascu-
lar disease (HARMONY outcomes): a double-blind, randomised placebo-controlled trial.
Lancet. 2018;392(10157):1519–29.
284. Greco EV, Russo G, Giandalia A, Viazzi F, Pontremoli R, De Cosmo S. GLP-1 receptor ago-
nists and kidney protection. Medicina (Kaunas). 2019;55(6):233.
285. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin
on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.
286. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. Effect of lina-
gliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardio-
vascular and renal risk: the Carmelina randomized clinical trial. JAMA. 2019;321(1):69–79.
287. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin
and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med.
2013;369(14):1317–26.
288. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al.
Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med.
2013;369(14):1327–35.
289. Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and
risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised
and observational studies. BMJ. 2016;352:i610.
290. Zhan S, Tang M, Liu F, Xia P, Shu M, Wu X. Ezetimibe for the prevention of cardiovascular
disease and all-cause mortality events. Cochrane Database Syst Rev. 2018;11:CD012502.
291. Scott R, O'Brien R, Fulcher G, Pardy C, D'Emden M, Tse D, et al. Effects of fenofibrate
treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various
components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD) study. Diabetes Care. 2009;32(3):493–8.
292. Ginsberg HN. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) lipid trial:
what we learn from subgroup analyses. Diabetes Care. 2011;34(Suppl 2):S107–8.
293. Millan J, Pinto X, Brea A, Blasco M, Hernandez-Mijares A, Ascaso J, et al. Fibrates in the
secondary prevention of cardiovascular disease (infarction and stroke). Results of a sys-
tematic review and meta-analysis of the Cochrane collaboration. Clin Investig Arterioscler.
2018;30(1):30–5.
294. Schmidt AF, Carter JL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, et al. PCSK9
monoclonal antibodies for the primary and secondary prevention of cardiovascular disease.
Cochrane Database Syst Rev. 2020;10:CD011748.
50 D. Chen et al.
295. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al.
Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med.
2017;376(18):1713–22.
296. Prattichizzo F, de Candia P, De Nigris V, Nicolucci A, Ceriello A. Legacy effect of inten-
sive glucose control on major adverse cardiovascular outcome: systematic review and meta-
analyses of trials according to different scenarios. Metabolism. 2020;110:154308.
297. Wang X, Qin LQ, Arafa A, Eshak ES, Hu Y, Dong JY. Smoking cessation, weight
gain, cardiovascular risk, and all-cause mortality: a meta-analysis. Nicotine Tob Res.
2021;23(12):1987–94.
298. Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart
disease. Cochrane Database Syst Rev. 2004;(1):CD003041.
299. Pranata R, Vania R, Victor AA. Statin reduces the incidence of diabetic retinopathy and
its need for intervention: a systematic review and meta-analysis. Eur J Ophthalmol.
2021;31(3):1216–24.
300. Shen X, Zhang Z, Zhang X, Zhao J, Zhou X, Xu Q, et al. Efficacy of statins in patients with
diabetic nephropathy: a meta-analysis of randomized controlled trials. Lipids Health Dis.
2016;15(1):179.
301. Morgan CL, Owens DR, Aubonnet P, Carr ES, Jenkins-Jones S, Poole CD, et al. Primary
prevention of diabetic retinopathy with fibrates: a retrospective, matched cohort study. BMJ
Open. 2013;3(12):e004025.
302. Rajamani K, Donoghoe M, Li L, Ting R-D, Colman PG, Drury P, et al. Abstract 18987:
Fenofibrate reduces peripheral neuropathy in type 2 diabetes: the Fenofibrate Intervention
and Event Lowering in Diabetes (FIELD) study. Circulation. 2010;122(suppl_21):A18987.
303. Do DV, Wang X, Vedula SS, Marrone M, Sleilati G, Hawkins BS, et al. Blood pressure con-
trol for diabetic retinopathy. Cochrane Database Syst Rev. 2015;1:CD006127.
304. Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, et al. Effect of candesartan
on progression and regression of retinopathy in type 2 diabetes (DIRECT-PROTECT 2): a
randomised placebo-controlled trial. Lancet. 2008;372(9647):1385–93.
305. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, et al. Olmesartan for the delay
or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364(10):907–17.
306. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovas-
cular and microvascular outcomes in people with diabetes mellitus: results of the hope study
and micro-hope substudy. Lancet. 2000;355(9200):253–9.
307. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic
microvascular complications in patients with hypertension and type 2 diabetes. Diabetes
Care. 2000;23(Suppl 2):B54–64.
308. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in
normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int.
2002;61(3):1086–97.
309. MacIsaac RJ, Jerums G, Ekinci EI. Effects of glycaemic management on diabetic kidney
disease. World J Diabetes. 2017;8(5):172–86.
310. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing
and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;(6):CD007543.
311. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons
from recent large clinical trials. Curr Diab Rep. 2014;14(9):528.
312. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and
risks of vascular events and death. N Engl J Med. 2010;363(15):1410–8.
313. Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 fatty acids and cardiovascu-
lar outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes.
2012;5(6):808–18.
314. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk
reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22.
315. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe
added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97.
1 Precision Medicine Approaches for Management of Type 2 Diabetes 51
316. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus
clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.
317. Aradi D, Komocsi A, Vorobcsuk A, Serebruany VL. Impact of clopidogrel and potent P2Y
12 -inhibitors on mortality and stroke in patients with acute coronary syndrome or under-
going percutaneous coronary intervention: a systematic review and meta-analysis. Thromb
Haemost. 2013;109(1):93–101.
318. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al.
Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med.
2007;357(20):2001–15.
319. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/AHA
guideline focused update on duration of dual antiplatelet therapy in patients with coronary
artery disease: a report of the American College of Cardiology/American Heart Association
task force on clinical practice guidelines: an update of the 2011 ACCF/AHA/SCAI guide-
line for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery
bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diag-
nosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA
guideline for the management of ST-elevation myocardial infarction, 2014 AHA/ACC guide-
line for the management of patients with non-ST-elevation acute coronary syndromes, and
2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of
patients undergoing noncardiac surgery. Circulation. 2016;134(10):e123–55.
320. Saha SA, Molnar J, Arora RR. Tissue ace inhibitors for secondary prevention of cardiovas-
cular disease in patients with preserved left ventricular function: a pooled meta-analysis of
randomized placebo-controlled trials. J Cardiovasc Pharmacol Ther. 2007;12(3):192–204.
321. Saha SA, Molnar J, Arora RR. Tissue angiotensin-converting enzyme inhibitors for the pre-
vention of cardiovascular disease in patients with diabetes mellitus without left ventricular
systolic dysfunction or clinical evidence of heart failure: a pooled meta-analysis of random-
ized placebo-controlled clinical trials. Diabetes Obes Metab. 2008;10(1):41–52.
322. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective
aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
N Engl J Med. 2003;348(14):1309–21.
323. Chatterjee S, Moeller C, Shah N, Bolorunduro O, Lichstein E, Moskovits N, et al.
Eplerenone is not superior to older and less expensive aldosterone antagonists. Am J Med.
2012;125(8):817–25.
324. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after myocardial
infarction: systematic review and meta regression analysis. BMJ. 1999;318(7200):1730–7.
325. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management
of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes
Association (ADA) and the European Association for the Study of Diabetes (EASD).
Diabetes Care. 2018;41(12):2669–701.
326. Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart failure. A Bayesian
meta-analysis. Ann Intern Med. 2001;134(7):550–60.
327. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors
on mortality and morbidity in patients with heart failure. Collaborative group on ACE inhibi-
tor trials. JAMA. 1995;273(18):1450–6.
328. Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM. Angiotensin receptor blockers for
heart failure. Cochrane Database Syst Rev. 2012;(4):CD003040.
329. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of
vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans
Administration cooperative study. N Engl J Med. 1986;314(24):1547–52.
330. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of enala-
pril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.
N Engl J Med. 1991;325(5):303–10.
52 D. Chen et al.
331. Faris RF, Flather M, Purcell H, Poole-Wilson PA, Coats AJ. Diuretics for heart failure.
Cochrane Database Syst Rev. 2012;(2):CD003838.
332. Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction: a sys-
tematic review of randomized clinical trials. Eur Heart J. 2009;30(4):469–77.
333. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine
and outcomes in chronic heart failure (shift): a randomised placebo-controlled study. Lancet.
2010;376(9744):875–85.
334. Nanthakumar K, Epstein AE, Kay GN, Plumb VJ, Lee DS. Prophylactic implantable
cardioverter-defibrillator therapy in patients with left ventricular systolic dysfunction: a
pooled analysis of 10 primary prevention trials. J Am Coll Cardiol. 2004;44(11):2166–72.
335. Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J, et al. An indi-
vidual patient meta-analysis of five randomized trials assessing the effects of cardiac resyn-
chronization therapy on morbidity and mortality in patients with symptomatic heart failure.
Eur Heart J. 2013;34(46):3547–56.
336. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment
of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev.
2004;(2):CD002901.
337. Vilsboll T, Bain SC, Leiter LA, Lingvay I, Matthews D, Simo R, et al. Semaglutide, reduc-
tion in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab.
2018;20(4):889–97.
338. Wright AD, Dodson PM. Medical management of diabetic retinopathy: Fenofibrate and
accord eye studies. Eye (Lond). 2011;25(7):843–9.
339. Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and
treatment strategies. JCI Insight. 2017;2(14):e93751.
340. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, et al. Angiotensin-receptor
blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J
Med. 2004;351(19):1952–61.
341. Neumiller JJ, Kalyani RR. How does credence inform best use of SGLT2 inhibitors in CKD?
Clin J Am Soc Nephrol. 2019;14(11):1667–9.
342. Ting RD, Keech AC, Drury PL, Donoghoe MW, Hedley J, Jenkins AJ, et al. Benefits and
safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment:
the FIELD study. Diabetes Care. 2012;35(2):218–25.
343. Mychaleckyj JC, Craven T, Nayak U, Buse J, Crouse JR, Elam M, et al. Reversibility of
fenofibrate therapy-induced renal function impairment in accord type 2 diabetic participants.
Diabetes Care. 2012;35(5):1008–14.
344. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treat-
ment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled
trials across a range of doses. Diabetes Care. 2008;31(7):1448–54.
345. Quilici S, Chancellor J, Lothgren M, Simon D, Said G, Le TK, et al. Meta-analysis of dulox-
etine vs. Pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain.
BMC Neurol. 2009;9:6.
346. Wernicke JF, Pritchett YL, D'Souza DN, Waninger A, Tran P, Iyengar S, et al. A random-
ized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology.
2006;67(8):1411–20.
347. Joss JD. Tricyclic antidepressant use in diabetic neuropathy. Ann Pharmacother.
1999;33(9):996–1000.
348. Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic acid and diabetic neuropathy. Rev
Diabet Stud. 2009;6(4):230–6.
349. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind,
vehicle-controlled study. The capsaicin study group. Arch Intern Med. 1991;151(11):2225–9.
350. Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults.
Cochrane Database Syst Rev. 2014;(7):CD010958.
Chapter 2
Precision Medicine for Diabetes
and Cardiovascular Disease
Introduction
Cardiovascular disease is one of the leading causes of morbidity and mortality in the
world, and diabetes mellitus plays a significant role in the development and progres-
sion of the most common types of heart disease. Understanding how these two enti-
ties are intricately connected allows for better risk stratification, prevention,
prognostication, and management of patients with both diabetes and heart disease.
The development of heart failure in diabetes mellitus is complex and involves mul-
tiple mechanisms. Diabetes can lead to heart failure development, and heart failure
can lead to diabetes development. Diabetes leads to hyperglycemia, insulin resis-
tance, and hyperinsulinemia, resulting in heart failure development. This promotes
coronary artery disease due to increased inflammation, hyperlipidemia, microvascu-
lar and macrovascular disease, and endothelial dysfunction. Additionally, diabetes
results in direct hypertrophy of cardiomyocytes, increased fibrosis due to activation
of the renin angiotensin aldosterone system, and formation of advanced glycation
end products [1, 2]. These mechanisms comprise diabetic cardiomyopathy and sub-
sequently lead to heart failure.
S.-H. Wan
Minneapolis Heart Institute, United Hospital, Saint Paul, MN, USA
H. H. Chen (*)
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
e-mail: [email protected]
Heart failure also leads to the development of diabetes. In heart failure, increased
sympathetic nervous system activation and increased renin angiotensin aldosterone
activation lead to cytokine release and vasoconstriction. Increased free fatty acids
and effects on the pancreas, muscles, and liver result in hyperglycemia as well as
insulin resistance, leading to diabetes [3].
Heart failure is a risk factor for diabetes mellitus development. Whereas the gen-
eral population incidence of diabetes is approximately 10 per 1000 person years,
those with heart failure have an incidence of 20–30 per 1000 person years [4].
Additionally, those with heart failure and the following comorbidities are at even
higher risk of incident diabetes development: obesity, tobacco history, elevated
HbA1c, higher blood pressure, longer duration of heart failure, diuretic therapy, and
worse NYHA functional class.
There is increasingly greater evidence that natriuretic peptides have favorable
cardiometabolic effects, including on fat metabolism and glucose handling [5].
Several studies have demonstrated an inverse relationship between plasma natri-
uretic peptides levels and the risk for development of type 2 diabetes [6–8]. In obe-
sity, as well as exogenous insulin administration, natriuretic peptide levels are low
with downregulation of the receptor, and this deficiency of the natriuretic peptide
system may be linked to diabetes development [9]. Natriuretic peptide deficiency
therefore is associated with an increased risk for diabetes. Genetic variants that
result in an elevation of natriuretic peptides are linked to lower risk of metabolic
syndrome and diabetes [10]. Infusion of BNP was shown to improve insulin sensi-
tivity and blood glucose control [11, 12].
Given the cardiometabolic and neurohormonal dysfunction in diabetes and heart
failure, natriuretic peptides play an important role in rescuing the failing heart.
Natriuretic peptides ANP and BNP are released when there is fluid overload. For the
cardiovascular system, natriuretic peptides result in natriuresis, vasodilation, inhibi-
tion of the renin angiotensin aldosterone system, and anti-fibrosis and relaxation.
For metabolic effects, ANP results in increased fatty oxidation in the muscles,
increased lipolysis, decreased inflammation, and subsequent increase in insulin sen-
sitivity and improved glycemic control [13]. Therefore, natriuretic peptides have
beneficial cardiovascular and endocrine effects, making them potential treatment
candidates for diabetic heart disease.
Heart failure
Diabetic Diastolic with reduced
cardiomyopathy dysfunction or preserved
ejection
Endothelial
dysfunction
Microvascular
disease Accelerated Myocardial
atherosclerosis infarction
Macrovascular Hypertension
disease
Hyperlipidemia
Stroke
There is also increased risk of coronary thrombosis and plaque rupture in diabe-
tes. There is platelet dysfunction and increased platelet activation and aggregation
in diabetes [20]. Other mechanisms include increase in fibrinogen with reduction in
fibrinolysis, increased lipid composition of plaque, and greater risk of rupture [21–
23]. These mechanisms result in greater risk of myocardial infarctions and strokes.
One of the challenges of managing patients with coronary artery disease and
diabetes is that the variety of mechanisms by which diabetes acts result in atypical
patient presentations. Symptoms of coronary artery disease may be atypical angina,
or patients may be completely asymptomatic, which increases the importance of
early aggressive prevention. Neuropathy and autonomic denervation in diabetes
result in atypical symptoms or the absence of symptoms [24].
Hypertension
Diabetic Cardiomyopathy
Myocardial damage can arise from ischemic heart disease and coronary artery dis-
ease. In addition, further damage is caused by the entity of diabetic cardiomyopathy,
or direct myocardial damage and increased fibrosis from increased inflammation
and oxidative stress associated with the diabetic state that cannot be explained by
coronary artery disease or hypertension. Advanced glycation end products deposit
in the myocardium. Diabetic cardiomyopathy is characterized structurally by
increased left ventricular mass, diastolic dysfunction, and, in latter stages, systolic
dysfunction [26]. Pathologically, this is reflected by myocardial fibrosis, interstitial
infiltration, and myocardial capillary disarray.
Population-based studies have demonstrated that those with diabetes mellitus
and diastolic dysfunction are twice as likely to develop symptomatic heart failure
and have worse mortality outcomes [27].
Heart Failure
The development of heart failure is multifactorial and includes all the above dis-
cussed mechanism. Coronary artery disease and hypertension lead to ischemic heart
disease and can subsequently result in heart failure. Diabetes results in myocyte
2 Precision Medicine for Diabetes and Cardiovascular Disease 57
There is a strong association between diabetes and coronary artery disease. Subjects
with type 2 diabetes are at significantly increased risk of developing myocardial
infarction and death (Table 2.1). Those with type 2 diabetes are at a 20% risk of
developing a myocardial infarction over a 7-year period [28]. Diabetes is an inde-
pendent risk factor for cardiovascular disease and increases risk in the population by
2 to 3 times [29]. In general, the presence of diabetes increases risk to such an extent
that its presence alone is equivalent to a prior myocardial infarction [28].
Mortality is similarly increased, with 10% versus 3% mortality over a 12-year
period among those with diabetes versus those without [30].
Additionally, there is gender disparity in risk. Females have increased risk for
worse cardiovascular outcomes with diabetes, compared to males [31].
Heart Failure
Those with diabetes are at significantly increased risk of developing heart failure. In
population studies, diabetes was found to be an independent predictor for the devel-
opment of heart failure. Those with diabetes have a two times higher incidence of
heart failure development than those without diabetes, even after adjusting for age
and gender, and using multivariable cox regression analysis [32]. Risk ranges from
2 to 10 times compared to those without diabetes and may be higher for females and
younger individuals [4, 33–39]. Additionally, increased risk of heart failure in dia-
betes is also correlated with longer duration of diabetes, poor glycemic control,
Hypertension
Hyperlipidemia
Those with diabetes are more likely to have dyslipidemia. Those with type 2 diabe-
tes tend to have hypertriglyceridemia and high LDL cholesterol, which may be sec-
ondary to insulin resistance and increased serum levels of insulin. Studies suggest
treatment with aggressive lipid lowering, particularly with statin class medications
for LDL reduction [43–45].
Glycemic Control
Pharmacologic Agents
While traditionally, metformin and insulin for aggressive glycemic control (target
HbA1c ≤7%) have been the treatment of choice for those with diabetes, more recent
data have supported benefits of specific classes of diabetes pharmacologic agents [51].
For those with concurrent heart failure with reduced ejection fraction and diabe-
tes, treatment should focus on guideline-directed medical therapy for heart failure
with reduced ejection fraction (HFrEF). Studies have demonstrated that regardless
of diabetes status, guideline-directed medical therapy for HFrEF has similar benefi-
cial effects in outcomes including hospitalization and mortality in patients.
Pharmacologic agents that act on the renin-angiotensin-aldosterone system, such
as ACE inhibitors, angiotensin receptor blockers, and angiotensin receptor-
neprilysin inhibitors, have beneficial effects in this population [4]. Additionally, the
use of such agents in those with diabetes may portend long-term beneficial renal
effects.
Beta-blockers also have an important role in the treatment of heart failure with
reduced ejection fraction. Among those with diabetes, there is a similar benefit in
reducing hospitalization and mortality. Furthermore, of the recommended beta-
blockers for HFrEF, carvedilol, metoprolol succinate, and bisoprolol, carvedilol
may be preferred due to greater effects on glycemic reduction [52].
Mineralocorticoid receptor antagonists (MRA), including spironolactone, also
have proven benefit in HFrEF. Caution though should be implemented, as in the
presence of diabetes and particularly renal dysfunction, these agents can cause
hyperkalemia and should be avoided in this situation. MRAs may also have a benefit
among those with heart failure with preserved ejection fraction [53].
SGLT2 Inhibitors
There has been recent robust data for the benefit of SGLT2 inhibitors for patients
with diabetes and heart failure [57]. Specifically, heart failure hospitalization and
cardiovascular mortality are reduced with this class of agents. This benefit is thought
to be in addition to that provided by serum glucose reduction and is a pharmaco-
logic agent class effect. Furthermore, there is also benefit in prevention of worsen-
ing renal disease in addition to glycemic control and cardiovascular benefit [58].
GLP1 Agonists
Natriuretic Peptides
Summary
In summary, cardiovascular disease and diabetes are closely related and major con-
tributors to worldwide morbidity and mortality. Mechanism of cardiovascular dis-
ease in diabetes is multifactorial and includes microvascular and macrovascular
damage, accelerated atherosclerosis, increased inflammatory pathways, direct
2 Precision Medicine for Diabetes and Cardiovascular Disease 61
myocardial damage, and development of heart failure. These two conditions are
prevalent, and diabetes increases development and progression of heart disease. The
foundation of treatment is glycemic control for microvascular benefit, but novel
pharmacologic agents such as SGLT2 inhibitors and GLP1 agonists provide addi-
tional improvements in cardiovascular morbidity and mortality.
References
1. Horwich TB, Fonarow GC. Glucose, obesity, metabolic syndrome, and diabetes relevance to
incidence of heart failure. J Am Coll Cardiol. 2010;55(4):283–93.
2. Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, et al. Impact of diabetes
on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail.
2015;3(2):136–45.
3. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation.
2007;116(4):434–48.
4. Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, et al. Type 2 diabetes
mellitus and heart failure: a scientific statement from the American Heart Association and
the Heart Failure Society of America: this statement does not represent an update of the 2017
ACC/AHA/HFSA heart failure guideline update. Circulation. 2019;140(7):e294–324.
5. Vinnakota S, Chen HH. The importance of natriuretic peptides in cardiometabolic diseases. J
Endocr Soc. 2020;4(6):bvaa052.
6. Lazo M, Young JH, Brancati FL, Coresh J, Whelton S, Ndumele CE, et al. NH2-terminal pro-
brain natriuretic peptide and risk of diabetes. Diabetes. 2013;62(9):3189–93.
7. Jujic A, Nilsson PM, Engstrom G, Hedblad B, Melander O, Magnusson M. Atrial natriuretic
peptide and type 2 diabetes development--biomarker and genotype association study. PLoS
One. 2014;9(2):e89201.
8. Pfister R, Sharp S, Luben R, Welsh P, Barroso I, Salomaa V, et al. Mendelian randomization
study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from
population studies. PLoS Med. 2011;8(10):e1001112.
9. Bachmann KN, Deger SM, Alsouqi A, Huang S, Xu M, Ferguson JF, et al. Acute effects of
insulin on circulating natriuretic peptide levels in humans. PLoS One. 2018;13(5):e0196869.
10. Cannone V, Boerrigter G, Cataliotti A, Costello-Boerrigter LC, Olson TM, McKie PM, et al. A
genetic variant of the atrial natriuretic peptide gene is associated with cardiometabolic protec-
tion in the general community. J Am Coll Cardiol. 2011;58(6):629–36.
11. Coue M, Badin PM, Vila IK, Laurens C, Louche K, Marques MA, et al. Defective natri-
uretic peptide receptor signaling in skeletal muscle links obesity to type 2 diabetes. Diabetes.
2015;64(12):4033–45.
12. Neeland IJ, Winders BR, Ayers CR, Das SR, Chang AY, Berry JD, et al. Higher natriuretic
peptide levels associate with a favorable adipose tissue distribution profile. J Am Coll Cardiol.
2013;62(8):752–60.
13. Jordan J, Birkenfeld AL, Melander O, Moro C. Natriuretic peptides in cardiovascular and met-
abolic crosstalk: implications for hypertension management. Hypertension. 2018;72(2):270–6.
14. Granger CB, Califf RM, Young S, Candela R, Samaha J, Worley S, et al. Outcome of patients
with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The
Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. J Am Coll
Cardiol. 1993;21(4):920–5.
62 S.-H. Wan and H. H. Chen
34. Bahrami H, Bluemke DA, Kronmal R, Bertoni AG, Lloyd-Jones DM, Shahar E, et al. Novel
metabolic risk factors for incident heart failure and their relationship with obesity: the MESA
(Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol. 2008;51(18):1775–83.
35. Marwick TH, Ritchie R, Shaw JE, Kaye D. Implications of underlying mechanisms for the rec-
ognition and management of diabetic cardiomyopathy. J Am Coll Cardiol. 2018;71(3):339–51.
36. Ohkuma T, Komorita Y, Peters SAE, Woodward M. Diabetes as a risk factor for heart failure
in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million
individuals. Diabetologia. 2019;62(9):1550–60.
37. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart fail-
ure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care.
2004;27(3):699–703.
38. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al. Glycemic control and heart
failure among adult patients with diabetes. Circulation. 2001;103(22):2668–73.
39. Barzilay JI, Kronmal RA, Gottdiener JS, Smith NL, Burke GL, Tracy R, et al. The association
of fasting glucose levels with congestive heart failure in diabetic adults > or =65 years: the
Cardiovascular Health Study. J Am Coll Cardiol. 2004;43(12):2236–41.
40. Dandamudi S, Slusser J, Mahoney DW, Redfield MM, Rodeheffer RJ, Chen HH. The preva-
lence of diabetic cardiomyopathy: a population-based study in Olmsted County, Minnesota. J
Card Fail. 2014;20(5):304–9.
41. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, et al. Impact
of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an
analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and mor-
bidity (CHARM) programme. Eur Heart J. 2008;29(11):1377–85.
42. Kristensen SL, Preiss D, Jhund PS, Squire I, Cardoso JS, Merkely B, et al. Risk related to pre-
diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction: insights
from prospective comparison of ARNI with ACEI to determine impact on global mortality and
morbidity in heart failure trial. Circ Heart Fail. 2016;9(1):e002560.
43. Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care.
1990;13(2):153–69.
44. O'Brien T, Nguyen TT, Zimmerman BR. Hyperlipidemia and diabetes mellitus. Mayo Clin
Proc. 1998;73(10):969–76.
45. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors
in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking
before the onset of clinical diabetes? JAMA. 1990;263(21):2893–8.
46. Bittner V, Bertolet M, Barraza Felix R, Farkouh ME, Goldberg S, Ramanathan KB, et al.
Comprehensive cardiovascular risk factor control improves survival: the BARI 2D trial. J Am
Coll Cardiol. 2015;66(7):765–73.
47. Gregg EW, Gerzoff RB, Caspersen CJ, Williamson DF, Narayan KM. Relationship of walking
to mortality among US adults with diabetes. Arch Intern Med. 2003;163(12):1440–7.
48. Singer DE, Nathan DM, Anderson KM, Wilson PW, Evans JC. Association of HbA1c with
prevalent cardiovascular disease in the original cohort of the Framingham Heart Study.
Diabetes. 1992;41(2):202–8.
49. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin
A1c with cardiovascular disease and mortality in adults: the European prospective investiga-
tion into cancer in Norfolk. Ann Intern Med. 2004;141(6):413–20.
50. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al. Meta-analysis:
glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med.
2004;141(6):421–31.
51. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-
2020. Diabetes Care. 2020;43(Suppl 1):S66–76.
52. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic
effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension:
a randomized controlled trial. JAMA. 2004;292(18):2227–36.
64 S.-H. Wan and H. H. Chen
53. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for
heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92.
54. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and car-
diovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.
55. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, car-
diovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
56. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and
cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.
57. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al.
Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med.
2019;381(21):1995–2008.
58. American Diabetes Association. 11. Microvascular complications and foot care: standards of
medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S135–S51.
59. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and
basal insulin combination treatment for the management of type 2 diabetes: a systematic
review and meta-analysis. Lancet. 2014;384(9961):2228–34.
60. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide
and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.
61. Wang TJ. Natriuretic peptide deficiency-when there is too little of a good thing. JAMA Cardiol.
2018;3(1):7–9.
62. Newton-Cheh C, Larson MG, Vasan RS, Levy D, Bloch KD, Surti A, et al. Association of com-
mon variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat
Genet. 2009;41(3):348–53.
63. Gruden G, Landi A, Bruno G. Natriuretic peptides, heart, and adipose tissue: new findings and
future developments for diabetes research. Diabetes Care. 2014;37(11):2899–908.
64. Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, et al. Effect of
sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and
diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol.
2017;5(5):333–40.
65. Heinisch BB, Vila G, Resl M, Riedl M, Dieplinger B, Mueller T, et al. B-type natriuretic pep-
tide (BNP) affects the initial response to intravenous glucose: a randomised placebo-controlled
cross-over study in healthy men. Diabetologia. 2012;55(5):1400–5.
Chapter 3
Precision Medicine for Diabetes
and Dyslipidemia
Introduction
Pathogenesis
Treatment
Statins
Statins are established as first-line therapy for diabetic dyslipidemia and play a
crucial role in both primary and secondary cardiovascular prevention. The clinical
practice guidelines of the Endocrine Society recommend routine statin therapy
with an LDL-C target of 70 mg/dL for patients without established CVD and
55 mg/dL for those with established CVD [26]. The guidelines of the American
3 Precision Medicine for Diabetes and Dyslipidemia 67
College of Cardiology and the American Heart Association advise the use of at
least a moderate-intensity statin in patients with diabetes aged 40–75 and a high-
intensity statin if the 10-year pooled-cohort atherosclerotic cardiovascular
(ASCVD) risk calculator is significant or there are other risk factors for ASCVD
[27–29]. The presence versus absence of dyslipidemia does not influence the rec-
ommendations in either guideline.
The mechanism by which statins lower LDL-C involves inhibition of
hydroxymethylglutaryl-CoA (HMG-CoA) reductase, a key enzyme in the biochem-
ical cholesterol synthesis pathway [30]. In addition to their well-known effects on
LDL-C levels, statins have been shown to both lower triglycerides and raise HDL-C
concentrations [31, 32]; this effect may be due in part to an increase in both pre-
heparin and post-heparin plasma lipase activity [22]. However, effects of statins on
LDL particle size are small [33] to negligible [34, 35]. Bempedoic acid, which is
discussed below, inhibits another enzyme in this same biochemical pathway [36].
Secondary Prevention
The Scandinavian Simvastatin Survival Study (4S study) was a randomized, double-
blind placebo-controlled trial involving over 4000 patients with previous coronary
heart disease or ongoing angina followed for an average of 5.4 years; it compared
simvastatin 40 mg daily to placebo in regard to outcomes that included cardiovascu-
lar and all-cause mortality [37]. In the placebo group, cardiovascular events were
greater than twofold higher in people with diabetes than in nondiabetic individuals.
Patients in the treatment arm had lower mean LDL-C, total cholesterol, and elevated
HDL-C (−35%, −25%, and + 8%, respectively), together with a 42% decrease in
cardiovascular death and a 30% reduction in all-cause mortality [37]. This study
was the first to show that treatment of dyslipidemia in diabetic subjects significantly
decreases cardiovascular events; in a subgroup analysis, reduction in events in
patients with diabetes was greater than in the patients without diabetes (55% versus
32%, respectively), although the number of people with diabetes was small and the
difference in all-cause mortality was not significant [37, 38].
There is substantial evidence from secondary prevention studies that high statin
doses produce greater reduction in events than lower doses. In the PROVE IT-TIMI
22 trial, approximately 4200 patients with acute coronary syndrome were random-
ized to receive either pravastatin 40 mg daily or atorvastatin 80 mg daily [39]. The
more intense treatment with atorvastatin produced lower LDL-C concentrations
compared with pravastatin (62 mg/dL vs 95 mg/dL) and also resulted in a Kaplan-
Meier estimate of a composite of cardiovascular events at 2 years that was 16%
lower in those receiving high-intensity atorvastatin compared with pravastatin
(p = 0.005) [39]. The benefit of high-intensity atorvastatin over pravastatin was
equivalent in subjects with and without diabetes [39]. Another study used intravas-
cular ultrasound and found that atorvastatin 80 mg daily, but not pravastatin 40 mg
daily, halted the progression of atherosclerosis [40]. When interpreting these two
68 E. Alexander et al.
Primary Prevention
reductions in all-cause mortality (OR 0.86, 95% CI 0.79 to 0.94), combined fatal
and non-fatal myocardial infarction and stroke, as well as need for revascularization
with statin therapy [53].
PCSK-9 Inhibitors
Ezetimibe
Bempedoic Acid
Bempedoic acid is a small molecule that has recently been approved for the purpose
of lowering LDL cholesterol. Its mechanism of action is to inhibit ATP citrate lyase
in the liver, an enzyme in the same pathway but upstream from HMG-CoA reduc-
tase. The effectiveness of bempedoic acid in LDL-C lowering was evaluated in
high-risk patients on maximally tolerated statins in the CLEAR Wisdom trial [80].
This study involved 779 patients (236 with T2DM) with cardiovascular disease and/
or heterozygous familial hypercholesterolemia randomized 2:1 to 180 mg of bem-
pedoic acid daily or placebo for 52 weeks. Primary outcomes were LDL-C change
from baseline, and secondary endpoints included measurements of other lipopro-
teins and biomarkers. At the 12-week mark, mean LDL-C levels were significantly
lower in the treatment group vs the placebo group (−15.1% vs 2.4%), and non-
HDL, total cholesterol, apolipoprotein B, and hsCRP were all lower in the treatment
72 E. Alexander et al.
group [80]. A meta-analysis of five trials (n = 3629) found that treatment with bem-
pedoic acid resulted in a 34% reduction in new-onset diabetes or worsening of pre-
existing diabetes [81]. A second meta-analysis (11 trials, n = 4392) also found a
reduction in new onset or worsening diabetes (RR 0.65) as well as a reduction in
composite cardiovascular outcomes (RR 0.75) [82]. To our knowledge, there are no
studies of the effects of bempedoic acid that have been conducted specifically in
diabetic patients with dyslipidemia. Nonetheless, bempedoic acid used in conjunc-
tion with a maximally tolerated statin may be of use in diabetic patients who are not
at their lipid goals.
Fibrates
Although statins substantially reduce cardiovascular risk, they do not eliminate it;
the majority of statin-treated patients still have events on this therapy [83].
Individuals with low HDL-C have increased risk in spite of statin treatment [84].
The fibrate class of medication made its first appearance over 50 years ago and is
well-known to decrease triglycerides, raise HDL-C, and increase LDL particle size
[34, 35, 85, 86]. The increase in LDL-C particle size with fibrate use is inversely
correlated with the decrease in serum triglyceride level [87]. Fibrate medications
should theoretically therefore be an ideal treatment, in combination with statins, for
patients with dyslipidemia. In fact, fibrates should be considered complementary to
statins, which lower triglycerides and raise HDL-C, but do not normalize them [88],
and which have little to no effect on LDL particle size [33–35]. The effects of
fibrates are mediated primarily via activation of the peroxisome proliferator-
activated receptor-alpha (PPAR-α) transcription factor, increasing triglyceride
clearance and raising HDL-C [89, 90].
Nonetheless, fibrates are not recommended by many experts in the management
of patients with lipid disorders. The guidelines of the American College of
Cardiology and the American Heart Association point out that the triglyceride-
lowering properties of statins are similar to those of fibrates; use of fibrates is rec-
ommended only in patients with severe hypertriglyceridemia and not as an add-on
to statin therapy [79]. On the other hand, the clinical practice guidelines of the
3 Precision Medicine for Diabetes and Dyslipidemia 73
Endocrine Society indicate that fibrates may be used in high-risk T2DM patients
with even mild hypertriglyceridemia and should be used in patients with diabetic
retinopathy [26]. The ambivalence concerning fibrate use is in part because random-
ized, controlled trials have produced mixed results with respect to cardiovascular
benefit when fibrates are given as monotherapy [91–94] or in combination with
statins [95].
The Helsinki Heart Study was a primary prevention trial investigating cardiovas-
cular benefits of gemfibrozil in middle-aged men. At 5 years, the rate of cumulative
cardiac endpoints was 27.3 per 1000 in the treatment group (2051 men receiving
600 mg twice daily) and 41.4 per 1000 in the placebo group, p < 0.05. Gemfibrozil
treatment resulted in a significant increase in HDL-C and reductions in triglycer-
ides, LDL-C, and non-HDL cholesterol [91]. Only 3% of the participants had dia-
betes. VA-HIT was a secondary prevention study that also tested the potential benefit
of gemfibrozil treatment [96]. This double-blind placebo-controlled trial compared
1200 mg of gemfibrozil daily to placebo in 2531 men with established coronary
heart disease, an HDL-C of less than 40 mg/dl, and LDL-C ≤140 mg/dl [96]. The
relative risk of a cardiovascular event was reduced by 22% in the gemfibrozil group
compared to placebo (p < 0.01). There was a 41% decrease in coronary death
(P = 0.02) in participants with diabetes. There was also a significant (p < 0.05)
decrease in stroke in those with diabetes, but not in nondiabetic individuals.
However, other large studies, including FIELD [91], the Bezafibrate Infarction
Prevention study [93], and ACCORD [95], showed no benefit from addition of a
fibrate. This explains why some organizations are at best lukewarm regarding the
use of fibrates for prevention of cardiovascular events.
It has been pointed out that many of the subjects in the above trials did not have
dyslipidemia [6] and therefore might not be expected to benefit from fibrate therapy.
In fact, post hoc analyses of these studies have shown benefit in the subgroups with
dyslipidemia [93]. Sacks pooled data from five large trials and in a post hoc analysis
found a 35% reduction in cardiovascular events among individuals with dyslipid-
emia [97]. Table 3.1 shows mean lipid values in five major fibrate trials. It can be
inferred from the data that many of the participants in these trials did not have dys-
lipidemia and would thus be less likely to benefit from a treatment that targets
dyslipidemia.
A Cochrane Database Review evaluating fibrates for the primary prevention of
cardiovascular events analyzed six eligible trials, four of which involved patients
with T2DM, including over 16,000 patients [98]. The review found a 16% reduction
in cardiovascular death, nonfatal MI, and nonfatal stroke [98]. Wang et al. published
another Cochrane review evaluating fibrates for the secondary prevention of cardio-
vascular disease and stroke and included seven studies when clofibrate was excluded
[99]. The analysis, which involved over 10,000 patients, found that fibrates did not
decrease the risk of primary composite outcomes. However, the review found that
fibrates did prevent myocardial infarction [99].
The effects of fenofibrate on renal function are of interest. In two large clinical
trials, fenofibrate produced an acute, sustained increase in creatinine levels [94, 95].
In a washout substudy of the FIELD trial involving 661 patients, fenofibrate caused
an acute rise in creatinine followed by a slower chronic increase compared to pla-
cebo, together with a decrease in urinary albumin (p = 0.01). With washout, creati-
nine was lower in those treated with fenofibrate compared with placebo, indicating
preservation of eGFR [100]. There was great preservation of renal function in
patients with dyslipidemia compared with non-dyslipidemic individuals [100].
These findings (an acute decrease in eGFR followed by preservation of renal func-
tion) would benefit from confirmation; they are strikingly similar to effects of
SGLT2 medications on renal function and suggest reversal of hyperfiltration [101].
In summary, clinical trial results on the use of fibrates have been inconsistent and
have been confounded by inclusion of participants without dyslipidemia. Post hoc
analyses tend to suggest that subjects with dyslipidemia will benefit from addition
of a fibrate medication to statin therapy. Additional studies are underway to investi-
gate potential benefits of fibrates in patients with true dyslipidemia; hopefully, those
results will provide further clarity on the subject. The FIELD trial results regarding
effects of fenofibrate on renal function need confirmation but suggest that there may
be off-target renal benefits of fibrate therapy. Taking the above data together, we
tend to favor selective use of fibrates in high-risk patients with true dyslipidemia.
In 1999, the GISSI Prevenzione study was published, showing a significant decrease
in a composite MACE 3 endpoint in post-myocardial infarction patients treated for
3.5 years with an omega-3 fatty acid supplement containing eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) ethyl esters [102], generating considerable
excitement about the potential for omega-3 fatty acids in cardiovascular risk reduc-
tion [103]. Subsequently, the JELIS trial demonstrated a 19% decrease in major
coronary events in patients on low-dose statins who were given EPA 1.8 g daily
(EPA) versus low-dose statin therapy alone [104]. Later research failed to confirm
the findings in those studies [105–107], and interest in the idea that omega-3 fatty
acids might confer cardiovascular protection faded to some extent.
In diabetic patients who are treated with statins, significant residual cardiovascu-
lar risk can remain, as discussed previously. Hypertriglyceridemia has been shown
to be an independent risk factor for cardiovascular disease [108–110]. The
REDUCE-IT trial was a 4.9-year study conducted to determine if 4 g/day icosapent
3 Precision Medicine for Diabetes and Dyslipidemia 75
ethyl, an ester of EPA, would reduce ischemic cardiovascular events versus placebo
[111]. Over 8000 statin-treated patients with cardiovascular disease or diabetes with
additional risk factors and elevated triglycerides were enrolled and randomized
[111]. Icosapent ethyl resulted in a relative reduction in cardiovascular events
(MACE 5) of 25% versus placebo. A subsequent analysis of the United States cohort
of REDUCE-IT (n = 3146, of whom nearly 70% had diabetes) revealed a risk reduc-
tion of 31% [112]. Perhaps as a result, the 2020 Endocrine Society lipid manage-
ment guidelines suggest that for diabetic patients on maximally tolerated statin
therapy who have two additional risk factors for cardiovascular disease and triglyc-
eride levels >150 mg/dL, 4 grams of EPA is added daily to reduce the risk of cardio-
vascular events [26]. Although the results of the clinical trials reviewed above have
been inconsistent, a recent meta-analysis found significant benefit from omega-3 on
total and fatal myocardial infarction and on total and fatal cardiovascular
events [113].
The mechanism that accounts for the benefit in icosapent ethyl-treated patients in
REDUCE-IT is unclear. Candidates include modulation of the immune system with
reduced inflammatory response and alteration of cardiac sympathetic tone [114].
The role of lipoproteins is uncertain. Triglyceride levels decreased by only 18% in
icosapent-treated subjects in REDUCE-IT, and risk reduction in subjects with base-
line triglycerides 135–150 mg/dl was similar to that in those with baseline triglyc-
erides >200 mg/dl; HDL-C did not change. A diet enriched in omega-3 fatty acids
has been shown to decrease triglycerides and sdLDL [115]. An increase in LDL
particle size has been shown with EPA treatment [116, 117], and omega-3 fatty acid
treatment decreases HDL3 cholesterol (small particles) while not changing HDL2
(larger particles) [117, 118]. Thus, changes in lipoprotein particles that are not
detected by standard clinical lipid tests may contribute to beneficial effects of
omega-3 fatty acids.
Another possible mechanism for benefit from icosapent ethyl is an effect on
platelet function. In the REDUCE-IT study, there was a nearly significant (p = 0.06)
increase in serious bleeding events (2.6% vs 2.1% in the two groups). The potential
for omega-3 fatty acid inhibition of platelet function was suggested many centuries
ago; an ancient Norse document (Historia Norvegiae) written in 1170 AD describes
the first encounter between Vikings and Inuit people in Greenland:
On the other side of Greenland, toward the North, hunters have found some little people…
when mortally wounded their blood will hardly stop running [119].
Prolonged bleeding times have since been demonstrated in the Inuit, who have a
diet high in omega-3 fatty acids and a very low incidence of cardiovascular disease
[120]. The potential for a contribution of altered platelet function in REDUCE-IT
has been reviewed in detail recently [121]. In support of a cardioprotective role for
impaired platelet function, a population-based study in Sweden recently found that
although patients with von Willebrand disease do have cardiovascular disease, car-
diovascular mortality was reduced in this condition by 60% compared with the gen-
eral population [122]. However, clinically significant bleeding is generally not
observed when omega-3 fatty acids are given at a dose of 4 g/day [123].
76 E. Alexander et al.
In summary, omega-3 fatty acids, especially EPA, appear to have a role for car-
diovascular risk reduction in selected high-risk patients with hypertriglyceridemia.
Diabetes-Specific Medications
Metformin
GLP-1 receptor agonists (GLP-1Ras) have assumed a prominent role in the treat-
ment of type 2 diabetes since their introduction more than 15 years ago. Most are
given by subcutaneous injection, although an oral form is available [136]. GLP-1 is
secreted by the enteroendocrine cells of the gut in response to postprandial
3 Precision Medicine for Diabetes and Dyslipidemia 77
glycemic excursion and helps potentiate insulin secretion from the pancreas and
limit the impact of glucagon secretion [137]. Although the effects on insulin and
glucagon secretion are most often cited as the principal mechanism of action of
these agents, they also delay gastric emptying, decrease satiety, and decrease energy
intake [137, 138] [139]; these effects may be more important in the use of these
medications than the effects on insulin and glucagon secretion.
The SUSTAIN-6 study was conducted in ~3300 patients with uncontrolled
T2DM and a history of cardiovascular events. Semaglutide given over a median
follow-up of 2.1 years resulted in a 26% decrease in MACE-4 events [140]. The
LEADER study of cardiovascular effects of liraglutide, published in the same year,
also showed cardiovascular benefit with a 13% decrease in events over a 3.8-year
follow-up [141]. A study of albiglutide versus placebo in 9300 patients with T2DM
found a 22% decrease in cardiovascular events over a 1.9-year period of observation
[142]. A more recent trial in 9900 T2DM patients with cardiovascular disease con-
ducted over 5.4 years demonstrated a 12% decrease in MACE 3 events with dula-
glutide 1.5 mg weekly treatment [143].
The lipid-lowering properties of GLP-1RAs have received little attention; lipids
are not reported consistently in the large clinical trials mentioned above. A recent
study found an increase in LDL particle size after 4 months of treatment with lira-
glutide [144]. We were able to find six published studies that provide triglyceride
data at baseline and at follow-up [140, 145–149]. Figure 3.1 shows the relationship
between median baseline triglyceride concentrations and the decrease in triglycer-
ides that was observed during the study. There was a strong correlation between the
degree of hypertriglyceridemia and the magnitude of triglyceride lowering observed
(r = 0.90, p = 0.01). There was also an association between the average amount of
weight loss and decrease in triglycerides, but it was not significant in this small data
set (r = 0.50, p = NS, not shown). These results suggest that the lipid effects of
GLP-1RAs depend on the magnitude of the lipid abnormality.
Thiazolidinediones
300
y = 2.6634x + 121.59
R2 = 0.8135
250 P = 0.015
148
Baseline triglycerides (mg/dl)
147
145
200
140
146
150
149
100
0 10 20 30 40 50
Decrease in triglycerides (mg/dl)
Fig. 3.1 Relationship between average baseline triglyceride concentrations and the decrease in
triglyceride level observed in response to treatment with a GLP-1 receptor agonist in six studies.
The number next to each data point corresponds to the reference for the study
Summary
References
1. Ahmad FB, Anderson RN. The leading causes of death in the US for 2020.
JAMA. 2021;325(18):1829–30.
2. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr car-
diovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes
Care. 1993;16(2):434–44.
3 Precision Medicine for Diabetes and Dyslipidemia 79
3. Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national
cohort of the U.S. population, 1971-1993. Diabetes Care. 1998;21(7):1138–45.
4. Raghavan S, Vassy JL, Ho YL, Song RJ, Gagnon DR, Cho K, Wilson PWF, Phillips
LS. Diabetes mellitus-related all-cause and cardiovascular mortality in a National Cohort of
adults. J Am Heart Assoc. 2019;8(4):e011295.
5. Ginsberg HN. REVIEW: efficacy and mechanisms of action of statins in the treatment of
diabetic dyslipidemia. J Clin Endocrinol Metab. 2006;91(2):383–92.
6. Anabtawi A, Moriarty PM, Miles JM. Pharmacologic treatment of dyslipidemia in diabetes:
a case for therapies in addition to statins. Curr Cardiol Rep. 2017;19(7):62.
7. Third Report of the National Cholesterol Education Program (NCEP) expert panel on detec-
tion, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)
final report. Circulation. 2002;106(25):3143–421.
8. Taskinen MR, Borén J. New insights into the pathophysiology of dyslipidemia in type 2
diabetes. Atherosclerosis. 2015;239(2):483–95.
9. Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J
Cardiol. 1999;83(9b):25f–9f.
10. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, Descamps OS,
Fisher E, Kovanen PT, Kuivenhoven JA, et al. Triglyceride-rich lipoproteins and high-density
lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guid-
ance for management. Eur Heart J. 2011;32(11):1345–61.
11. Howard BV, Mayer-Davis EJ, Goff D, Zaccaro DJ, Laws A, Robbins DC, Saad MF, Selby J,
Hamman RF, Krauss RM, et al. Relationships between insulin resistance and lipoproteins in
nondiabetic African Americans, Hispanics, and non-Hispanic whites: the insulin resistance
atherosclerosis study. Metab Clin Exp. 1998;47(10):1174–9.
12. Bjornstad P, Snell-Bergeon JK, Rewers M, Jalal D, Chonchol MB, Johnson RJ, Maahs
DM. Early diabetic nephropathy: a complication of reduced insulin sensitivity in type 1 dia-
betes. Diabetes Care. 2013;36(11):3678–83.
13. Priya G, Kalra S. A review of insulin resistance in type 1 diabetes: is there a place for adjunc-
tive metformin? Diabetes Therapy: Research, Treatment and Education of Diabetes and
Related Disorders. 2018;9(1):349–61.
14. McGarry JD. What if Minkowski had been ageusic? An alternative angle on diabetes.
Science. 1992;258:766–70.
15. Tilly-Kiesi M, Knudsen P, Groop L, Taskinen MR. Hyperinsulinemia and insulin resistance
are associated with multiple abnormalities of lipoprotein subclasses in glucose-tolerant rela-
tives of NIDDM patients. Botnia Study Group. J Lipid Res. 1996;37(7):1569–78.
16. Karelis AD, Pasternyk SM, Messier L, St-Pierre DH, Lavoie JM, Garrel D, Rabasa-Lhoret
R. Relationship between insulin sensitivity and the triglyceride-HDL-C ratio in overweight
and obese postmenopausal women: a MONET study. Applied physiology, nutrition, and
metabolism = Physiologie appliquee, nutrition et metabolisme. 2007;32(6):1089–96.
17. Iwani NA, Jalaludin MY, Zin RM, Fuziah MZ, Hong JY, Abqariyah Y, Mokhtar AH, Wan
Nazaimoon WM. Triglyceride to HDL-C ratio is associated with insulin resistance in over-
weight and obese children. Scientific reports. 2017;7:40055.
18. Guerrero-Romero F, Simental-Mendía LE, González-Ortiz M, Martínez-Abundis E, Ramos-
Zavala MG, Hernández-González SO, Jacques-Camarena O, Rodríguez-Morán M. The prod-
uct of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the
euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab. 2010;95(7):3347–51.
19. Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM. LDL subclass phenotypes and
triglyceride metabolism in non-insulin-dependent diabetes. Arteriosclerosis Thrombosis: A
Journal of Vascular Biology. 1992;12(12):1496–502.
20. Bays H, Conard S, Leiter LA, Bird S, Jensen E, Hanson ME, Shah A, Tershakovec AM. Are
post-treatment low-density lipoprotein subclass pattern analyses potentially misleading?.
Lipids Health Dis. 2010;9:136.
21. Klop B, Elte JW, Cabezas MC. Dyslipidemia in obesity: mechanisms and potential targets.
Nutrients. 2013;5(4):1218–40.
80 E. Alexander et al.
22. Isley WL, Miles JM, Patterson BW, Harris WS. The effect of high-dose simvastatin on
triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus. J Lipid
Res. 2006;47(1):193–200.
23. Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids
and insulin in the acute control of very low density lipoprotein production in humans. J Clin
Invest. 1995;95(1):158–66.
24. Muthusamy K, Nelson R, Singh E, Vlazny D, Smailovic A, Miles J. Effect of insulin infusion
on spillover of meal-derived fatty acids. J Clin Endocrinol Metab. 2012;97:4201–5.
25. Sam S, Haffner S, Davidson MH, D'Agostino RB Sr, Feinstein S, Kondos G, Perez A,
Mazzone T. Relationship of abdominal visceral and subcutaneous adipose tissue with lipo-
protein particle number and size in type 2 diabetes. Diabetes. 2008;57(8):2022–7.
26. Newman CB, Blaha MJ, Boord JB, Cariou B, Chait A, Fein HG, Ginsberg HN, Goldberg IJ,
Murad MH, Subramanian S, et al. Lipid management in patients with endocrine disorders: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2020;105(12).
27. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb
CD, Khera A, Lloyd-Jones D, McEvoy JW, et al. 2019 ACC/AHA guideline on the pri-
mary prevention of cardiovascular disease: a report of the American College of Cardiology/
American Heart Association task force on clinical practice guidelines. Circulation.
2019;140(11):e596–646.
28. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, Greenland
P, Lackland DT, Levy D, O'Donnell CJ, et al. 2013 ACC/AHA guideline on the assessment
of cardiovascular risk: a report of the American College of Cardiology/American Heart
Association task force on practice guidelines. Circulation. 2014;129(25 Suppl 2):S49–73.
29. Muntner P, Colantonio LD, Cushman M, Goff DC Jr, Howard G, Howard VJ, Kissela B,
Levitan EB, Lloyd-Jones DM, Safford MM. Validation of the atherosclerotic cardiovascular
disease pooled cohort risk equations. JAMA. 2014;311(14):1406–15.
30. Istvan ES. Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coen-
zyme a reductase. Am Heart J. 2002;144(6 Suppl):S27–32.
31. Schaefer EJ, McNamara JR, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein
JJ. Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and
simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease
versus control subjects. Am J Cardiol. 2004;93(1):31–9.
32. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto
JW. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin,
and pravastatin across doses (STELLAR* trial). Am J Cardiol. 2003;92(2):152–60.
33. Wakatsuki A, Okatani Y, Ikenoue N. Effects of combination therapy with estrogen plus simv-
astatin on lipoprotein metabolism in postmenopausal women with type IIa hypercholesterol-
emia. Atherosclerosis. 2000;150(1):103–11.
34. Lemieux I, Laperrière L, Dzavik V, Tremblay G, Bourgeois J, Després JP. A 16-week fenofi-
brate treatment increases LDL particle size in type IIA dyslipidemic patients. Atherosclerosis.
2002;162(2):363–71.
35. Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and toler-
ability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J
Cardiol. 2005;95(4):462–8.
36. Markham A. Bempedoic acid: first approval. Drugs. 2020;80(7):747–53.
37. Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus
J, Pyorala K. Reduced coronary events in simvastatin-treated patients with coronary heart
disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian
simvastatin survival study. Arch Intern Med. 1999;159(22):2661–7.
38. Haffner SM. The Scandinavian simvastatin survival study (4S) subgroup analysis of dia-
betic subjects: implications for the prevention of coronary heart disease. Diabetes Care.
1997;20(4):469–71.
3 Precision Medicine for Diabetes and Dyslipidemia 81
39. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA,
Pfeffer MA, Skene AM. Intensive versus moderate lipid lowering with statins after acute
coronary syndromes. N Engl J Med. 2004;350(15):1495–504.
40. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard
G, Cooper CJ, Brodie B, et al. Effect of intensive compared with moderate lipid-lowering
therapy on progression of coronary atherosclerosis: a randomized controlled trial.
JAMA. 2004;291(9):1071–80.
41. Naci H, Brugts JJ, Fleurence R, Ades AE. Dose-comparative effects of different statins on
serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized con-
trolled trials. Eur J Prev Cardiol. 2013;20(4):658–70.
42. Deedwania P, Barter P, Carmena R, Fruchart JC, Grundy SM, Haffner S, Kastelein JJ, LaRosa
JC, Schachner H, Shepherd J, et al. Reduction of low-density lipoprotein cholesterol in
patients with coronary heart disease and metabolic syndrome: analysis of the treating to new
targets study. Lancet. 2006;368(9539):919–28.
43. Backes JM, Venero CV, Gibson CA, Ruisinger JF, Howard PA, Thompson PD, Moriarty
PM. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with
prior statin intolerance. Ann Pharmacother. 2008;42(3):341–6.
44. Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J
Cardiol. 2006;97(8a):44c–51c.
45. Backes JM, Ruisinger JF, Gibson CA, Moriarty PM. Statin-associated muscle symptoms-
managing the highly intolerant. J Clin Lipidol. 2017;11(1):24–33.
46. Bays H, Stein EA. Pharmacotherapy for dyslipidaemia--current therapies and future agents.
Expert Opin Pharmacother. 2003;4(11):1901–38.
47. Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding statin use in America and gaps
in patient education (USAGE): an internet-based survey of 10,138 current and former statin
users. J Clin Lipidol. 2012;6(3):208–15.
48. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason
MJ, Mackness MI, Charlton-Menys V, Fuller JH. Primary prevention of cardiovascular disease
with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS):
multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685–96.
49. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE,
Kristinsson A, McInnes GT, et al. Prevention of coronary and stroke events with atorvastatin
in hypertensive patients who have average or lower-than-average cholesterol concentrations,
in the Anglo-Scandinavian cardiac outcomes trial--lipid lowering arm (ASCOT-LLA): a mul-
ticentre randomised controlled trial. Lancet. 2003;361(9364):1149–58.
50. Sever PS, Poulter NR, Dahlof B, Wedel H, Collins R, Beevers G, Caulfield M, Kjeldsen
SE, Kristinsson A, McInnes GT, et al. Reduction in cardiovascular events with atorvastatin
in 2,532 patients with type 2 diabetes: Anglo-Scandinavian cardiac outcomes trial--lipid-
lowering arm (ASCOT-LLA). Diabetes Care. 2005;28(5):1151–7.
51. Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the pre-
vention of cardiovascular end points in subjects with type 2 diabetes: the atorvastatin study
for prevention of coronary heart disease endpoints in non-insulin-dependent diabetes mellitus
(ASPEN). Diabetes Care. 2006;29(7):1478–85.
52. Gazi IF, Mikhailidis DP. Efficacy and safety of atorvastatin in the prevention of cardiovas-
cular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of
Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN):
response to Knopp. Diabetes Care. 2006;29(11):2561; author reply −2.
53. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim
S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Sys Rev.
2013;2013(1):Cd004816.
54. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby
P, Lorenzatti AJ, MacFadyen JG, et al. Rosuvastatin to prevent vascular events in men and
women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.
82 E. Alexander et al.
55. FDA. FDA drug safety communication: important safety label changes to cholesterol-lowering
statin drugs. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-com-
munication-important-safety-label-changes-cholesterol-lowering-statin-drugs. 2012.
56. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and
diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.
Lancet. 2012;380(9841):565–71.
57. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin ther-
apy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(10):
1924–9.
58. Cai T, Abel L. Associations between statins and adverse events in primary prevention of
cardiovascular disease: systematic review with pairwise, network, and dose-response meta-
analyses. 2021;374:n1537.
59. Lavie G, Hoshen M, Leibowitz M, Benis A, Akriv A, Balicer R, Reges O. Statin therapy for
primary prevention in the elderly and its association with new-onset diabetes, cardiovascular
events, and all-cause mortality. Am J Med. 2021;134(5):643–52.
60. Bell DSH, Goncalves E. Diabetogenic effects of cardioprotective drugs. 2021;23(4):877–85.
61. Brown MS, Anderson RG, Goldstein JL. Recycling receptors: the round-trip itinerary of
migrant membrane proteins. Cell. 1983;32(3):663–7.
62. Handelsman Y, Lepor NE. PCSK9 inhibitors in lipid management of patients with diabetes
mellitus and high cardiovascular risk: a review. J Am Heart Associat. 2018;7(13).
63. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular
health. Circ Res. 2014;114(6):1022–36.
64. Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in
cells. Curr Opin Lipidol. 2014;25(5):387–93.
65. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF,
Wang H, Liu T, Wasserman SM, et al. Evolocumab and clinical outcomes in patients with
cardiovascular disease. N Engl J Med. 2017;376(18):1713–22.
66. Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, Murphy
SA, Kuder JF, Gouni-Berthold I, Lewis BS, et al. Cardiovascular safety and efficacy of
the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of
evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the
FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–50.
67. Schwartz GG, Steg PG, Szarek M, Bhatt DL. Alirocumab and cardiovascular outcomes after
acute coronary syndrome. 2018;379(22):2097–107.
68. Leiter LA, Cariou B, Müller-Wieland D, Colhoun HM, Del Prato S. Efficacy and safety of
alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascu-
lar risk: The ODYSSEY DM-INSULIN randomized trial. 2017;19(12):1781–92.
69. Mani P, Ren HY, Neeland IJ, McGuire DK, Ayers CR, Khera A, Rohatgi A. The association
between HDL particle concentration and incident metabolic syndrome in the multi-ethnic
Dallas Heart Study. Diabetes Metabol Synd. 2017;11(Suppl 1):S175–9.
70. Ingueneau C, Hollstein T, Grenkowitz T, Ruidavets JB, Kassner U, Duparc T, Combes G,
Perret B, Genoux A, Schumann F, et al. Treatment with PCSK9 inhibitors induces a more
anti-atherogenic HDL lipid profile in patients at high cardiovascular risk. Vascular Pharmacol.
2020;135:106804.
71. Hollstein T, Vogt A, Grenkowitz T, Stojakovic T, März W, Laufs U, Bölükbasi B, Steinhagen-
Thiessen E, Scharnagl H, Kassner U. Treatment with PCSK9 inhibitors reduces atherogenic
VLDL remnants in a real-world study. Vascular Pharmacol. 2019;116:8–15.
72. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis
BS, Ophuis TO, Jukema JW, et al. Ezetimibe added to statin therapy after acute coronary
syndromes. N Engl J Med. 2015;372(25):2387–97.
73. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB. Ezetimibe:
a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet.
2005;44(5):467–94.
3 Precision Medicine for Diabetes and Dyslipidemia 83
74. Nutescu EA, Shapiro NL. Ezetimibe: a selective cholesterol absorption inhibitor.
Pharmacotherapy. 2003;23(11):1463–74.
75. Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalán R, Špinar J, Park JG, White
JA, Bohula EA, Braunwald E. Benefit of adding ezetimibe to statin therapy on cardiovas-
cular outcomes and safety in patients with versus without diabetes mellitus: results from
IMPROVE-IT (improved reduction of outcomes: Vytorin efficacy international trial).
Circulation. 2018;137(15):1571–82.
76. Conard S, Bays H, Leiter LA, Bird S, Lin J, Hanson ME, Shah A, Tershakovec AM. Ezetimibe
added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for
coronary heart disease with diabetes mellitus, metabolic syndrome or neither. Diabetes Obes
Metab. 2010;12(3):210–8.
77. Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, Stroes ES, MacDougall
D, Zhao X, Catapano AL. Bempedoic acid plus ezetimibe fixed-dose combination in patients
with hypercholesterolemia and high CVD risk treated with maximally tolerated statin ther-
apy. Eur J Prev Cardiol. 2020;27(6):593–603.
78. Tribble DL, Farnier M, Macdonell G, Perevozskaya I, Davies MJ, Gumbiner B, Musliner
TA. Effects of fenofibrate and ezetimibe, both as monotherapy and in coadministration, on
cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle
size in patients with mixed hyperlipidemia. Metab Clin Exp. 2008;57(6):796–801.
79. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de
Ferranti S, Faiella-Tommasino J, Forman DE, et al. 2018 AHA/ACC/AACVPR/AAPA/
ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the Management of Blood
Cholesterol: a report of the American College of Cardiology/American Heart Association
task force on clinical practice guidelines. Circulation. 2019;139(25):e1082–e143.
80. Goldberg AC, Leiter LA, Stroes ESG, Baum SJ, Hanselman JC, Bloedon LT, Lalwani ND,
Patel PM, Zhao X, Duell PB. Effect of Bempedoic acid vs placebo added to maximally toler-
ated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular
disease: the CLEAR wisdom randomized clinical trial. JAMA. 2019;322(18):1780–8.
81. Masson W, Lobo M, Lavalle-Cobo A, Masson G, Molinero G. Effect of bempedoic acid on
new onset or worsening diabetes: a meta-analysis. Diabetes Res Clin Pract. 2020;168:108369.
82. Wang X, Zhang Y, Tan H, Wang P, Zha X, Chong W, Zhou L, Fang F. Efficacy and safety of
bempedoic acid for prevention of cardiovascular events and diabetes: a systematic review and
meta-analysis. 2020;19(1):128.
83. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am
Coll Cardiol. 2005;46(7):1225–8.
84. Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM, Keech A, Packard
C, Simes J, Byington R, et al. Effect of pravastatin on coronary disease events in subgroups
defined by coronary risk factors: the Prospective pravastatin pooling project. Circulation.
2000;102(16):1893–900.
85. Vakkilainen J, Steiner G, Ansquer JC, Perttunen-Nio H, Taskinen MR. Fenofibrate lowers
plasma triglycerides and increases LDL particle diameter in subjects with type 2 diabetes.
Diabetes Care. 2002;25(3):627–8.
86. Shipman KE, Strange RC, Ramachandran S. Use of fibrates in the metabolic syndrome: a
review. World J Diabetes. 2016;7(5):74–88.
87. Davidson MH, Bays HE, Stein E, Maki KC, Shalwitz RA, Doyle R. Effects of fenofibrate on
atherogenic dyslipidemia in hypertriglyceridemic subjects. Clin Cardiol. 2006;29(6):268–73.
88. McTaggart F, Jones P. Effects of statins on high-density lipoproteins: a potential contribution
to cardiovascular benefit. Cardiovasc Drugs Ther. 2008;22(4):321–38.
89. Remick J, Weintraub H, Setton R, Offenbacher J, Fisher E, Schwartzbard A. Fibrate therapy:
an update. Cardiol Rev. 2008;16(3):129–41.
90. Fruchart JC, Hermans MP, Fruchart-Najib J, Kodama T. Selective peroxisome proliferator-
activated receptor alpha modulators (SPPARMα) in the metabolic syndrome: is Pemafibrate
light at the end of the tunnel? Curr Atheroscler Rep. 2021;23(1):3.
84 E. Alexander et al.
91. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P,
Koskinen P, Manninen V, et al. Helsinki heart study: primary-prevention trial with gemfibro-
zil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and
incidence of coronary heart disease. N Engl J Med. 1987;317(20):1237–45.
92. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares
E, Schaefer EJ, Schectman G, et al. Gemfibrozil for the secondary prevention of coro-
nary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans
affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med.
1999;341(6):410–8.
93. Group BS. Secondary prevention by raising HDL cholesterol and reducing triglycerides in
patients with coronary artery disease. Circulation. 2000;102(1):21–7.
94. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T,
Glasziou P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795
people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet.
2005;366(9500):1849–61.
95. Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse
JB, Gerstein HC, Probstfield J, et al. Effects of combination lipid therapy in type 2 diabetes
mellitus. N Engl J Med. 2010;362(17):1563–74.
96. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara
JR, Kashyap ML, Hershman JM, Wexler LF, et al. Relation of gemfibrozil treatment
and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.
JAMA. 2001;285(12):1585–91.
97. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J
Med. 2010;363(7):692–4. author reply 4-5.
98. Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-Gonzalez I, Briel M. Fibrates for pri-
mary prevention of cardiovascular disease events. Cochrane Database Systemat Rev.
2016;11:Cd009753.
99. Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular
disease and stroke. Cochrane Database Systemat Rev. 2015;10:Cd009580.
100. Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, Jenkins AJ, O'Connell
RL, Whiting MJ, Glasziou PP, et al. Effects of fenofibrate on renal function in patients with
type 2 diabetes mellitus: the Fenofibrate intervention and event lowering in diabetes (FIELD)
study. Diabetologia. 2011;54(2):280–90.
101. Cersosimo E, Miles JM. Hormonal, metabolic and hemodynamic adaptations to glycosuria in
type 2 diabetes patients treated with sodium-glucose co-transporter inhibitors. Curr Diabetes
Rev. 2019;15(4):314–27.
102. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG,
Geraci E, Levantesi G, Maggioni AP, et al. Early protection against sudden death by n-3
polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results
of the Gruppo Italiano per lo studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-
Prevenzione. Circulation. 2002;105(16):1897–903.
103. Leaf A. On the reanalysis of the GISSI-Prevenzione. Circulation. 2002;105(16):1874–5.
104. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki
J, Hishida H, Itakura H, et al. Effects of eicosapentaenoic acid on major coronary events in
hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
Lancet. 2007;369(9567):1090–8.
105. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vita-
mins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled
trial. BMJ. 2010;341:c6273.
106. Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, Maggiono AP, Probstfield J,
Ramachandran A, Riddle MC, et al. N-3 fatty acids and cardiovascular outcomes in patients
with dysglycemia. N Engl J Med. 2012;367(4):309–18.
3 Precision Medicine for Diabetes and Dyslipidemia 85
107. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3
fatty acid supplementation and risk of major cardiovascular disease events: a systematic
review and meta-analysis. JAMA. 2012;308(10):1024–33.
108. Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased cardiovascular risk
in Hypertriglyceridemic patients with statin-controlled LDL cholesterol. J Clin Endocrinol
Metab. 2018;103(8):3019–27.
109. Navar AM. The evolving story of triglycerides and coronary heart disease risk.
JAMA. 2019;321(4):347–9.
110. Nelson AJ, Navar AM, Mulder H, Wojdyla D, Philip S, Granowitz C, Peterson ED, Pagidipati
NJ. Association between triglycerides and residual cardiovascular risk in patients with type
2 diabetes mellitus and established cardiovascular disease (From the Bypass Angioplasty
Revascularization Investigation 2 Diabetes [BARI 2D] Trial). Am J Cardiol. 2020;132:36–43.
111. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano
RA, Jiao L, Granowitz C, et al. Cardiovascular risk reduction with Icosapent ethyl for hyper-
triglyceridemia. N Engl J Med. 2019;380(1):11–22.
112. Bhatt DL, Miller M, Brinton EA, Jacobson TA, Steg PG, Ketchum SB, Doyle RT Jr, Juliano
RA, Jiao L, Granowitz C, et al. REDUCE-IT USA: results from the 3146 patients randomized
in the United States. Circulation. 2020;141(5):367–75.
113. Bernasconi AA, Wiest MM, Lavie CJ, Milani RV, Laukkanen JA. Effect of Omega-3 dosage
on cardiovascular outcomes: an updated meta-analysis and meta-regression of interventional
trials. Mayo Clin Proc. 2021;96(2):304–13.
114. Darwesh AM, Sosnowski DK, Lee TY, Keshavarz-Bahaghighat H, Seubert JM. Insights into
the cardioprotective properties of n-3 PUFAs against ischemic heart disease via modulation
of the innate immune system. Chemico-Biological Interactions. 2019;308:20–44.
115. Griffin MD, Sanders TA, Davies IG, Morgan LM, Millward DJ, Lewis F, Slaughter S, Cooper
JA, Miller GJ, Griffin BA. Effects of altering the ratio of dietary n-6 to n-3 fatty acids on insu-
lin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women
aged 45-70 y: the OPTILIP study. Am J Clin Nutr. 2006;84(6):1290–8.
116. Tani S, Nagao K, Matsumoto M, Hirayama A. Highly purified eicosapentaenoic acid may
increase low-density lipoprotein particle size by improving triglyceride metabolism in patients
with hypertriglyceridemia. Circulat J Off J Japanese Circulat Soc. 2013;77(9):2349–57.
117. Mori TA, Burke V, Puddey IB, Watts GF, O'Neal DN, Best JD, Beilin LJ. Purified eicosa-
pentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipopro-
teins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr.
2000;71(5):1085–94.
118. Tani S, Matsuo R, Yagi T, Matsumoto N. Administration of eicosapentaenoic acid may alter
high-density lipoprotein heterogeneity in statin-treated patients with stable coronary artery
disease: a 6-month randomized trial. J Cardiol. 2020;75(3):282–8.
119. McGovern TH. Cows, harp seals and churchbells: adaption and extinction in Norse Greenland.
Human Ecol. 1980;8:245–75.
120. Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in
Eskimos. Lancet. 1979;2(8140):433–5.
121. Sheikh O, Vande Hei AG, Battisha A, Hammad T, Pham S, Chilton R. Cardiovascular, elec-
trophysiologic, and hematologic effects of omega-3 fatty acids beyond reducing hypertri-
glyceridemia: as it pertains to the recently published REDUCE-IT trial. Cardiovasc Diabetol.
2019;18(1):84.
122. Holm E, Osooli M. Cardiovascular disease-related hospitalization and mortality among per-
sons with von Willebrand disease: a nationwide register study in Sweden. 2019;25(1):109–15.
123. Jeansen S, Witkamp RF, Garthoff JA, van Helvoort A, Calder PC. Fish oil LC-PUFAs do
not affect blood coagulation parameters and bleeding manifestations: analysis of 8 clini-
cal studies with selected patient groups on omega-3-enriched medical nutrition. Clin Nutr.
2018;37(3):948–57.
86 E. Alexander et al.
comes in patients with type 2 diabetes and cardiovascular disease (harmony outcomes): a
double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519–29.
143. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J,
Riesmeyer JS, Riddle MC, Rydén L, et al. Dulaglutide and cardiovascular outcomes in
type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet.
2019;394(10193):121–30.
144. Nikolic D, Giglio RV, Rizvi AA, Patti AM, Montalto G, Maranta F, Cianflone D, Stoian
AP, Rizzo M. Liraglutide reduces carotid intima-media thickness by reducing small dense
low-density lipoproteins in a real-world setting of patients with type 2 diabetes: a novel anti-
Atherogenic effect. Diabetes Therapy: Research, Treatment and Education of Diabetes and
Related Disorders. 2021;12(1):261–74.
145. Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Wintle ME, Maggs
DG. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic bio-
markers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin.
2008;24(1):275–86.
146. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L. Exenatide
once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label,
non-inferiority study. Lancet. 2008;372(9645):1240–50.
147. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, Hale PM, Zdravkovic M,
Blonde L. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in
combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4
met+TZD). Diabetes Care. 2009;32(7):1224–30.
148. Blonde L, Pencek R, MacConell L. Association among weight change, glycemic control, and
markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with
type 2 diabetes. Cardiovasc Diabetol. 2015;14(12).
149. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen
OK, Lingvay I, Mosenzon O, Pedersen SD, et al. Oral Semaglutide and cardiovascular out-
comes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841–51.
150. Betteridge DJ. Effects of pioglitazone on lipid and lipoprotein metabolism. Diabetes Obes
Metab. 2007;9(5):640–7.
151. Deeg MA, Buse JB, Goldberg RB, Kendall DM, Zagar AJ, Jacober SJ, Khan MA, Perez AT,
Tan MH. Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle
concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes Care.
2007;30(10):2458–64.
152. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD,
Lovejoy AM, Peduzzi PN, Conwit R, et al. Pioglitazone after ischemic stroke or transient
ischemic attack. N Engl J Med. 2016;374(14):1321–31.
153. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK,
Skene AM, Tan MH, Lefebvre PJ, Murray GD, et al. Secondary prevention of macrovas-
cular events in patients with type 2 diabetes in the PROactive study (PROspective pio-
glitAzone clinical trial in macroVascular events): a randomised controlled trial. Lancet.
2005;366(9493):1279–89.
Chapter 4
Imaging in Precision Medicine for Diabetes
diabetes-related sequelae, which could help pave the road for precise, targeted pre-
vention and treatment [3, 5–8].
Precision medicine in diabetes [5, 9], which we prefer to term precision diabetol-
ogy, holds promise to improve prevention and treatment of this multifactorial dis-
ease on various levels. Imaging tools can help discriminate subgroups of patients
with specific structural, functional, or molecular abnormalities, who are otherwise
classified under the broad umbrella of type 1 diabetes or type 2 diabetes, and pro-
vide the basis for optimal preventive or therapeutic measures [8, 10].
Questions remain regarding the clinical utility of these data and how best to incorpo-
rate them into routine diabetes care [11, 12]. In addition to advances in clinical decision-
making tools, there is also a need to integrate other types of “omics” ((epi)genomics,
metabolomics, lipidomics, proteomics, or transcriptomics) but also diverse imaging
techniques to provide a full landscape of the correlations between disease pathways,
phenotypes, and treatment response. To this end, it is required to provide an optimized
framework encompassing established -omics and biomarkers, together with imaging
and spectroscopic data, allowing for in vivo metabolic flux analysis (fluxomics) and to
incorporate this data into clinical records for evaluation of validity, efficacy, and cost-
effectiveness [13]. In addition, more research efforts are required to build the clinical
evidence and roadmap for achieving consensus and developing guidelines [14] in the
pursuit of precision medicine for optimal disease management outcome.
This chapter will focus on noninvasive in vivo imaging tools for assessing tissue-
specific abnormalities and alterations of fluxomics in the context of diabetes melli-
tus and its role for its targeted prevention, diagnosis, and treatment.
Superficial
subcutaneous
Subcutaneous adipose tissue
adipose tissue Deep
subcutaneous
adipose tissue
Internal Intraabdomino
Pancreatic
adipose tissue -pelvic
Non-visceral Skeletal
Renal
adipose tissue muscle
Fig. 4.1 Adipose tissue compartments. Proposed classification of adipose tissue compartments
based on imaging. (Adapted from [17])
a b
Fig. 4.2 Subcutaneous adipose tissue compartments. Subcutaneous adipose tissue compartments
(deep and superficial subcutaneous adipose tissue, DSAT and SSAT) in volunteers with normal
glucose tolerance (a) and with type 2 diabetes (b). (Modified from [21])
When obesity develops, triglycerides are primarily stored in adipose tissue, but with
increasing adipose tissue dysfunction, triglycerides, fatty acids, and glycerol are
also distributed to non-adipose tissues such as skeletal muscle cells, hepatocytes, or
cardiomyocytes, where triglycerides accumulate within small lipid droplets in the
cytoplasm. This phenomenon is known as “ectopic” fat storage. The lipid accumu-
lation in muscle tissue could further refine the precise characterization of humans
with diabetes.
more reliable IMCL measures [39–41].The origin of the separation of the IMCL
and EMCL signals in the 1H-MR spectrum is a magnetic susceptibility effect, which
results in the separation of the IMCL and EMCL resonances of up to 0.2 ppm [41,
42]. The magnitude of this separation depends on the relative orientation of the
adipose tissue layers of EMCL to the main magnetic field, and therefore, maximal
separation (and therefore most reliable quantification) is reached in muscles where
the muscle fibers run parallel to the leg and when the leg is placed parallel to the
main magnetic field [41]. Therefore, IMCL content is often investigated in the tibi-
alis anterior and the soleus muscle where fiber orientation is favorable. In line, the
quantification in the vastuslateralis muscle is more challenging, due to the variable
direction of muscle fibers, which results in a lesser separation of the IMCL and
EMCL resonances. As pointed out above, the EMCL signal originates from adipose
tissue that is “marbelling” skeletal muscle. Of note, in contrast to IMCL, the quan-
tification of this EMCL signal by MR spectroscopy is not realistic, as the adipose
tissue signal is highly variable, depending on the placement of the region of interest
(voxel). In order to quantify such adipose tissue that infiltrates muscle, MRI imag-
ing or CT is better suitable. Based on images with good contrast between adipose
tissue and muscle tissue, segmentation of the images can be performed, and the
volume of adipose tissue (EMCL) can be determined. Therefore, while EMCL can
be quantified by imaging methods (MRI and CT) based on segmentation, this is not
valid for IMCL determination, which depends on MR spectroscopy, as on an MRI
or CT image, the partial volume effect prevents the quantification of IMCL without
EMCL contamination [43].
Monitoring specific metabolites can make it possible to draw conclusions about the
rate-limiting steps in series of reactions. To this end, 31P MRS is commonly used.
An elegant example of how this principle was used is the classical studies that show
that insulin resistance in skeletal muscle results in lower concentrations of glucose-6
phosphate during insulin-stimulated glucose disposal [39, 49]. These results indi-
cate that glucose transport and phosphorylation rather than the subsequent glycogen
synthesis is responsible for muscle insulin resistance [50]. Thus, real-time monitor-
ing of intracellular metabolites under standardized situations allows for gaining
mechanistic insights and may in the future help identify specific abnormalities in
(pre)diabetes subgroups [8].
Recently, 1H-MRS was shown to be able to quantify acetylcarnitine concentra-
tions directly in vivo in skeletal muscle and to be negatively correlated with insulin
sensitivity [51]. A recent study in people with type 2 diabetes shows that carnitine
supplementation can increase acetylcarnitine concentrations in muscle and at the
same time improve insulin sensitivity. While these results are promising, the bio-
logical mechanisms involved and the exact interpretation of acetylcarnitine need to
be investigated in more detail in future studies, and it will need to investigate which
subgroups of patients can profit most from carnitine supplementation.
Metabolic disorders, such as obesity and diabetes mellitus, also tightly associate
with increased risk and accelerated progression of non-alcoholic fatty liver disease
(NAFLD), which comprises various pathologies ranging from simple fatty liver
(hepatic steatosis or non-alcoholic fatty liver disease, NAFL) over non-alcoholic
steatohepatitis (NASH) to fibrosis and cirrhosis [1, 52, 53]. NAFL is one important
example of ectopic triglyceride accumulation and coexists with insulin resistance,
and associates with adipose tissue dysfunction, defined by local inflammation,
excessive lipolysis, and altered adipocytokine secretion [1, 52, 53]. Moreover, obese
individuals feature altered adaptation of hepatic mitochondria to higher lipid flux
[54] with subsequent intracellular accumulation of diacylglycerols and/or cerami-
des [55, 56], which may underlie the association between hepatocellular lipids
(HCL)and insulin resistance [1, 57, 58].
There is strong evidence that NAFL is associated with insulin resistance and an
important risk factor for diabetes mellitus. In fact, individuals with NAFL were as
96 O. P. Zaharia et al.
insulin resistant as age- and BMI-matched patients with type 2 diabetes [59]. Next
to an increased risk to develop diabetes, NAFL also predisposes to the progression
of liver disease, specifically to inflammation and fibrosis. To this end, early detec-
tion of increased liver fat content is crucial, and here, MR spectroscopy methods can
be used, but also MRI imaging is a valuable tool, as in the liver, there are no adipose
tissue infiltrations and all fat signal can be interpreted as signal from lipid droplets
in hepatocytes (= truly ectopic intracellular fat).
Especially fat- and water-selective MRI methods are currently widely applied to
determine hepatic fat content. Compared to ultrasound sonography, which detects
hyperintense liver tissue as NAFL only when steatosis is severe (above a liver fat
content of about 10%), MRI is much more sensitive and can be useful in detecting
an even slightly increased liver fat content. When compared to MR spectroscopy,
MRI has the advantage of being fast and easy in analysis (vendors provide recon-
structed maps of proton density fat fraction (PDFF) based on the water and fat MRI
images) and to cover the whole liver, while MRS is restricted to a volume of interest
of a few cm3. Thus, MRI is superior to single-voxel MRS for detecting inhomoge-
neous fat accumulation within the liver (focal steatosis). The easy and noninvasive
screening for NAFL is important to identify individuals with NAFL and monitor
them more stringently for progression to either diabetes or NASH.
MR spectroscopy has the advantage that next to only fat content, more informa-
tion can be deduced, and, for example, the fatty acid composition in terms of rela-
tive percentage of saturated fatty acids (SFA), mono-unsaturated FA (MUFA), and
poly-unsaturated FA(PUFA) can be determined. It was recently shown that the SFA
content is a marker for de novo lipogenesis (DNL) [60], and therefore, people with
NAFL and high SFA may be treated in order to specifically decrease DNL, for
example, by dietary means (decreasing fructose intake and lowering the glycemic
index of the diet). Therefore, the determination of fatty acid composition by means
of MRS may add to a more stratified NAFL management.
Progression of NAFLD
An advantage of determining liver fat with MRI or MRS is that it can be combined
with noninvasive measurements that give indications of progression of NAFL, for
example, magnetic resonance elastography (MRE) regarding the development of
fibrosis. MRE yields information about the stiffness of tissue by assessing the prop-
agation of mechanical waves through the tissue with a special MRI technique. MRE
is mainly being used clinically for the assessment of patients with chronic liver
diseases and is emerging as a safe, reliable, and noninvasive alternative to liver
biopsy for staging hepatic fibrosis [61] (Fig. 4.3).
It has been shown that humans with diabetes can be allocated to specific clusters
that present differences in the presence and severity of NAFLD [3, 62]. Specifically,
patients with severe insulin-resistant diabetes present with high HCL and are more
4 Imaging in Precision Medicine for Diabetes 97
a b c
d e f
Fig. 4.3 Magnetic resonance elastography of the liver. Images (a–c) show physiological liver
parameters, while images (d–f) show manifestations of NAFLD. Panels (a and d) show magnitude
image, panels (b and e) show wave image, and panels (c and f) show liver stiffness
likely to exhibit NAFLD progression during the early course of diabetes. Genetic
variants may further contribute to the susceptibility toward NAFLD progression for
certain subgroups [62]. Therefore, it is of increased relevance to identify early
changes in HCL and liver fibrosis and initiate early treatment in patients with diabe-
tes that are at high risk for NAFLD.
Mitochondrial Function
Mitochondrial function can be also investigated by quantifying the flux through the
TCA cycle, by applying 13C MR spectroscopy in the muscle and liver, in combina-
tion with infusion of 13C-labelled acetate. Using these measurements, it was shown
that mitochondrial flux was decreased in insulin resistance [32, 63]. Subsequent
studies revealed that increased HCL relates to upregulated mitochondrial respira-
tion and increased acetyl-CoA flux [64], whereas in vivo 13C MRS found no relevant
alterations in rates of hepatic mitochondrial oxidation and pyruvate cycling at least
in non-obese NAFLD [65]. The differences between these studies may result from
the quality of metabolic control and duration of obesity or diabetes.
In the liver, type 2 diabetes mellitus was associated with lower absolute concen-
trations of ATP, as compared to age- and BMI-matched groups [66–68]. Future
research needs to investigate how absolute ATP concentrations are related to mito-
chondrial function in the liver.
98 O. P. Zaharia et al.
The principle of using a 13C-labelled substrate and following the signal by MRS into
other tissues or monitoring the conversion into other metabolites can also be used in
a broader sense. A feasibility study demonstrated that it is possible to “follow”
13
C-labelled fatty acids that were consumed with a meal to the liver by determining
the 13C enrichment of the hepatic lipid signal over time [51]. Refinement of the
technical aspects of such measurements paves the way to a broader application. This
has the potential to quantify the importance of the various pathways that contribute
to the development of fatty liver in individuals in order to cluster and treat them
accordingly.
The challenge of the relatively low sensitivity of the MR signal can be addressed
by hyperpolarizing metabolites and injecting them as tracers. Hyperpolarization
increases the MR visibility manyfold for a short time. Immediately after injection,
the metabolite can be detected and can be followed while it is converted to other
metabolites. Thereby, metabolic conversions can be visualized, and fluxes can be
determined. A caveat of these experiments is that plasma concentrations of the
hyperpolarized metabolite typically change quite strongly, which will also influence
kinetics, rendering the experiment not completely physiological. However, experi-
ments yielded certainly valuable information. For example, in this way, it was
shown that pyruvate is converted to acetylcarnitine in the heart, thereby buffering
acetyl-CoA concentrations [69].
Cardiac imaging refers to noninvasive imaging of the heart using ultrasound, MRI,
CT, or imaging with PET or SPECT including myocardial perfusion imaging.
Transthoracic echocardiography uses ultrasonic waves for continuous heart
chamber and blood movement visualization. It is the most commonly used imaging
tool for diagnosing heart disease, as it allows noninvasive visualization of the heart
and the blood flow through the heart, using a technique known as Doppler.
Transesophageal echocardiography uses a specialized probe and is only indicated
for specific examinations.
MRI is able to measure the size, shape, function, and tissue characteristics of the
heart. It is more reproducible than echocardiography with lower inter-observer vari-
ability. Additional benefits from cardiac MRI include the ability to detect fibrosis
using late gadolinium enhancement, and MRS techniques may identify myocellular
lipid infiltrations. Disadvantages of MRI include lengthy protocols and the potential
for claustrophobia.
Certain subgroups of patients with diabetes have exhibited nominally increased
cardiac risk [7], specifically for major adverse cardiac events [70]. A targeted
4 Imaging in Precision Medicine for Diabetes 99
prevention and diagnosis may be therefore of high clinical relevance in the context
of precision diabetology.
Recent experimental data suggest that adiposity, next to elevating the well-known
cardiovascular health risks such as increasing blood pressure and increasing the risk
for plaque formation, can also directly affect the heart by promoting ectopic deposi-
tion of triglyceride, a process known as myocardial steatosis. Using proton mag-
netic resonance spectroscopy (1H MRS) as an in vivo tool to measure myocardial
lipid content constitutes a reproducible technique for the measurement of myocar-
dial triglyceride levels [42]. Increased myocardial triglyceride content was accom-
panied by elevated left ventricular mass and suppressed septal wall thickening as
measured by cardiac imaging [42] (Fig. 4.4). However, the importance of cardiac
steatosis for clinically diminishment in cardiac function remains to be elucidated.
This holds promise especially for subgroups of persons with diabetes at excessive
cardiovascular risk [70].
a b
Fig. 4.4 MRS quantification of cardiac lipids. Image (a) shows the placement of the voxel on the
long axis of the interventricular septum (LA). Image (b) shows the short axis (SA). (Red Box,
Voxel; White Box, Voxel position for fat; Orange Box, Shim volume)
100 O. P. Zaharia et al.
a b
Fig. 4.5 Flow-mediated and nitroglycerin-mediated dilation of the brachial artery. Image (a)
shows a baseline image of the brachial artery, Image (b) shows the arterial section after 5 minutes
of compression, and Image (c) shows the brachial artery after administration of nitroglycerin spray
Radiotracers could potentially be used to target beta cell mass in relation to beta cell
function. This assessment is essential for further elucidating the pathophysiology of
diabetes in order to monitor disease progression. PET/SPECT imaging biomarkers
are under development that have the potential to change the way we look at the
pathophysiology of islet function in the context of diabetes. Among these, radiola-
belled exendin-4 has the highest sensitivity and specificity for beta cells. The in vivo
specificity of [18F]FP-dihydrotetrabenazine for beta cells suggests this tracer can
serve as a good biomarker of human beta cell mass. [11C]5-hydroxytryptamine(HTP)
may reflect total endocrine rather than beta cell mass. The combination of [11C]5-
HTP and radiolabeled exendin-4 imaging may increase specificity for beta cell
function and mass [91].
The role of the amount of pancreatic fat and its association with beta cell func-
tion in humans also remains controversially discussed. 1H-MRS and MRI tech-
niques are used to noninvasively quantify pancreatic fat compartments.
Pancreatic Steatosis
Also in the pancreas, lipids can accumulate, and potentially lipotoxic mechanisms
were suggested inducing apoptosis and hampering insulin secretion. While accumu-
lation of fat droplets in the pancreatic cells is indeed possible, if pancreatic fat is
determined by in vivo imaging techniques (MRI or MRS-based), the fat content
likely reflects a mixture of signal from parenchymal lipid droplets and from adipo-
cytes either from single, infiltrated adipocyte or from partial volume effects from
surrounding adipose tissue. The latter are minimized by the use of erosion filters
[92], but cannot be excluded completely. Fatty infiltrations are generally more
prominent when total visceral fat is increased and can be a potential confounder.
Nevertheless, some interesting correlations of such pancreatic fat with functional
outcomes, such as insulin secretion and glucose intolerance [93–95], were reported
in some but not all [96] studies. Potentially, the determination of pancreatic fat may
convey a tool to further characterize diabetic patients and cluster patients with a
similar phenotype; however, the specific added value of pancreatic fat requires fur-
ther study.
Similar to VAT, peripancreatic, interlobular, and intralobular adipose tissue may
alter beta cell function through the release of adipocytokines. On the other hand,
lipid accumulation in beta cells could result in parenchymal or intracellular pancre-
atic steatosis, activating cellular mechanisms in analogy to hepatic steatosis.
Distinguishing between these compartments in vivo could therefore aid in the accu-
rate assessment of the specific effects of individual fat depots on beta cell function
and lead to a more precise characterization of diabetes subphenotypes. This may be
of interest specifically for insulin-deficient diabetes subgroups.
4 Imaging in Precision Medicine for Diabetes 103
Patients with severe insulin-resistant diabetes have been shown to present with
advanced diabetic neuropathy, even at the time of diagnosis [3, 7]. Noninvasive
quantitative measurement of fibrosis in chronic kidney disease (CKD) would be
desirable diagnostically and therapeutically especially for patients at risk. In that
respect, MRE may also be used to monitor progression of kidney fibrosis [97].
Since decreased kidney perfusion decreases tissue stiffness, combined three-
dimensional MRE shear stiffness measurements with MR arterial spin labeling kid-
ney blood flow rates represent a new tool to evaluate fibrosis in diabetic nephropathy
[97]. MRI with arterial spin labeling blood flow rates can noninvasively measure
decreasing kidney cortical tissue perfusion and correlate with increasing fibrosis.
Differing from the liver, MRE shear stiffness surprisingly decreases with worsening
CKD, likely related to decreased tissue turgor from lower blood flow rates [97].
Concluding Remarks
References
1. Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature. 2019;576:51–60.
2. Faerch K, Hulman A, Solomon TP. Heterogeneity of pre-diabetes and type 2 diabetes:
implications for prediction, prevention and treatment responsiveness. Curr Diabetes Rev.
2016;12:30–41.
4 Imaging in Precision Medicine for Diabetes 105
19. Smith SR, Lovejoy JC, Greenway F, Ryan D, De Jonge L, De la Bretonne J. Contributions
of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose
tissue to the metabolic complications of obesity. Metab Clin Exp. 2001;50:425–35.
20. Van der Kooy K, Seidell JC. Techniques for the measurement of visceral fat: a practical
guide. Int J Obes. 1993;17:187.
21. Bódis K, Jelenik T, Lundbom J, Markgraf DF, Strom A, Zaharia O-P, Karusheva Y, Burkart V,
Müssig K, Kupriyanova Y, Ouni M, Wolkersdorfer M, Hwang J-H, Ziegler D, Schürmann A,
Roden M, Szendroedi J, Group GDSs. Expansion and impaired mitochondrial efficiency of
deep subcutaneous adipose tissue in recent-onset type 2 diabetes. J Clin Endocrinol Metabol.
2019:dgz267.
22. Kelley DE, Thaete FL, Troost F, Huwe T, Goodpaster BH. Subdivisions of subcuta-
neous abdominal adipose tissue and insulin resistance. Am J Phys Endocrinol Metab.
2000;278:E941–8.
23. Golan R, Shelef I, Rudich A, Gepner Y, Shemesh E, Chassidim Y, Harman-Boehm I, Henkin
Y, Schwarzfuchs D, Ben Avraham S, Witkow S, Liberty IF, Tangi-Rosental O, Sarusi B,
Stampfer MJ, Shai I. Abdominal superficial subcutaneous fat: a putative distinct protective
fat subdepot in type 2 diabetes. Diabetes Care. 2012;35:640–7.
24. Lundbom J, Hakkarainen A, Lundbom N, Taskinen MR. Deep subcutaneous adipose tissue is
more saturated than superficial subcutaneous adipose tissue. Int J Obes. 2013;37:620–2.
25. Zou X, Zhou X, Zhu Z, Ji L. Novel subgroups of patients with adult-onset diabetes in Chinese
and US populations. Lancet Diabetes Endocrinol. 2019;7:9–11.
26. Ginde SR, Geliebter A, Rubiano F, Silva AM, Wang J, Heshka S, Heymsfield SB. Air
displacement plethysmography: validation in overweight and obese subjects. Obes Res.
2005;13:1232–7.
27. Bazzocchi A, Ponti F, Albisinni U, Battista G, Guglielmi G. DXA: technical aspects and
application. Eur J Radiol. 2016;85:1481–92.
28. Elbers J, Haumann G, Asscheman H, Seidell J, Gooren LJ. Reproducibility of fat area mea-
surements in young, non-obese subjects by computerized analysis of magnetic resonance
images. Int J Obes. 1997;21:1121–9.
29. Seidell JC, Bakker C, van der Kooy K. Imaging techniques for measuring adipose-tissue
distribution--a comparison between computed tomography and 1.5-T magnetic resonance.
Am J Clin Nutr. 1990;51:953–7.
30. Ross R, Léger L, Morris D, de Guise J, Guardo R. Quantification of adipose tissue by MRI:
relationship with anthropometric variables. J Appl Physiol (1985). 1992;72:787–95.
31. Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick
F, Claussen CD, Häring HU. Association of increased intramyocellular lipid content
with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes.
1999;48:1113–9.
32. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW,
Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance.
Science (New York, NY). 2003;300:1140–2.
33. Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin
resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab.
2001;86:5755–61.
34. van Loon LJ, Goodpaster BH. Increased intramuscular lipid storage in the insulin-resistant
and endurance-trained state. Pflugers Archiv Europ J Physiol. 2006;451:606–16.
35. Thamer C, Machann J, Bachmann O, Haap M, Dahl D, Wietek B, Tschritter O, Niess A, Brechtel
K, Fritsche A, Claussen C, Jacob S, Schick F, Häring HU, Stumvoll M. Intramyocellular
lipids: anthropometric determinants and relationships with maximal aerobic capacity and
insulin sensitivity. J Clin Endocrinol Metab. 2003;88:1785–91.
36. Phillips DI, Caddy S, Ilic V, Fielding BA, Frayn KN, Borthwick AC, Taylor R. Intramuscular
triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic sub-
jects. Metabolism. 1996;45:947–50.
4 Imaging in Precision Medicine for Diabetes 107
69. Schroeder MA, Atherton HJ, Dodd MS, Lee P, Cochlin LE, Radda GK, Clarke K, Tyler
DJ. The cycling of acetyl-coenzyme a through acetylcarnitine buffers cardiac substrate sup-
ply: a hyperpolarized 13C magnetic resonance study. Circ Cardiovasc Imaging. 2012;5:201–9.
70. Kahkoska AR, Geybels MS, Klein KR, Kreiner FF, Marx N, Nauck MA, Pratley RE, Wolthers
BO, Buse JB. Validation of distinct type 2 diabetes clusters and their association with dia-
betes complications in the DEVOTE, LEADER and SUSTAIN-6 cardiovascular outcomes
trials. Diabetes Obes Metab. 2020;22:1537–47.
71. Schrauwen-Hinderling VB, Kooi ME, Schrauwen P. Mitochondrial function and diabe-
tes: consequences for skeletal and cardiac muscle metabolism. Antioxid Redox Signal.
2016;24:39–51.
72. Rijzewijk LJ, Jonker JT, van der Meer RW, Lubberink M, de Jong HW, Romijn JA, Bax JJ, de
Roos A, Heine RJ, Twisk JW, Windhorst AD, Lammertsma AA, Smit JW, Diamant M, Lamb
HJ. Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am
Coll Cardiol. 2010;56:225–33.
73. Scheuermann-Freestone M, Clarke K. Abnormal cardiac high-energy phosphate metabolism
in a patient with type 2 diabetes mellitus. J Cardiometab Syndr. 2006;1:366–8.
74. Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P,
Radda GK, Neubauer S, Clarke K. Abnormal cardiac and skeletal muscle energy metabolism
in patients with type 2 diabetes. Circulation. 2003;107:3040–6.
75. Rahman A, Moizuddin M, Ahmad M, Salim M. Vasculopathy in patients with diabetic foot
using Doppler ultrasound. Pak J Med Sci. 2009;25:428–33.
76. Yoshida M, Mita T, Yamamoto R, Shimizu T, Ikeda F, Ohmura C, Kanazawa A, Hirose T,
Kawamori R, Watada H. Combination of the Framingham risk score and carotid intima-
media thickness improves the prediction of cardiovascular events in patients with type 2
diabetes. Diabetes Care. 2012;35:178–80.
77. Katakami N, Kaneto H, Shimomura I. Carotid ultrasonography: a potent tool for better
clinical practice in diagnosis of atherosclerosis in diabetic patients. J Diabetes Investig.
2014;5:3–13.
78. Esposito K, Giugliano D, Nappo F, Marfella R. Regression of carotid atherosclerosis by con-
trol of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation. 2004;110:214–9.
79. Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, Kosugi K,
Hori M. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid
intima-media thickness in subjects with type 2 diabetes. Diabetologia. 2004;47:1906–13.
80. Davidson M, Meyer PM, Haffner S, Feinstein S, D'Agostino R Sr, Kondos GT, Perez A,
Chen Z, Mazzone T. Increased high-density lipoprotein cholesterol predicts the pioglitazone-
mediated reduction of carotid intima-media thickness progression in patients with type 2
diabetes mellitus. Circulation. 2008;117:2123–30.
81. Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM,
Luscher TF, Shechter M, Taddei S, Vita JA, Lerman A. The assessment of endothelial func-
tion: from research into clinical practice. Circulation. 2012;126:753–67.
82. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial dysfunction as a target for
prevention of cardiovascular disease. Diabetes Care. 2009;32(Suppl 2):S314–21.
83. De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dys-
function in diabetes. Br J Pharmacol. 2000;130:963–74.
84. Kawano N, Emoto M, Mori K, Yamazaki Y, Urata H, Tsuchikura S, Motoyama K, Morioka
T, Fukumoto S, Shoji T, Koyama H, Okuno Y, Nishizawa Y, Inaba M. Association of endo-
thelial and vascular smooth muscle dysfunction with cardiovascular risk factors, vascular
complications, and subclinical carotid atherosclerosis in type 2 diabetic patients. J Atheroscler
Thromb. 2012;19:276–84.
85. Englund EK, Langham MC. Quantitative and dynamic MRI measures of peripheral vascular
function. Front Physiol. 2020;11:120.
110 O. P. Zaharia et al.
86. Medarova Z, Greiner DL, Ifediba M, Dai G, Bolotin E, Castillo G, Bogdanov A, Kumar M,
Moore A. Imaging the pancreatic vasculature in diabetes models. Diabetes Metab Res Rev.
2011;27:767–72.
87. De Paepe M, Corriveau M, Tannous W, Seemayer T, Colle E. Increased vascular permeability
in pancreas of diabetic rats: detection with high resolution protein A-gold cytochemistry.
Diabetologia. 1992;35:1118–24.
88. McAteer MA, Sibson NR, von Zur MC, Schneider JE, Lowe AS, Warrick N, Channon KM,
Anthony DC, Choudhury RP. In vivo magnetic resonance imaging of acute brain inflamma-
tion using microparticles of iron oxide. Nat Med. 2007;13:1253–8.
89. Morishige K, Kacher DF, Libby P, Josephson L, Ganz P, Weissleder R, Aikawa M. High-
resolution magnetic resonance imaging enhanced with superparamagnetic nanoparticles
measures macrophage burden in atherosclerosis. Circulation. 2010;122:1707–15.
90. Flögel U, Ding Z, Hardung H, Jander S, Reichmann G, Jacoby C, Schubert R, Schrader J. In
vivo monitoring of inflammation after cardiac and cerebral ischemia by 19F magnetic reso-
nance imaging. Circulation. 2008;118:140.
91. Eriksson O, Laughlin M, Brom M, Nuutila P, Roden M, Hwa A, Bonadonna R, Gotthardt
M. In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommen-
dations for development and use. Diabetologia. 2016;59:1340–9.
92. Al-Mrabeh A, Hollingsworth KG, Steven S, Tiniakos D, Taylor R. Quantification of intrapan-
creatic fat in type 2 diabetes by MRI. PLoS One. 2017;12:e0174660.
93. Heni M, Machann J, Staiger H, Schwenzer NF, Peter A, Schick F, Claussen CD, Stefan N,
Häring HU, Fritsche A. Pancreatic fat is negatively associated with insulin secretion in indi-
viduals with impaired fasting glucose and/or impaired glucose tolerance: a nuclear magnetic
resonance study. Diabetes Metab Res Rev. 2010;26:200–5.
94. Tushuizen ME, Bunck MC, Pouwels PJ, Bontemps S, van Waesberghe JH, Schindhelm RK,
Mari A, Heine RJ, Diamant M. Pancreatic fat content and beta-cell function in men with and
without type 2 diabetes. Diabetes Care. 2007;30:2916–21.
95. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type
2 diabetes: normalisation of beta cell function in association with decreased pancreas and
liver triacylglycerol. Diabetologia. 2011;54:2506–14.
96. Begovatz P, Koliaki C, Weber K, Strassburger K, Nowotny B, Nowotny P, Müssig K, Bunke J,
Pacini G, Szendrödi J, Roden M. Pancreatic adipose tissue infiltration, parenchymal steatosis
and beta cell function in humans. Diabetologia. 2015;58:1646–55.
97. Brown RS, Sun MRM, Stillman IE, Russell TL, Rosas SE, Wei JL. The utility of magnetic
resonance imaging for noninvasive evaluation of diabetic nephropathy. Nephrology Dialysis
Transplantation. 2020;35:970–8.
98. Sun Z, Yang D, Tang Z, Ng DS, Cheung CY. Optical coherence tomography angiography in
diabetic retinopathy: an updated review. Eye. 2020.
99. Salz DA, Witkin AJ. Imaging in diabetic retinopathy. Middle East Afr J Ophthalmol.
2015;22:145–50.
100. Wessel MM, Nair N, Aaker GD, Ehrlich JR, D'Amico DJ, Kiss S. Peripheral retinal isch-
aemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic
macular oedema. Br J Ophthalmol. 2012;96:694–8.
101. Muqit MM, Marcellino GR, Henson DB, Young LB, Patton N, Charles SJ, Turner GS, Stanga
PE. Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in prolifera-
tive diabetic retinopathy. Acta Ophthalmol. 2013;91:251–8.
Chapter 5
Implementation of Precision Genetic
Approaches for Type 1 and 2 Diabetes
Introduction
The genomic revolution and discoveries in the genetics of type 1 (T1D) and type 2
diabetes (T2D) have been a major driving force in the development and realization
of the potential of precision medicine in diabetes. Although delivering precision
medicine does not need to include genetic markers, it is very much the advances in
genetic research in diabetes which have spearheaded the movement to develop a
precision medicine approach to diabetes management. The advent of genomic tech-
nology, sequencing of the human genome and the rise of genome-wide association
studies (GWAS) in diabetes and related traits have led to the identification of novel
gene regions as well as genetic markers that can be used for risk prediction.
Furthermore, these findings have given rise to the development of different tools,
including polygenic risk scores (PRS), which are accessible and ready for incorpo-
ration into clinical practice.
For example, genome-wide association studies (GWAS), with its agnostic and
hypothesis-generating approach, have led to the identification 78 loci for T1D [1]
and more than 300 loci for T2D [2, 3]. The functional validation and fine-mapping
for the causal variants and genes are still underway for many of the regions, but the
identification of these association signals has led to the development of PRS based
on findings from GWAS studies. Furthermore, other “omics” discoveries have
R. C. W. Ma (*) · J. C. N. Chan
Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
Hong Kong, China
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong,
Hong Kong, China
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong,
Hong Kong, China
e-mail: [email protected]; [email protected]
vastly expanded our knowledge of biomarkers associated with diabetes and its
related traits and complications, hence providing great opportunities to utilize these
additional biomarkers to improve care.
Whilst precision approach to diabetes management does not necessarily involve
genetics or other biomarkers, genetics do offer different opportunities especially
before the appearance of clinical phenotypes to provide a more individualized and
tailored approach for prevention and treatment purposes. Other “biomarkers” which
might be of use for precision medicine include approaches that incorporate clinical
risk factors, risk scores, algorithms, imaging data as well as a variety of “omics”
technology including proteomics, metabolomics, epigenomics, miRNA markers
and others, to guide clinical care. In addition to individual genetic markers that have
been found to be associated with diabetes or diabetes-related outcomes, approaches
to construct PRS, or genome-wide PRS (gwPRS), are additional approaches that are
becoming feasible and more popular (Fig. 5.1).
The American Diabetes Association (ADA), for example, has recently launched
a Precision Medicine in Diabetes Initiative (PMDI) and, in its first consensus report
for the initiative, has provided a framework for considering how precision medicine
can be implemented in diabetes [4]. The Consensus report conceptualizes the pillars
of precision medicine as applied to diabetes management and can serve as a useful
framework for reviewing the current state of knowledge with regard to precision
Fig. 5.1 Examples of tools and approaches for delivering precision medicine in diabetes. (Last
figure reprinted from Advance in Genetics, Vol. 93, Yan V. Sun and Yi-Juan Hu, Chap. 3- Integrative
analysis of multi-omics data for discovery and functional studies of human complex diseases,
Pages 147–190, copyright (2016), with permission from Elsevier)
5 Implementation of Precision Genetic Approaches for Type 1 and 2 Diabetes 113
Precision Medicine
In Diabetes
prognostics
diagnostics
prevention
treatment
Precision
Precision
Precision
Precision
Diabetes Prediction of Selection of Risk algorithms
Examples subtypes diabetes risk treatment based on or biomarkers for
include: and tailored side effects (e.g. diabetes
Subclassification prevention hypoglycaemia) complications
Fig. 5.2 The pillars of precision medicine as applied to Precision Medicine in Diabetes
medications [7]) and, importantly, the cognitive-psychosocial factors [8] that under-
lie a patient’s values and perspectives in determining behaviours are additional fac-
tors needed in the holistic evaluation and management of patients who have or are
at risk of having diabetes.
These premises set out the framework by which precision medicine can be con-
sidered and implemented in diabetes care. In particular, the PMDI has outlined
some of the key steps in the implementation of precision medicine in diabetes, as
will be discussed in more detail in the closing section of this chapter. The PMDI is
currently undertaking multiple systematic reviews to generate the evidence and
identify gaps in knowledge with regard to precision medicine in diabetes. For the
remaining parts of the chapter, we will use this framework to discuss some emerg-
ing examples of how precision medicine in diabetes may be implemented. We will
discuss this in the context of traditional classification of T1D versus T2D, though as
will be appreciated later in the discussion, the development and implementation of
precision medicine in diabetes also lend itself towards renewed efforts to gain novel
insights and may potentially facilitate better classification and sub-phenotyping of
diabetes itself.
Optimal management of T1D, or any type of diabetes, for that matter, requires sta-
ble control of blood glucose and prevention of hypoglycaemia. This is particularly
challenging among patients with T1D, especially those with long disease duration
who often have minimal residual islet function with reduced secretion of both insu-
lin and glucagon and autonomic dysfunction putting them at high risk of hypogly-
caemia unawareness. Advances in diabetes technology have led to major
improvement in glucose monitoring, with availability of different continuous glu-
cose monitoring systems (CGMS), as well as ambulatory CGM. These provide
opportunities for patients to receive more detailed, and more importantly, real-time
feedback of interstitial glucose values, to guide patient and clinician interventions to
address postprandial glucose excursions, optimize treatment targets and facilitate
prevention of hypoglycaemia. Using risk factors or algorithms to identify individu-
als who are at high risk of severe hypoglycaemia and thus at need of additional
monitoring would likely be most cost-effective and most beneficial.
All patients with T1D are treated with insulin following diagnosis. Nevertheless,
there are emerging strategies to facilitate subtype classification, for example,
according to whether there is residual C-peptide production. These subtypes may be
matched to different treatment strategies, including intensive insulin therapy, or
selection of patients for continuous subcutaneous insulin infusion (CSII) or, more
116 R. C. W. Ma and J. C. N. Chan
recently, hybrid-closed loop insulin infusion pumps [14]. For example, a machine-
learning artificial intelligence platform has been developed to guide insulin dosage
for patients with T1D and may be used to improve glycaemic outcomes [15].
There is also the possibility of matching specific treatments based on better
understanding of an individual’s underlying pathophysiology. This has been high-
lighted by a recent case of T1D with recurrent respiratory infections, which was
later found to carry a gain-of-function mutation in the signal transducer and activa-
tor of transcription 1 (STAT1) gene. Treatment with ruxolitinib, an inhibitor of
Janus kinase (JAK) 1 and 2 and the STAT signaling pathway, was associated with
remission of T1D as well as his chronic mucocutaneous candidiasis [16]. Although
an unusual case, this case highlights the possibility of using immunomodulating
agents to modify the natural history of T1D.
Another example of precision treatment in T1D is the use of cell replacement
therapy. Although islet cell transplantation is the mainstay approach, stem cell-
based therapies are emerging as potential options in the future. These alternative
sources of beta-cells include those derived from embryonic stem cells, human plu-
ripotent stem cells and induced pluripotent stem cells (iPSCs), among others, and
can include cells obtained from the patient and expanded ex vivo before being
returned to the patient, although ongoing autoimmune destruction may remain a
challenge. A detailed discussion of cell replacement in T1D is beyond the scope of
this chapter, and readers can refer to several excellent review articles [17, 18] for
additional details. The use of patient-specific cell lines may have applications in
T1D or other forms of diabetes and related complications.
markers, with or without additional inclusion of clinical risk factors, for the predic-
tion of future complications, may facilitate better risk stratification for intensive
treatment.
Similar to what has been described for T1D, comparable strategies can be adapted
to deliver precision medicine in T2D. Nevertheless, the current classification of dia-
betes into T1D, T2D and other forms of diabetes, including monogenic diabetes, is
itself subject to revision following increasing understanding of the underlying biol-
ogy and emergence of strategies of sub-classification based on underlying patho-
physiology or complication risk [24–26].
Although a diagnosis of T2D in adults is by far the most common type of diabetes,
diagnosis has traditionally been achieved through exclusion of other forms of diabe-
tes. As mentioned earlier, a T1D PRS has been found to be more useful to differenti-
ate between T1D, T2D and maturity-onset diabetes of the young (MODY) in young
adults presenting with diabetes, compared to, for example, a PRS constructed based
on genetic variants for T2D [10]. Furthermore, using a MODY calculator, supple-
mented by molecular testing, to exclude monogenic forms of diabetes is also impor-
tant, especially among those with young-onset diabetes. In the original study
involving 594 subjects with MODY, 278 with T1D and 319 with T2D, use of the
prediction model based on clinical characteristics improved considerably the sensi-
tivity and specificity for identifying MODY compared with standard criteria of
diagnosis before age 25 and an affected parent [27]. A diagnosis of MODY would
have significant treatment implications, as patients with glucokinase (GCK)-MODY
(MODY 2) would in general not require glucose-lowering treatment, the introduc-
tion of a new class of GCK activator may offer new opportunity for correcting this
metabolic defect [28]. On the other hand, individuals with hepatic nuclear factor
(HNF)-1A (MODY 3) or HNF-4A MODY (MODY 1) would respond well to low-
dose sulphonylurea treatment [29].
In addition to using algorithms with or without biomarkers to diagnose T2D, it
has also become possible to utilize these strategies to identify subtypes of T2D
according to underlying pathophysiology or by clustering of clinical features. In one
of the best-known examples from Sweden, the use of clinical data from 8980
patients with newly diagnosed diabetes from the Swedish All New Diabetics in
Scania (ANDIS) cohort, data-driven cluster analysis using K-means clustering and
hierarchical clustering led to the identification of five individual clusters of patients
with diabetes. Importantly, these different clusters (or “subtypes”) of diabetes had
118 R. C. W. Ma and J. C. N. Chan
The need for self-monitoring and the use of more advanced glycaemic monitoring
such as ambulatory CGM can be adjusted according to clinical profile and overall
glucose control. Another potential application of precision monitoring is the
5 Implementation of Precision Genetic Approaches for Type 1 and 2 Diabetes 119
model 2 [54]. A series of risk equations have also been developed to predict risk of
diabetes complications in Asians with T2D [55].
In Hong Kong, as part of a quality improvement program, the Hong Kong
Diabetes Register (HKDR) was set up in 1995 where nurses performed periodic
assessment of risk factors and complications (blood, urine, eye and feet), guided by
a protocol. This systematic data collection was used to stratify risk, empower self-
management, identify care gaps and facilitate shared decision-making. Leveraging
the unique healthcare system with a territory-wide electronic medical record sys-
tem, we were able to develop a series of risk equations with different combinations
of risk factors to predict multiple complications including stroke, CAD, heart fail-
ure, end-stage kidney disease and all-cause death with 70–90% specificity and sen-
sitivity [56]. This risk stratification program was subsequently incorporated into the
web-based Joint Asia Diabetes Evaluation (JADE) portal complete with care proto-
col, risk engine, personalized reporting system with data visualization including
treatment targets and trends supplemented by individualized decision support for
implementation in real-world setting [55].
Very few studies have evaluated the utility of incorporating such risk algorithms
in clinical practice. In a retrospective analysis comparing diabetes management in
three different settings, including routine care in public hospital setting, care in
public hospital incorporating the JADE system with nurse-led group education and
a community-based nurse-led university diabetes centre utilizing the JADE system
with individualized nurse explanation and annual phone reminder for engagement,
this data-driven personalized diabetes management, augmented by information and
communications technology (ICT), was associated with reduced clinical events and
mortality in Chinese patients with T2D [57]. In a broad range of clinical settings in
Asia, the implementation of the JADE Program combining the use of data and algo-
rithms delivered by a doctor-nurse team had also been shown to be effective in
reducing multiple risk factors, empowering self-management and reducing default
[58, 59].
In addition to risk stratification using clinical risk scores, recent advances from
genetic studies are also making use of genome-wide PRS (gwPRS) as potential
tools for risk stratification in clinical practice [60]. Researchers had used different
PRS constructed based on genetic variants for CAD or lipid traits to stratify cardio-
vascular risk in individuals with T2D [61, 62]. Large international genetic consortia
have also identified a large number of genetic variants associated with renal func-
tion traits, with potential applications in the stratification of diabetic kidney disease
[63, 64]. A strategy that incorporates these different genetic markers for prediction
and management of T2D across the course of the disease is illustrated in Fig. 5.2 [29].
In addition to use of genetic variants and PRS for risk stratification, other studies
have investigated other “omics” associated with diabetes complications. For exam-
ple, epigenetic markers such as cytosine methylation markers have been found to
improve prediction of renal function decline in diabetic kidney disease [65, 66].
Other epigenetic markers such as circulating microRNA (miRNA) are also showing
promise as potential tools for risk stratification for diabetes complications [67]
(Fig. 5.3).
122 R. C. W. Ma and J. C. N. Chan
Macrovascular complications
Microvascular complications
β-cell function
Insulin
resistance
Blood
glucose
Pre-diabetes Type 2 diabetes
Moleuclar Sequencing
diagnosis for MODY
genes
Fig. 5.3 A schematic diagram highlighting potential applications of precision medicine at differ-
ent stages of type 2 diabetes. (Reproduced with permission from Xie, et al. [29])
Although much of the discussion so far has centred on the identification of strate-
gies or biomarkers that can facilitate the delivery of precision medicine in diabetes,
the identification of such disease-specific biomarkers only represents one of the first
steps in the realization of precision medicine. The path to precision medicine, as
5 Implementation of Precision Genetic Approaches for Type 1 and 2 Diabetes 123
Understanding Vertical
the disease integration of
(risk factors, Biomarkers and
mechanisms, Generation of Patient Clinician Patient
natural history) Algorithms engagement education HEA feedback
Fig. 5.4 The path towards implementation of precision medicine in diabetes. HEA, health eco-
nomic assessment. (Reproduced with permission from Fitapaldi, et al. [70])
payors and policymakers whilst taking into consideration the local setting and
cultures.
Whilst the implementation of precision medicine does pose certain challenges as
described above, there has been increasing interest and enthusiasm from the diabe-
tes community to incorporate precision medicine into practice. Pilot trials incorpo-
rating personalized genetic counselling to motivate diabetes prevention have
demonstrated the feasibility to test these hypotheses in clinical settings [71]. In an
8-week randomized clinical trial comparing participants at risk of diabetes given
standard lifestyle advice (N = 190), lifestyle advice together with genetic risk esti-
mate for T2D (N = 189) or lifestyle advice supplemented with phenotypic risk for
T2D (N = 190) yielded similar outcomes in terms of self-reported diet, self-reported
weight, worry and anxiety [72]. In a systematic review including 18 studies report-
ing on seven different behavioural outcomes, including smoking cessation, diet and
physical activity, the meta-analysis revealed no significant effects of communicat-
ing DNA-based risk estimates on these health-related behaviours [73]. Future stud-
ies would need to explore how best to utilize risk information to enhance preventive
strategies. With regard to other biomarkers for risk stratification, most have not been
evaluated formally in clinical trial settings. Several clinical trials incorporating bio-
markers for diabetes complications are ongoing or have recently been completed
which may provide further guidance toward future implementation of precision
medicine in diabetes [69]. For example, we have recently completed a randomized
clinical trial to examine the utility of implementation of genetic testing for variants
related to the risk of diabetes complications [74]. Another trial is currently under-
way to explore the utility of bio-genetic testing for the management of young-onset
diabetes [75]. Against this background, given the genetic and phenotypic heteroge-
neity underlying the risks for diabetes and its complications, the needs of technolo-
gies including devices and medications to alter such risks as well as the
cognitive-psychological-social factors that determine behavioural changes, a multi-
component strategy focusing on access to care, provider-patient relationships, data
sharing and personalized decision, supported by a practising environment condu-
cive to this model of care delivery, is essential in order to create impact of precision
medicine [76].
Conclusions
In this chapter, we have provided some emerging examples of how precision medi-
cine can be helpful in the management of T1D and T2D and some of the challenges
involved. Implementation of precision medicine in diabetes requires a multi-
pronged approach in biomarker discovery, validation, clinician education and
patient empowerment, as well as regulatory support and reimbursement. Whilst
there are still many unknowns, several large international initiatives are underway to
systematically evaluate the evidence to help support implementation of precision
medicine in diabetes. By combining our existing knowledge and newer
5 Implementation of Precision Genetic Approaches for Type 1 and 2 Diabetes 125
Acknowledgement RCWM acknowledges support from the Research Grants Council Research
Impact Fund (CU R4012-18) and a Croucher Senior Medical Research Fellowship. JCNC
acknowledges the support of the Hong Kong Government Health and Medical Research Fund for
an implementation study of Precision Medicine to Redefine Insulin Secretion and Monogenic
Diabetes in Chinese Patients with Young-onset Diabetes (PRISM).
References
1. Robertson CC, Inshaw JRJ, Onengut-Gumuscu S, Chen WM, Santa Cruz DF, Yang H, et al.
Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and
drug targets for type 1 diabetes. Nat Genet. 2021;53(7):962–71.
2. Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, et al. Fine-mapping
type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific
epigenome maps. Nat Genet. 2018;50(11):1505–13.
3. Spracklen CN, Horikoshi M, Kim YJ, Lin K, Bragg F, Moon S, et al. Identification of type 2
diabetes loci in 433,540 east Asian individuals. Nature. 2020;582(7811):240–5.
4. Chung WK, Erion K, Florez JC, Hattersley AT, Hivert MF, Lee CG, et al. Precision medicine in
diabetes: a consensus report from the American Diabetes Association (ADA) and the European
Association for the Study of diabetes (EASD). Diabetes Care. 2020;43(7):1617–35.
5. Ewald N, Hardt PD. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis.
World J Gastroenterol. 2013;19(42):7276–81.
6. Lao TT, Chan BC, Leung WC, Ho LF, Tse KY. Maternal hepatitis B infection and gestational
diabetes mellitus. J Hepatol. 2007;47(1):46–50.
7. Ma RC, Kong AP, Chan N, Tong PC, Chan JC. Drug-induced endocrine and metabolic disor-
ders. Drug Saf. 2007;30(3):215–45.
8. Fisher EB, Chan JC, Nan H, Sartorius N, Oldenburg B. Co-occurrence of diabetes and depres-
sion: conceptual considerations for an emerging global health challenge. J Affect Disord.
2012;142(Suppl):S56–66.
9. Jones AG, McDonald TJ, Shields BM, Hagopian W, Hattersley AT. Latent autoimmune dia-
betes of adults (LADA) is likely to represent a mixed population of autoimmune (type 1) and
nonautoimmune (type 2) diabetes. Diabetes Care. 2021.
10. Oram RA, Patel K, Hill A, Shields B, McDonald TJ, Jones A, et al. A type 1 diabetes genetic
risk score can aid discrimination between type 1 and type 2 diabetes in young adults. Diabetes
Care. 2016;39(3):337–44.
11. Bingley PJ, Wherrett DK, Shultz A, Rafkin LE, Atkinson MA, Greenbaum CJ. Type 1 diabetes
TrialNet: a multifaceted approach to bringing disease-modifying therapy to clinical use in type
1 diabetes. Diabetes Care. 2018;41(4):653–61.
12. Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, et al. An anti-CD3
antibody, Teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med. 2019;381(7):603–13.
126 R. C. W. Ma and J. C. N. Chan
13. Ferrat LA, Vehik K, Sharp SA, Lernmark A, Rewers MJ, She JX, et al. A combined risk
score enhances prediction of type 1 diabetes among susceptible children. Nat Med.
2020;26(8):1247–55.
14. McAuley SA, Lee MH, Paldus B, Vogrin S, de Bock MI, Abraham MB, et al. Six months
of hybrid closed-loop versus manual insulin delivery with Fingerprick blood glucose
monitoring in adults with type 1 diabetes: a randomized controlled trial. Diabetes Care.
2020;43(12):3024–33.
15. Tyler NS, Mosquera-Lopez CM, Wilson LM, Dodier RH, Branigan DL, Gabo VB, et al. An
artificial intelligence decision support system for the management of type 1 diabetes. Nat
Metab. 2020;2(7):612–9.
16. Chaimowitz NS, Ebenezer SJ, Hanson IC, Anderson M, Forbes LR. STAT1 gain of function,
type 1 diabetes, and reversal with JAK inhibition. N Engl J Med. 2020;383(15):1494–6.
17. Akil AA, Yassin E, Al-Maraghi A, Aliyev E, Al-Malki K, Fakhro KA. Diagnosis and treatment
of type 1 diabetes at the dawn of the personalized medicine era. J Transl Med. 2021;19(1):137.
18. Chen S, Du K, Zou C. Current progress in stem cell therapy for type 1 diabetes mellitus. Stem
Cell Res Ther. 2020;11(1):275.
19. Ma RC. Genetics of cardiovascular and renal complications in diabetes. J Diabetes Investig.
2016;7(2):139–54.
20. Ma RC, Cooper ME. Genetics of diabetic kidney disease-from the worst of nightmares to the
light of Dawn? J Am Soc Nephrol. 2017;28(2):389–93.
21. Sandholm N, Groop PH. Genetic basis of diabetic kidney disease and other diabetic complica-
tions. Curr Opin Genet Dev. 2018;50:17–24.
22. Salem RM, Todd JN, Sandholm N, Cole JB, Chen WM, Andrews D, et al. Genome-wide asso-
ciation study of diabetic kidney disease highlights biology involved in glomerular basement
membrane collagen. J Am Soc Nephrol. 2019;30(10):2000–16.
23. Costacou T, Ferrell RE, Orchard TJ. Haptoglobin genotype: a determinant of cardiovascular
complication risk in type 1 diabetes. Diabetes. 2008;57(6):1702–6.
24. Redondo MJ, Hagopian WA, Oram R, Steck AK, Vehik K, Weedon M, et al. The clinical
consequences of heterogeneity within and between different diabetes types. Diabetologia.
2020;63(10):2040–8.
25. Ahlqvist E, Tuomi T, Groop L. Clusters provide a better holistic view of type 2 diabetes than
simple clinical features. Lancet Diabetes Endocrinol. 2019;7(9):668–9.
26. Udler MS, Kim J, von Grotthuss M, Bonas-Guarch S, Cole JB, Chiou J, et al. Type 2 diabetes
genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: a
soft clustering analysis. PLoS Med. 2018;15(9):e1002654.
27. Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT. The development
and validation of a clinical prediction model to determine the probability of MODY in patients
with young-onset diabetes. Diabetologia. 2012;55(5):1265–72.
28. Zhu D, Gan S, Liu Y, Ma J, Dong X, Song W, et al. Dorzagliatin monotherapy in Chinese
patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled,
phase 2 study. The lancet Diabetes & endocrinology. 2018;6:627–36.
29. Xie F, Chan JC, Ma RC. Precision medicine in diabetes prevention, classification and manage-
ment. J Diabetes Investig. 2018.
30. Langenberg C, Sharp SJ, Franks PW, Scott RA, Deloukas P, Forouhi NG, et al. Gene-
lifestyle interaction and type 2 diabetes: the EPIC InterAct Case-cohort study. PLoS Med.
2014;11(5):e1001647.
31. Chan JCN, Lim LL, Wareham NJ, Shaw JE, Orchard TJ, Zhang P, et al. The lancet com-
mission on diabetes: using data to transform diabetes care and patient lives. Lancet.
2021;396(10267):2019–82.
32. Raghavan S, Jablonski K, Delahanty LM, Maruthur NM, Leong A, Franks PW, et al.
Interaction of diabetes genetic risk and successful lifestyle modification in the diabetes pre-
vention Programme. Diabetes Obes Metab. 2021;23(4):1030–40.
5 Implementation of Precision Genetic Approaches for Type 1 and 2 Diabetes 127
33. Wheeler E, Leong A, Liu CT, Hivert MF, Strawbridge RJ, Podmore C, et al. Impact of
common genetic determinants of hemoglobin A1c on type 2 diabetes risk and diagnosis
in ancestrally diverse populations: a transethnic genome-wide meta-analysis. PLoS Med.
2017;14(9):e1002383.
34. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-
led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-
randomised trial. Lancet. 2018;391(10120):541–51.
35. Ko GT, So WY, Tong PC, Chan WB, Yang X, Ma RC, et al. Effect of interactions between C
peptide levels and insulin treatment on clinical outcomes among patients with type 2 diabetes
mellitus. CMAJ. 2009;180(9):919–26.
36. Luk AOY, Lau ESH, Lim C, Kong APS, Chow E, Ma RCW, et al. Diabetes-related complica-
tions and mortality in patients with young-onset latent autoimmune diabetes: a 14-year analy-
sis of the prospective Hong Kong diabetes register. Diabetes Care. 2019;42(6):1042–50.
37. Fan B, Wu H, Shi M, Yang A, Lau ESH, Tam CHT, et al. associations of the homa2-%b and
homa2-ir with progression to diabetes and glycaemic deterioration in young and middle-aged
chinese. Diabetes/metabolism research and reviews. 2022:e3525.
38. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, Action to Control Cardiovascular
Risk in Diabetes Study G, et al. Effects of intensive glucose lowering in type 2 diabetes. New
England J Med. 2008;358(24):2545–59.
39. Kong AP, Yang X, Luk A, Ma RC, So WY, Ozaki R, et al. Severe hypoglycemia identifies vul-
nerable patients with type 2 diabetes at risk for premature death and all-site cancer: the Hong
Kong diabetes registry. Diabetes Care. 2014;37(4):1024–31.
40. Kong AP, Yang X, Luk A, Cheung KK, Ma RC, So WY, et al. Hypoglycaemia, chronic kidney
disease and death in type 2 diabetes: the Hong Kong diabetes registry. BMC Endocr Disord.
2014;14:48.
41. Pozzilli P, Leslie RD, Chan J, De Fronzo R, Monnier L, Raz I, et al. The A1C and ABCD
of glycaemia management in type 2 diabetes: a physician's personalized approach. Diabetes
Metab Res Rev. 2010;26(4):239–44.
42. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management
of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the
American Diabetes Association (ADA) and the European Association for the Study of diabetes
(EASD). Diabetologia. 2012;55(6):1577–96.
43. Shah HS, Gao H, Morieri ML, Skupien J, Marvel S, Pare G, et al. Genetic predictors of car-
diovascular mortality during intensive glycemic control in type 2 diabetes: findings from the
ACCORD clinical trial. Diabetes Care. 2016;39(11):1915–24.
44. Zhou K, Donnelly LA, Morris AD, Franks PW, Jennison C, Palmer CN, et al. Clinical and
genetic determinants of progression of type 2 diabetes: a DIRECT study. Diabetes Care.
2014;37(3):718–24.
45. Jiang G, Luk AO, Tam CHT, Lau ES, Ozaki R, Chow EYK, et al. Obesity, clinical, and
genetic predictors for glycemic progression in Chinese patients with type 2 diabetes: a cohort
study using the Hong Kong diabetes register and Hong Kong diabetes biobank. PLoS Med.
2020;17(7):e1003209.
46. Zhou K, Donnelly L, Burch L, Tavendale R, Doney AS, Leese G, et al. Loss-of-function
CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a go-
DARTS study. Clin Pharmacol Ther. 2010;87(1):52–6.
47. Zhou K, Bellenguez C, Spencer CC, GoDarts, Group UDPS, Wellcome Trust Case Control C,
et al. Common variants near ATM are associated with glycemic response to metformin in type
2 diabetes. Nat Genet. 2011;43(2):117–20.
48. Zhou K, Yee SW, Seiser EL, van Leeuwen N, Tavendale R, Bennett AJ, et al. Variation in the
glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat
Genet. 2016;48(9):1055–9.
128 R. C. W. Ma and J. C. N. Chan
49. Wang K, Yang A, Shi M, Tam CCH, Lau ESH, Fan B, et al. CYP2C19 Loss-of-function
polymorphisms are associated with reduced risk of sulfonylurea treatment failure in chinese
patients with type 2 diabetes. Clinical pharmacology and therapeutics. 2021.
50. Stevens RJ, Coleman RL, Adler AI, Stratton IM, Matthews DR, Holman RR. Risk factors
for myocardial infarction case fatality and stroke case fatality in type 2 diabetes: UKPDS 66.
Diabetes Care. 2004;27(1):201–7.
51. Basu S, Sussman JB, Berkowitz SA, Hayward RA, Yudkin JS. Development and validation
of risk equations for complications of type 2 diabetes (RECODe) using individual participant
data from randomised trials. Lancet Diabetes Endocrinol. 2017;5(10):788–98.
52. Bannister CA, Poole CD, Jenkins-Jones S, Morgan CL, Elwyn G, Spasic I, et al. External vali-
dation of the UKPDS risk engine in incident type 2 diabetes: a need for new type 2 diabetes-
specific risk equations. Diabetes Care. 2014;37(2):537–45.
53. Yang X, So WY, Kong AP, Ma RC, Ko GT, Ho CS, et al. Development and valida-
tion of a total coronary heart disease risk score in type 2 diabetes mellitus. Am J Cardiol.
2008;101(5):596–601.
54. Basu S, Sussman JB, Berkowitz SA, Hayward RA, Bertoni AG, Correa A, et al. Validation of
risk equations for complications of type 2 diabetes (RECODe) using individual participant
data from diverse longitudinal cohorts in the U.S. Diabetes Care. 2018;41(3):586–95.
55. Chan JCN, Lim LL, Luk AOY, Ozaki R, Kong APS, Ma RCW, et al. From Hong Kong
diabetes register to JADE program to RAMP-DM for data-driven actions. Diabetes Care.
2019;42(11):2022–31.
56. Chan JC, So W, Ma RC, Tong PC, Wong R, Yang X. The complexity of vascular and non-
vascular complications of diabetes: the Hong Kong diabetes registry. Curr Cardiovasc Risk
Rep. 2011;5(3):230–9.
57. Lim LL, Lau ESH, Ozaki R, Chung H, Fu AWC, Chan W, et al. Association of technologically
assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the pro-
spective JADE program: a retrospective cohort analysis. PLoS Med. 2020;17(10):e1003367.
58. Tutino GE, Yang WY, Li X, Li WH, Zhang YY, Guo XH, et al. A multicentre demonstration
project to evaluate the effectiveness and acceptability of the web-based joint Asia diabetes
evaluation (JADE) programme with or without nurse support in Chinese patients with type 2
diabetes. Diabet Med. 2017;34(3):440–50.
59. Lim LL, Lau ESH, Fu AWC, Ray S, Hung YJ, Tan ATB, et al. Effects of a technology-assisted
integrated diabetes care program on Cardiometabolic risk factors among patients with type 2
diabetes in the Asia-Pacific region: the JADE program randomized clinical trial. JAMA Netw
Open. 2021;4(4):e217557.
60. Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, et al. Genome-wide poly-
genic scores for common diseases identify individuals with risk equivalent to monogenic
mutations. Nat Genet. 2018;50(9):1219–24.
61. Morieri ML, Gao H, Pigeyre M, Shah HS, Sjaarda J, Mendonca C, et al. Genetic tools for
coronary risk assessment in type 2 diabetes: a cohort study from the ACCORD clinical trial.
Diabetes Care. 2018;41(11):2404–13.
62. Tam CHT, Lim CKP, Luk AOY, Ng ACW, Lee HM, Jiang G, et al. Development of genome-
wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclini-
cal atherosclerosis, and diabetes cardiovascular complications among east Asians. Genome
Med. 2021;13(1):29.
63. Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, et al. A catalog of genetic loci associ-
ated with kidney function from analyses of a million individuals. Nat Genet. 2019;51(6):957–72.
64. Stanzick KJ, Li Y, Schlosser P, Gorski M, Wuttke M, Thomas LF, et al. Discovery and priori-
tization of variants and genes for kidney function in >1.2 million individuals. Nat Commun.
2021;12(1):4350.
65. Qiu C, Hanson RL, Fufaa G, Kobes S, Gluck C, Huang J, et al. Cytosine methylation predicts
renal function decline in American Indians. Kidney Int. 2018;93(6):1417–31.
5 Implementation of Precision Genetic Approaches for Type 1 and 2 Diabetes 129
66. Gluck C, Qiu C, Han SY, Palmer M, Park J, Ko YA, et al. Kidney cytosine methylation
changes improve renal function decline estimation in patients with diabetic kidney disease.
Nat Commun. 2019;10(1):2461.
67. Fan B, Luk AOY, Chan JCN, Ma RCW. MicroRNA and diabetic complications: a clinical
perspective. Antioxid Redox Signal. 2018;29(11):1041–63.
68. Lindhardt M, Persson F, Zurbig P, Stalmach A, Mischak H, de Zeeuw D, et al. Urinary pro-
teomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a
sub-study of the DIRECT-protect 2 study. Nephrol Dial Transplant. 2017;32(11):1866–73.
69. Tofte N, Lindhardt M, Adamova K, Bakker SJL, Beige J, Beulens JWJ, et al. Early detection
of diabetic kidney disease by urinary proteomics and subsequent intervention with spirono-
lactone to delay progression (PRIORITY): a prospective observational study and embedded
randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2020;8(4):301–12.
70. Fitipaldi H, McCarthy MI, Florez JC, Franks PW. A global overview of precision medicine in
type 2 diabetes. Diabetes. 2018;67(10):1911–22.
71. Grant RW, O'Brien KE, Waxler JL, Vassy JL, Delahanty LM, Bissett LG, et al. Personalized
genetic risk counseling to motivate diabetes prevention: a randomized trial. Diabetes Care.
2013;36(1):13–9.
72. Godino JG, van Sluijs EM, Marteau TM, Sutton S, Sharp SJ, Griffin SJ. Lifestyle advice
combined with personalized estimates of genetic or phenotypic risk of type 2 diabetes,
and objectively measured physical activity: a randomized controlled trial. PLoS Med.
2016;13(11):e1002185.
73. Hollands GJ, French DP, Griffin SJ, Prevost AT, Sutton S, King S, et al. The impact of com-
municating genetic risks of disease on risk-reducing health behaviour: systematic review with
meta-analysis. BMJ (Clinical Res Ed). 2016;352:i1102.
74. Ma RC, Xie F, Lim CJ, Lau SH, Luk AO, Ozaki R, et al. Genetic testing and counseling to
reduce diabetic complications (NCT02364323). Available from: https://clinicaltrials.gov/ct2/
show/NCT02364323?term=ma%2C+ronald&draw=2&rank=1. Last accessed 14 Aug, 2021.
75. Chan JC. Precision medicine in chinese patients with young onset diabetes (NCT04049149).
Available from: https://clinicaltrials.gov/ct2/show/NCT04049149?term=chan%2C+juliana&c
ond=diabetes+AND+prism&draw=2&rank=1. Last accessed 14 Aug, 2021.
76. Lim LL, Lau ESH, Kong APS, Davies MJ, Levitt NS, Eliasson B, et al. Aspects of multi-
component integrated care promote sustained improvement in surrogate clinical outcomes: a
systematic review and meta-analysis. Diabetes Care. 2018;41(6):1312–20.
Chapter 6
Precision Genetics for Monogenic Diabetes
Introduction
Monogenic diabetes arises from mutation in a single gene and accounts for roughly
1–3% of people with young-onset diabetes [1, 2]. The mode of inheritance may be
autosomal dominant or recessive, although some mutations may occur de novo.
People with monogenic diabetes generally present at a young age (below 30 years)
and report a strong family history of diabetes [3]. They are typically lean without
signs of insulin resistance and are not insulin-dependent. Because of the similarity
in clinical presentation, monogenic diabetes may be incorrectly diagnosed as type 1
diabetes or type 2 diabetes. Confirmation of monogenic diabetes requires molecular
genetic testing. To date, around 40 monogenic diabetes genes have been identified,
the majority of which regulate pancreatic beta-cell function. The most common
monogenic diabetes form is maturity-onset diabetes of the young (MODY), and the
most commonly implicated genes are glucokinase (GCK), hepatocyte nuclear factor
1-alpha (HNF1A), hepatocyte nuclear factor 4-alpha (HNF4A), and hepatocyte
nuclear factor 1-beta (HNF1B).
A. O. Y. Luk (*)
Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
Hong Kong, SAR, China
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong,
Hong Kong, SAR, China
e-mail: [email protected]
L.-L. Lim
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong,
Hong Kong, SAR, China
Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Table 6.1 Four common subtypes of maturity-onset diabetes of the young (MODY) [9, 28, 32, 37, 38, 49, 52, 57, 60]
Genetic Function on Extra pancreatic
defect beta-cell Inheritance Clinical features features Treatment Implications on pregnancy
GCK Glucose Autosomal Incidental diagnosis via Nil First line: Fetal genotype and serial fetal growth
sensor dominant screening of asymptomatic Diet and exercise guide treatment decisions
individuals Glucose-lowering If both the mother and offspring have
Mild fasting hyperglycemia drugs: Not GCK mutations: Insulin is not required
OGTT: Increment indicated, unless due to an increased risk of low birth
<3.0 mmol/L there is coexisting weight
Slow deterioration in beta-cell type 1 or type 2 If the mother has GCK mutations and
function with age (comparable diabetes, obesity, the offspring is unaffected: To initiate
to the general population) or pregnancy insulin if fetal abdominal
Very low prevalence of circumference >75th centile
microvascular and
macrovascular complications
Precision Genetics for Monogenic Diabetes
It was estimated that over 80% of cases of MODY were not detected in clinical
practice highlighting the need for better case finding [6, 15]. From the Young
Diabetes in Oxford study which actively recruited people from community and
hospital-based clinics, 10% of those previously labelled type 1 diabetes and 15% of
those diagnosed to have type 2 diabetes up to the age of 45 years had mutation in
MODY genes [16]. The low diagnostic rate is multifactorial. Firstly, genetic testing
is expensive and not widely available. In areas that do not have a well-developed
genetic service, samples will need to be sent to other cities or countries for sequenc-
ing. Secondly, as it is not feasible to test everyone with diabetes, the selection of
individuals to undergo genetic testing is at the discretion of the physicians. However,
the current recommendations are very restrictive leaving many people undiagnosed.
The awareness of this condition is also low among general physicians and even
among endocrinologists. Thirdly, Sanger sequencing may miss detecting rare mono-
genic diabetes forms because only the few common genes are tested.
Early guidelines recommend MODY testing for people with age of diabetes
diagnosis <25 years, who have known parental history of diabetes, and who are non-
insulin dependent. Additionally, low body mass index (BMI) has been frequently
identified as one of the discriminatory features for MODY. However, such criteria
are neither sensitive nor specific.
Young-onset type 2 diabetes is becoming increasingly common as a result of a
rising prevalence of childhood obesity [17, 18]. Exposed to the same obesogenic
environment, people with monogenic diabetes are equally as likely to acquire the
metabolic syndrome as the general population. In the Young Diabetes in Oxford
study, metabolic syndrome was present in a quarter of those with newly confirmed
MODY [16]. Among 47 people aged <20 years with screen-detected MODY, acan-
thosis nigricans was found in 40% and dyslipidemia in 60% [6]. Hence, an obese
phenotype and indicators of insulin resistance do not rule out the possibility
of MODY.
Positive family history of diabetes is prevalent in type 2 diabetes. Up to 60% of
young people with type 2 diabetes report having at least one affected family mem-
ber [19]. It is noteworthy that with the growing preference for smaller sized fami-
lies, pedigree analysis as a tool to identify inheritance patterns may become less
reliable because the number of family members available to study is few. In this
connection, only half of the individuals with MODY detected through population
screening reported a transgenerational history of diabetes [6, 16].
6 Precision Genetics for Monogenic Diabetes 137
Given poor discriminative value of traditional criteria, several research groups have
developed risk equations or screening algorithms to improve pre-test probability for
genetic testing. Using data from 1191 patients with confirmed MODY and type 1
and type 2 diabetes, investigators from Exeter, UK, constructed risk calculators that
demonstrated good performance in differentiating individuals with MODY from the
other two diabetes types [20]. Usability of the risk calculator was enhanced by
incorporation of simple clinical variables including age of diagnosis, present age,
gender, parental history, BMI, HbA1c, and use of insulin or oral glucose-lowering
drugs. Of note, the risk calculator has not been validated in non-White ethnic groups.
Biomarkers can also help identify people who are more likely to have monogenic
diabetes. These biomarkers include C-peptide, islet autoimmune antibodies, high-
sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol [21–24].
C-peptide is a protein that is co-secreted with insulin in equimolar quantities and
may serve as a surrogate of insulin secretion. C-peptide levels are undetectable in
people with absolute insulin deficiency and therefore can be used to differentiate
between type 1 and non-type 1 diabetes [21]. It should be pointed out that endoge-
nous insulin secretion may persist for several years or during honeymoon period in
people with type 1 diabetes. Duration of diabetes should be considered when inter-
preting C-peptide levels.
Anti-islet autoimmune markers include anti-glutamate decarboxylase (GAD),
tyrosine phosphatase-related islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A),
and (pro)insulin (IAA) autoantibodies. In general, the presence of anti-islet autoan-
tibodies indicates type 1 diabetes. However, about 10–20% of White people with
type 1 diabetes and close to 40% of their non-White counterparts do not harbor
anti-islet autoantibodies [5, 25]. Overtime, autoantibody titers decline and serocon-
version may occur. As such, absence of antibodies does not fully exclude type 1
diabetes especially for non-White populations.
A study conducted in the UK tested the diagnostic value of a screening pathway
consisting of biomarkers in 1365 people with diabetes onset <30 years and an enrol-
ment age <50 years [1]. In this algorithm, molecular genetic testing was performed
for individuals with evidence of endogenous insulin secretion based on non-use of
insulin therapy or detectable urine C-peptide to creatinine ratio, and negative anti-
islet autoantibodies. Using this pathway, monogenic diabetes will be uncovered in
one of every five people sequenced, improving the efficiency and cost-effectiveness
of testing. In another study consisting of 3933 people aged 1–18 years with newly
diagnosed diabetes, 88% were positive for at least one of four anti-islet autoantibod-
ies. MODY was detected in 15% of people who were autoantibody negative and in
none of those with positive autoantibodies who likely had type 1 diabetes. As
expected, people with MODY had less severe hyperglycemia and were less likely to
present with osmotic symptoms or diabetic ketoacidosis. Narrowing the case selec-
tion to those with negative autoantibody and either an HbA1c level <7.5% at
138 A. O. Y. Luk and L.-L. Lim
GCK-MODY
People with GCK-MODY have mild fasting hyperglycemia with a slow deteriora-
tion of beta-cell function over time. Glucose homeostasis is tightly regulated at a
higher set point with the HbA1c levels range between 5.8 and 7.6% (40–60 mmol/
mol) and a fasting plasma glucose level of 5.4–8.3 mmol/L (97–149 mg/dL)
(Table 6.1) [27, 28]. They are usually non-obese and have normal blood pressure
and lipid levels [29, 30].
A cross-sectional study in the UK evaluated the prevalence and severity of
diabetes-related complications in 99 individuals with GCK-MODY (median age
48.6 years; median HbA1c 6.9% [52 mmol/mol]), 91 non-mutation carriers without
diabetes (median age 52.2 years; median HbA1c 5.8% [40 mmol/mol]), and 83
patients with young-onset type 2 diabetes (median age 54.7 years; median HbA1c
7.8% [62 mmol/mol]) [9]. Despite prolonged exposure to mild fasting hyperglyce-
mia from birth, long-term complications are uncommon in patients with GCK-
MODY. Compared with non-mutation carriers without diabetes, people with
GCK-MODY reported a similar prevalence of microvascular complications (defined
as either persistent albuminuria or preproliferative and advanced stages of retinopa-
thy; 1% versus 3%) and macrovascular complications (4% versus 11%) [9]. The
6 Precision Genetics for Monogenic Diabetes 139
corresponding prevalence was lower than people with young-onset type 2 diabetes
(1% versus 36% for microvascular complications and 4% versus 30% for macrovas-
cular complications) [9]. Although people with GCK-MODY had a higher preva-
lence of non-proliferative retinopathy than non-mutation carriers (30% versus
14%), 81% of them were mild in severity with fewer than five microaneurysms [9].
Given its low yield, annual screening for retinopathy is currently not recommended
for GCK-MODY [28, 31].
Although adequate glycemic control is required to prevent complications in
other types of diabetes, people with GCK-MODY do not usually require glucose-
lowering drugs [31, 32] in the absence of coexisting type 1 or type 2 diabetes, obe-
sity, or pregnancy [28]. The Exeter group reported that 13.5% and 7.5% of people
with GCK-MODY were treated with a low dose of oral glucose-lowering drugs
(5 mg glibenclamide and 660 mg metformin daily) and insulin therapy (0.1–0.8 units/
kg/day), respectively, prior to genetic testing [32]. HbA1c levels were not signifi-
cantly different in those with and without treatment (median HbA1c 6.5% [48 mmol/
mol] versus 6.4% [46 mmol/mol]) [32]. Of note, after genetic testing, HbA1c levels
remained unchanged post-cessation of treatment, indicating that glucose-lowering
treatment is generally not required in GCK-MODY [32].
The prevalence of MODY in women with gestational diabetes mellitus ranges
between 0.1% and 6.0% [28, 33]. To differentiate GCK-MODY from gestational
diabetes mellitus, genetic testing can be performed in women with a fasting glucose
level ≥5.5 mmol/L (99 mg/dL) and BMI <25 kg/m2 [34]. Compared with HNF1A-
MODY, GCK-MODY is more difficult to control with higher glycemic excursions
and higher rate of miscarriage (33.3% versus 14.0%), especially during the first
trimester of pregnancy [33]. Given the risk of miscarriage associated with invasive
fetal genotyping, serial monitoring of fetal growth is a pragmatic approach to guide
insulin use in pregnant women with GCK-MODY [31, 33, 35]. If the offspring
inherits the maternal GCK mutation, the offspring’s glucose setpoint is increased
with normal fetal growth, and thus, insulin therapy is not required during pregnancy
[28, 31]. Injudicious use of insulin therapy in such a case has been reported to
reduce endogenous maternal insulin secretion with increased risk of small for ges-
tational age [35, 36]. If the offspring is unaffected, in utero exposure to maternal
hyperglycemia increases fetal insulin secretion leading to macrosomia, defined as
fetal abdominal circumference >75th centile (Table 6.1). Insulin therapy is therefore
recommended with labor induction at 38 weeks in these pregnant women with
GCK-MODY [28, 31].
HNF1A-MODY
preconception, or [2] continue glyburide until late first trimester and complete tran-
sition to insulin therapy by 26 weeks gestation [50]. The latter is suggested only for
women with glyburide-treated HNF1A-MODY who have attained optimal glycemic
control preconception [50].
HNF4A-MODY
HNF1B-MODY
with insulin at diagnosis, which increased to 79% after 12 years of follow-up likely
due to progressive deterioration of beta-cell and kidney functions [60]. The median
total insulin dose was 0.55 units/kg/day (interquartile range [IQR] 0.39–0.70) with
a median HbA1c level of 7.3% (56 mmol/mol) (IQR 6.7–8.4% [50–68 mmol/mol])
[60, 61]. Similar to mutations in other HNF-transcription factors, HNF1B-MODY
is commonly associated with cardiovascular risk factors and diabetes-related com-
plications (Table 6.1) [60, 61].
Given its very low prevalence, evidence about the intrauterine effects of treat-
ment in pregnant women with HNF1B-MODY has been limited. In a UK study
involving 21 HNF1B mutation carriers, among offspring with HNF1B-MODY born
to unaffected mothers, their birthweights were significantly reduced (median 2.4 kg
[IQR 1.8–33]), of whom 69% were small for gestational age [62]. This is due to
reduced fetal insulin secretion, leading to a decrease in insulin-mediated fetal
growth. By contrast, when both mother and offspring had HNF1B-MODY, there
was an increase in birthweight (median 3.8 kg [IQR 3.3–4.6]) [62]. Despite HNF1B
mutations, pancreatic beta-cells of the offspring remain to be glucose-sensitive, and
thus, fetal insulin secretion is augmented in the presence of maternal hyperglyce-
mia, leading to an increase in fetal growth.
Individuals with neonatal diabetes usually present in the first 6 months of age. It
affects 1 in 90,000–160,000 live births [63]. The KCNJ11 and ABCC8 genes encode
for Kir6.2 (inner subunit) and SUR1 (outer subunit) of the ATP-sensitive potassium
(KATP) channel, respectively [64]. Mutations in KCNJ11 and ABCC8 account for
40% of cases of NDM with a marked reduction in pancreatic beta-cell insulin sec-
tion [63]. The median age of diagnosis in people with KCNJ11 or ABCC8 mutations
was 9.6 weeks (IQR 6.1–18.3 weeks) [65, 66].
Neonatal diabetes should be suspected in infants with acute hyperglycemia, typi-
cally with blood glucose levels persistently above 14 mmol/L (252 mg/dL) for more
than 7 days. Although neonatal diabetes is commonly diagnosed in the early neona-
tal period, it can still manifest up to 12 months of age with failure to thrive [67]. The
frequency of diabetic ketoacidosis at diagnosis ranges between 30% and 75% [65,
66]. Given that KATP channels are found in the brain, people with KCNJ11 mutations
may experience sleep disturbances and attention deficit hyperactivity disorder, and
even DEND syndrome which is a triad of developmental delays, seizures, and neo-
natal diabetes [68, 69].
People with KCNJ11 or ABCC8 mutations will usually require insulin therapy
during acute hyperglycemia. For the majority of them, treatment can be subse-
quently converted to high-dose sulfonylureas (typically 0.5–1.0 mg/kg/day of gly-
buride) [63]. A Monogenic Diabetes Registry reported a delay in having genetic
diagnosis of neonatal diabetes after clinical diagnosis by a median of 10.4 weeks
6 Precision Genetics for Monogenic Diabetes 143
(IQR 1.6–58.2) [70]. Given the potential for adverse neurocognitive effects, early
initiation of sulfonylureas should be considered even before genetic testing.
INS-NDM
Mutations in the insulin gene (INS) are the second most common cause of neonatal
diabetes [71]. These mutations lead to protein misfolding with increased endoplas-
mic reticulum stress and, subsequently, pancreatic beta-cell death [72]. Individuals
with INS mutations have similar presentations to that in those with early-onset type
1 diabetes, and 30% of them may present with diabetic ketoacidosis [63]. The
majority of cases are diagnosed in the first 6 months of age with a median age of
10 weeks (IQR 6.1–17.4) [63]. Insulin therapy is recommended in these people [63].
Conclusion
References
1. Shields BM, Shepherd M, Hudson M, McDonald TJ, Coldough K, Peters J, Knight B, Hyde C,
Ellard S, Pearson ER, Hattersley AT, on behalf of the UNITED study team. Population-based
assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in
young-onset patients. Diabetes Care. 2017;40:1017–25.
2. Irgens HU, Molnes J, Johansson BB, Ringdal M, Skrivarhaug T, Undlien DE, Sovik O,
Joner G, Molven A, Njolstad PR. Prevalence of monogenic diabetes in the population-based
Norwegian childhood diabetes registry. Diabetologia. 2013;56:1512–219.
3. Tattersall RB, Fajans SS, Arbor A. Prevalence of diabetes and glucose intolerance in 199 off-
spring of thirty-seven conjugal diabetic parents. Diabetes. 1975;24:452–62.
4. Schober E, Rami B, Grabert M, Thon A, Kapellen T, Reinehr T, Holl RW. Phenotypical aspects
of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes
mellitus (T2DM) in children and adolescents: experience from a large multicentre database.
Diabet Med. 2009;26:466–73.
144 A. O. Y. Luk and L.-L. Lim
22. McDonald TJ, Colclough K, Brown R, et al. Islet autoantibodies can discriminate maturity-
onset diabetes of the young (MODY) from type 1 diabetes. Diabet Med. 2011;28:1028–33.
23. Owen KR, Thanabalasingham G, James TJ, Karpe F, Farmer AJ, McCarthy MI, Gloyn
AL. Assessment of high-sensitivity C-reactive protein levels as diagnostic discrimina-
tor of maturity-onset diabetes of the young due to HNF1A mutations. Diabetes Care.
2010;33:1919–24.
24. Pal A, Farmer AJ, Dudley C, Selwood MP, Barrow BA, Klyne R, Grew JP, McCarthy MI,
Gloyn AL, Owen KR. Evaluation of serum 1,5anhydroglucitol levels as a clinical test to dif-
ferentiate subtypes of diabetes. Diabetes Care. 2010;33:252–7.
25. Tuomi T, Zimmet P, Rowley MJ, Min HK, Vichayanrat A, Lee HK, Rhee BD, Vannasaeng
S, Humphrey AR, Mackay IR. Differing frequency of autoantibodies to glutamic acid decar-
boxylase among Koreans, Thais, and Australians with diabetes mellitus. Clin Immumol
Immunopathol. 1995;74:202–6.
26. Xu JY, Dan QH, Chan V, Wat NM, Tam S, Tiu SC, Lee KF, Siu SC, Tsang MW, Fung LM,
Chan KW, Lam KS. Genetic and clinical characteristics of maturity-onset diabetes of the
young in Chinese patients. Eur J Hum Genet. 2005;13:422–7.
27. Steele AM, Wensley KJ, Ellard S, Murphy R, Shepherd M, Colclough K, et al. Use of HbA1c
in the identification of patients with hyperglycaemia caused by a glucokinase mutation: obser-
vational case control studies. PLoS One. 2013;8(6):e65326.
28. Chakera AJ, Steele AM, Gloyn AL, Shepherd MH, Shields B, Ellard S, et al. Recognition and
management of individuals with hyperglycemia because of a heterozygous glucokinase muta-
tion. Diabetes Care. 2015;38(7):1383–92.
29. Page RC, Hattersley AT, Levy JC, Barrow B, Patel P, Lo D, et al. Clinical characteristics of
subjects with a missense mutation in glucokinase. Diabet Med. 1995;12(3):209–17.
30. Velho G, Blanché H, Vaxillaire M, Bellanné-Chantelot C, Pardini VC, Timsit J, et al.
Identification of 14 new glucokinase mutations and description of the clinical profile of 42
MODY-2 families. Diabetologia. 1997;40(2):217–24.
31. Broome DT, Pantalone KM, Kashyap SR, Philipson LH. Approach to the patient with MODY-
monogenic diabetes. J Clin Endocrinol Metab. 2021;106(1):237–50.
32. Stride A, Shields B, Gill-Carey O, Chakera AJ, Colclough K, Ellard S, et al. Cross-sectional
and longitudinal studies suggest pharmacological treatment used in patients with glucokinase
mutations does not alter glycaemia. Diabetologia. 2014;57(1):54–6.
33. Bacon S, Schmid J, McCarthy A, Edwards J, Fleming A, Kinsley B, et al. The clinical manage-
ment of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young. Am
J Obstet Gynecol. 2015;213(2):236.e1–7.
34. Chakera AJ, Spyer G, Vincent N, Ellard S, Hattersley AT, Dunne FP. The 0.1% of the popu-
lation with glucokinase monogenic diabetes can be recognized by clinical characteristics in
pregnancy: the Atlantic diabetes in pregnancy cohort. Diabetes Care. 2014;37(5):1230–6.
35. Spyer G, Hattersley AT, Sykes JE, Sturley RH, MacLeod KM. Influence of maternal and fetal
glucokinase mutations in gestational diabetes. Am J Obstet Gynecol. 2001;185(1):240–1.
36. Spyer G, Macleod KM, Shepherd M, Ellard S, Hattersley AT. Pregnancy outcome in patients
with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med.
2009;26(1):14–8.
37. Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision making.
Diabetes Care. 2011;34(8):1878–84.
38. Hattersley AT, Patel KA. Precision diabetes: learning from monogenic diabetes. Diabetologia.
2017;60(5):769–77.
39. Bacon S, Kyithar MP, Rizvi SR, Donnelly E, McCarthy A, Burke M, et al. Successful main-
tenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY
cohort. Diabet Med. 2016;33(7):976–84.
40. Steele AM, Shields BM, Shepherd M, Ellard S, Hattersley AT, Pearson ER. Increased all-cause
and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A
gene. Diabet Med. 2010;27(2):157–61.
146 A. O. Y. Luk and L.-L. Lim
41. Shepherd MH, Shields BM, Hudson M, Pearson ER, Hyde C, Ellard S, Hattersley AT, Patel
KA, for the UNITED study. A UK nationwide prospective study of treatment change in
MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after
discontinuing insulin and metformin. Diabetologia. 2018;61:2520–7.
42. Tuomi T, Honkanen EH, Isomaa B, Sarelin L, Groop LC. Improved prandial glucose control
with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with
maturity-onset diabetes of the young type 3. Diabetes Care. 2006;29(2):189–94.
43. Docena MK, Faiman C, Stanley CM, Pantalone KM. Mody-3: novel HNF1A mutation
and the utility of glucagon-like peptide (GLP)-1 receptor agonist therapy. Endocr Pract.
2014;20(2):107–11.
44. Østoft SH, Bagger JI, Hansen T, Pedersen O, Faber J, Holst JJ, et al. Glucose-lowering effects
and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when
treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes
Care. 2014;37(7):1797–805.
45. Fantasia KL, Steenkamp DW. Optimal glycemic control in a patient with HNF1A MODY with
GLP-1 RA monotherapy: implications for future therapy. J Endocr Soc. 2019;3(12):2286–9.
46. Christensen AS, Hædersdal S, Støy J, Storgaard H, Kampmann U, Forman JL, et al. Efficacy
and safety of glimepiride with or without Linagliptin treatment in patients with HNF1A dia-
betes (maturity-onset diabetes of the young type 3): a randomized, double-blinded, placebo-
controlled, crossover trial (GLIMLINA). Diabetes Care. 2020;43(9):2025–33.
47. Pruhova S, Dusatkova P, Neumann D, Hollay E, Cinek O, Lebl J, et al. Two cases of diabetic
ketoacidosis in HNF1A-MODY linked to severe dehydration: is it time to change the diagnos-
tic criteria for MODY? Diabetes Care. 2013;36(9):2573–4.
48. Hohendorff J, Szopa M, Skupien J, Kapusta M, Zapala B, Platek T, et al. A single dose of
dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY
than in type 2 diabetes mellitus. Endocrine. 2017;57(2):272–9.
49. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperin-
sulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS
Med. 2007;4(4):e118.
50. Shepherd M, Brook AJ, Chakera AJ, Hattersley AT. Management of sulfonylurea-treated
monogenic diabetes in pregnancy: implications of placental glibenclamide transfer. Diabet
Med. 2017;34(10):1332–9.
51. Poolsup N, Suksomboon N, Amin M. Efficacy and safety of oral antidiabetic drugs in com-
parison to insulin in treating gestational diabetes mellitus: a meta-analysis. PLoS One.
2014;9(10):e109985.
52. Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HA, Lumb PJ, et al. Molecular genet-
ics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha muta-
tions in a large European collection. Diabetologia. 2005;48(5):878–85.
53. Bacon S, Kyithar MP, Condron EM, Vizzard N, Burke M, Byrne MM. Prolonged episodes of
hypoglycaemia in HNF4A-MODY mutation carriers with IGT. Evidence of persistent hyper-
insulinism into early adulthood. Acta Diabetol. 2016;53(6):965–72.
54. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT. Genetic cause of
hyperglycaemia and response to treatment in diabetes. Lancet. 2003;362(9392):1275–81.
55. Broome DT, Tekin Z, Pantalone KM, Mehta AE. Novel use of GLP-1 receptor agonist therapy
in HNF4A-MODY. Diabetes Care. 2020;43(6):e65.
56. Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in
the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha
in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat.
2013;34(5):669–885.
57. Dickens LT, Naylor RN. Clinical Management of Women with monogenic diabetes during
pregnancy. Curr Diab Rep. 2018;18(3):12.
6 Precision Genetics for Monogenic Diabetes 147
58. Warncke K, Kummer S, Raile K, Grulich-Henn J, Woelfle J, Steichen E, et al. Frequency and
characteristics of MODY 1 (HNF4A mutation) and MODY 5 (HNF1B mutation): analysis
from the DPV database. J Clin Endocrinol Metab. 2019;104(3):845–55.
59. Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and
extra-renal disease-an expanding clinical spectrum. Nat Rev Nephrol. 2015;11(2):102–12.
60. Dubois-Laforgue D, Cornu E, Saint-Martin C, Coste J, Bellanné-Chantelot C, Timsit
J. Diabetes, associated clinical Spectrum, long-term prognosis, and genotype/phenotype cor-
relations in 201 adult patients with hepatocyte nuclear factor 1B (HNF1B) molecular defects.
Diabetes Care. 2017;40(11):1436–43.
61. Pearson ER, Badman MK, Lockwood CR, Clark PM, Ellard S, Bingham C, et al. Contrasting
diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and -1beta mutations.
Diabetes Care. 2004;27(5):1102–7.
62. Edghill EL, Bingham C, Slingerland AS, Minton JA, Noordam C, Ellard S, et al. Hepatocyte
nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation:
support for a critical role of HNF-1beta in human pancreatic development. Diabet Med.
2006;23(12):1301–6.
63. Lemelman MB, Letourneau L, Greeley SAW. Neonatal diabetes mellitus: an update on diag-
nosis and management. Clin Perinatol. 2018;45(1):41–59.
64. Pipatpolkai T, Usher S, Stansfeld PJ, Ashcroft FM. New insights into K(ATP) channel gene
mutations and neonatal diabetes mellitus. Nat Rev Endocrinol. 2020;16(7):378–93.
65. Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT. Effective treatment
with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) muta-
tions. Diabetes Care. 2008;31(2):204–9.
66. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating
mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and per-
manent neonatal diabetes. N Engl J Med. 2004;350(18):1838–49.
67. Rubio-Cabezas O, Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity,
clinical approach to diagnosis, and therapeutic options. Horm Res Paediatr. 2013;80(3):137–46.
68. Carmody D, Pastore AN, Landmeier KA, Letourneau LR, Martin R, Hwang JL, et al. Patients
with KCNJ11-related diabetes frequently have neuropsychological impairments compared
with sibling controls. Diabet Med. 2016;33(10):1380–6.
69. Landmeier KA, Lanning M, Carmody D, Greeley SAW, Msall ME. ADHD, learning dif-
ficulties and sleep disturbances associated with KCNJ11-related neonatal diabetes. Pediatr
Diabetes. 2017;18(7):518–23.
70. Carmody D, Bell CD, Hwang JL, Dickens JT, Sima DI, Felipe DL, et al. Sulfonylurea treat-
ment before genetic testing in neonatal diabetes: pros and cons. J Clin Endocrinol Metab.
2014;99(12):E2709–R2714.
71. Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, et al. Insulin mutation
screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of
neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes.
2008;57(4):1034–42.
72. Park SY, Ye H, Steiner DF, Bell GI. Mutant proinsulin proteins associated with neonatal dia-
betes are retained in the endoplasmic reticulum and not efficiently secreted. Biochem Biophys
Res Commun. 2010;391(3):1449–54.
Chapter 7
Diabetic Kidney Disease: Identification,
Prevention, and Treatment
Abbreviations
M. L. Caramori (*)
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Division of
Pediatric Nephrology, Department of Pediatrics, University of Minnesota,
Minneapolis, MN, USA
e-mail: [email protected]
P. Rossing
Steno Diabetes Center Copenhagen, Herlev, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Diabetes and its complications are a very extensive public health problem, and
about 10% of the world’s population has diabetes [1]. Diabetes is associated with
increased mortality and morbidity, and it is the most common cause of end-stage
kidney disease (ESKD) in the USA and other developed countries [1], being
responsible for more than 47% of the new ESKD cases in the USA. This is in large
part due to type 2 diabetes (T2D) as most patients with diabetes have T2D rather
than type 1 diabetes (T1D). However, the proportion of individuals starting kidney
replacement therapy due to diabetes varies significantly, ranging from 13% in
China to 66% in Singapore [1]. The likelihood of a patient with diabetes developing
chronic kidney disease (CKD) is about 50% for patients with T1D and 30% for
those with T2D. Although data from NHANES have shown an overall stable preva-
lence of CKD among patients with T2D (about 28.4% in 1988–1994 and 26.2% in
2009–2014), there was an increase in the proportion of patients with T2D with
reduced GFR and a decline in the prevalence of albuminuria over time [2].
Importantly, patients with T2D and CKD are at a higher risk for cardiovascular
morbidity and mortality than those without CKD [3, 4]. The 10-year standardized
cardiovascular mortality increased from 3.4% in patients without diabetes or CKD
to 6.7% among those with diabetes and no CKD and to 19.6% (a 3x increase com-
pared to diabetes only) among those with both diabetes and CKD [4]. These patients
often require multiple therapies aimed at prevention of progressive CKD and its
associated comorbidities and mortality, which adds to their burden. Underserved/
under-represented populations are disproportionately affected by both T2D and
CKD. ESKD is devastating to the individual and their families and of enormous
financial and social consequences. Rare in the past, in the more recent decades, we
have observed a vast increase in the frequency of T2D in children and adolescents.
These individuals have a high prevalence of hypertension and albuminuria [5], and
ESKD and death are particularly common among underrepresented/underserved
youth [6–8].
Pathophysiology
Diabetic nephropathy is a chronic condition that develops over many years, and it is
characterized by a gradual increase in urinary albumin excretion, blood pressure
levels and cardiovascular risk, declining glomerular filtration rate (GFR), and even-
tual ESKD. Over the past two decades, studies indicate the presence of another
phenotype, one that does not follow the classical natural history of disease. Thus,
reduced GFR in the presence of normal urinary albumin levels has been reported in
25 to 50% of patients with T1D [9, 10] and 45–57% of those with T2D [11–13]. The
clinical syndrome is associated with characteristic histopathological features [14–
16] and also with other conditions such as hypertensive renal disease, and
7 Diabetic Kidney Disease: Identification, Prevention, and Treatment 151
Mildly to
G3a 45–59
moderately decreased
Fig. 7.1 Prognosis of chronic kidney disease by estimated glomerular filtration rate and albumin-
uria. (Source: Reprinted by permission from KDIGO – Kidney Disease: Improving Outcomes [158])
There are strong relationships between kidney structure and function in T1D [15,
27, 28]. Mesangial fractional volume is inversely correlated with GFR and directly
correlated with albuminuria [15, 28] and blood pressure [28, 29]. GBM width is a
strong independent predictor of progression to clinically advanced kidney disease
among normoalbuminuric patients with T1D [30]. Global glomerular sclerosis [30,
31] and interstitial expansion [25, 30] are additional independent predictors of GFR
loss in these patients. Although increases in podocyte foot process width also cor-
relate with albuminuria increases in T1D [32–34], our longitudinal studies indicate
that podocyte parameters did not predict progression in patients with T1D who had
no clinical manifestations of CKD at time of their research kidney biopsies [35].
Risk Factors
Multiple factors are associated with CKD in diabetes, and diabetes duration is one
of the strongest risk factors for diabetic nephropathy, particularly in T1D. Factors
that influence the development of kidney disease may not be the same as those influ-
encing its progression.
Blood Glucose
Data from multiple observational and intervention studies in both T1D and T2D
support indicate that hyperglycemia is an important risk factor for the development
and progression of diabetic nephropathy [36]. Greater variability in HbA1c is inde-
pendently associated with albuminuria and diabetic nephropathy [37–39], and vari-
ability in blood glucose by continuous glucose monitoring (CGM) has also been
associated with complications.
Blood Pressure
Elevated blood pressure levels are among the most important risk factors for the
development and progression of diabetic kidney disease. Variability in systolic and
diastolic blood pressure independently predicts the development of albuminuria in
T1D [37, 38]. Changes in blood pressure may be subtle, sometimes manifesting
only as reduced nocturnal diastolic blood pressure dipping [40]. Hypertension is
present in about 40% of newly diagnosed patients with T2D [41].
Additional risk factors include lipids [42–45],smoking [46], insulin resistance
[47, 48], uric acid levels [49], metabolic syndrome [50], ethnicity [51–55], and
genetic and epigenetic factors [56–62]. Many of the risk factors for kidney disease
in diabetes overlap with cardiovascular risk factors [63].
154 M. L. Caramori and P. Rossing
Some
patients
Anti-platelet
therapies
Most
patients
SGLT2 RAS
inhibitors blockade
All
patients
Blood
Glycemic pressure Lipid
control control management
Fig. 7.2 Management of risk factors for kidney and heart disease. (Source: Reprinted by permis-
sion from KDIGO – Kidney Disease: Improving Outcomes [20])
glucose and blood pressure control with RAS blockers, aspirin, and lipid-lowering
agents) had lower CKD rates [89].
The risk of developing diabetic nephropathy is significantly reduced by achieve-
ment and maintenance of good blood glucose and blood pressure control. Moreover,
multiple strategies are now available to reduce the rate of CKD progression slow in
diabetes.
Lifestyle and dietary modifications: Dietary modifications target sodium, pro-
tein, lipid content, and caloric content. Dietary sodium restriction reduces albumin-
uria [90] and potentiates ARB treatment effects [91] when added to RAS blockade.
Reduction of sodium intake to <2 g of sodium per day is recommended for patients
with diabetic nephropathy [88]. Low-protein diet (0.8 g protein/kg body weight/
day) improves GFR but not albuminuria in patients with diabetes on all stages of
nephropathy [92] and reduced mortality and progression to ESKD among protein-
uric patients with T1D [93]. However, a higher protein intake (1.0–1.2 g protein/kg
body weight/day) is recommended for patients in peritoneal dialysis [88]. The
eGFR and albuminuria impact of low-carbohydrate, Mediterranean, and low-fat
diets seem to be similar [94]. Bariatric surgery was also associated with reduced
156 M. L. Caramori and P. Rossing
albuminuria among adults with T2D [95] and adolescents with or without T2D [96].
While there have been no good trials of smoking cessation, smoking increases the
likelihood of CKD, and smoking cessation should be encouraged.
Glycemic Control
The Diabetes Control and Complications Trial (DCCT) indicate that patients ran-
domized to intensive control had a 39% relative risk reduction for development of
moderately elevated albuminuria (or microalbuminuria) and a 54% risk reduction
for development of macroalbuminuria or proteinuria [97]. Mean achieved HbA1c
was 7.0% and 9.1%, respectively. Importantly, there was no HbA1c threshold below
which risk was not reduced [98]. Additionally, the Epidemiology of Diabetes and Its
Complications (EDIC) follow-up of the DCCT cohort described a significant reduc-
tion in the risk of having eGFR <60 mL/min/1.73 m2 [98] and ESKD [99] among
individuals who were previously randomized to the intensive arm. Glycemic vari-
ability and time in range (time in glycemic target) in patients with T1D may also be
important for the development of renal complications [100, 101].
The UKPDS also demonstrated a significant benefit of improved glycemic con-
trol on the risk of developing elevated urinary albumin levels [102]. Like the T1D
data [98], no threshold of HbA1c and risk was observed [103]. In the ADVANCE
study, patients randomized to intensive therapy (HbA1c 6.5% versus 7.3%) had a
9% relative risk reduction of moderately elevated albuminuria, a 30% reduction in
the development of severely increased albuminuria, and a 65% reduction in ESKD
over 5 years [104, 105]. These findings were corroborated by the ACCORD study
[106]; progression of albuminuria was reduced and regression increased. However,
patients with CKD randomized to the intensive glucose management arm had a
significantly greater risk of cardiovascular and all-cause mortality [107], supporting
the recommendation of individualized HbA1c targets.
Organ Protection
SGLT2 Inhibitor
In the recent years, the concept of organ protection in diabetes has evolved, and cur-
rently specific classes of glucose-lowering agents are recommended for kidney and/
or cardiovascular protection. Although there are differences in the beneficial effects
and safety profile among the various FDA-approved sodium-glucose cotransporter-2
(SGLT2) inhibitors, these agents (empagliflozin, canagliflozin, and dapagliflozin)
have shown to reduce major adverse cardiovascular events, rates of hospitalization
for heart failure, and renal protection [108, 109]. CREDENCE, the first SGLT2
inhibitor study dedicated to T2D patients with CKD, showed a major benefit on
renal outcomes, heart failure, and major adverse cardiovascular events [110]. The
7 Diabetic Kidney Disease: Identification, Prevention, and Treatment 157
Physical activity
Lifestyle therapy Nutrition
Weight loss
Fig. 7.3 Treatment algorithm for selecting antihyperglycemic drugs for patients with type 2 dia-
betes and chronic kidney disease, in addition to lifestyle therapy. (Source: Reprinted by permission
from KDIGO – Kidney Disease: Improving Outcomes [20])
158 M. L. Caramori and P. Rossing
a higher risk of atrial fibrillation but also higher morbidity and mortality associated
with atrial fibrillation complications [144], and anticoagulation is often recom-
mended. Direct oral anticoagulants are usually preferred due to their reduced risk
for bleeding, equivalent or superior thrombosis prevention, and possible reduction
in progression of CKD [145].
Monitoring
In progressive CKD from stage 3 onward, bone chemistry, full blood count, and iron
stores should be assessed 3–6 monthly.
• Glucose control: Red blood cell and protein turnover are abnormal in CKD, mak-
ing the interpretation of HbA1c, glycated albumin, and fructosamine results dif-
ficult, especially when eGFR is <30 mL/min/1.73m2. Self-monitoring of blood
glucose and use of continuous glucose monitoring (CGM) systems are indicated,
particularly if treatment can cause hypoglycemia [88].
• Medication dosage: Metformin should be used with caution in patients with
eGFR <45 mL/min/1.73 m2 and discontinued when eGFR reaches 30 mL/
min/1.73 m2 [146]. The dose of some but not all DPP-4 inhibitors and GLP-1 RA
may need to be reduced as kidney function declines. SGLT2 inhibitors become
less effective as GFR falls but should not be discontinued as they continue to
confer cardiovascular protection. Sulfonylurea (glibenclamide, gliclazide, and
tolbutamide) dose needs to be reduced in CKD. Meglitinides have minimal renal
excretion and can be used in CKD. Thiazolidinediones (rosiglitazone and piogli-
tazone) are predominantly metabolized in the liver, but fluid retention may limit
their use in patients with advanced CKD and ESKD. It is important to consider
that insulin is also excreted by the kidney, and dose reduction may be indicated
once eGFR reaches 50 mL/min/1.73m2.
Pregnancy outcomes are poorer in patients with DKD [147]. Both T1D and T2D
patients with CKD have an even greater risk of hypertension, preeclampsia, abnor-
mal fetal growth, and preterm delivery than patients with diabetes and no CKD
[148, 149]. These patients are also at increased risk of retinopathy progression. Pre-
pregnancy counseling and pregnancy planning can potentially improve outcomes.
Glucose and blood pressure control should be optimized, glucose-lowering thera-
pies need to be revised and may require modification, and RAS inhibitors should be
discontinued and substituted by therapies which are safe in pregnancy. Statins are
also contraindicated in pregnancy.
160 M. L. Caramori and P. Rossing
Intensive
Kaplan-Meier Estimates Survival Conventional
1.00
Survival Probability
0.75
HR 0.55
p = 0.005
0.50
0.25
Fig. 7.4 Long-term effects of 8 years of intensive multifactorial intervention targeting lifestyle
and heart and kidney risk factors compared to standard of care
Organization of Care
Structured care of patients with T2D and CKD delivered by specialists working in
close collaboration and using clear protocols with specific treatment goals and tar-
gets reduces the rates of albuminuria [150, 151] and severe retinopathy and provides
greater kidney and cardiovascular benefits than routine care [88, 152–157]. The
8-year structured intensive multifactorial intervention described above (Steno-2
study) extended patients’ median survival for almost 8 years [154] (Fig. 7.4).
References
1. United States Renal Data System. 2020 USRDS Annual Data Report: Epidemiology of
Kidney Disease in the United States. In: National Institutes of Health NIoDaDaKD, editor.
Bethesda, MD; 2020.
2. Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical
manifestations of kidney Disease among US adults with diabetes, 1988–2014.
JAMA. 2016;316(6):602–10.
4. Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney
disease and increased mortality risk in type 2 diabetes. Journal of the American Society of
Nephrology : JASN. 2013;24(2):302–8.
3. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, et al. Associations
of kidney disease measures with mortality and end-stage renal disease in individuals with and
without diabetes: a meta-analysis. Lancet. 2012;380(9854):1662–73.
5. Group TS. Rapid rise in hypertension and nephropathy in youth with type 2 diabetes: the
TODAY clinical trial. Diabetes Care. 2013;36(6):1735–41.
6. Dyck RF, Jiang Y, Osgood ND. The long-term risks of end stage renal disease and mortality
among first nations and non-first nations people with youth-onset diabetes. Can J Diabetes.
2014;38(4):237–43.
7 Diabetic Kidney Disease: Identification, Prevention, and Treatment 161
7. Dart AB, Sellers EA, Martens PJ, Rigatto C, Brownell MD, Dean HJ. High burden of kidney
disease in youth-onset type 2 diabetes. Diabetes Care. 2012;35(6):1265–71.
8. Chan JC, Lau ES, Luk AO, Cheung KK, Kong AP, Yu LW, et al. Premature mortal-
ity and comorbidities in young-onset diabetes: a 7-year prospective analysis. Am J Med.
2014;127(7):616–24.
9. Molitch ME, Steffes M, Sun W, Rutledge B, Cleary P, de Boer IH, et al. Development and
progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes
in the diabetes control and complications trial and the epidemiology of diabetes interventions
and complications study. Diabetes Care. 2010;33(7):1536–43.
10. Krolewski AS, Niewczas MA, Skupien J, Gohda T, Smiles A, Eckfeldt JH, et al. Early pro-
gressive renal decline precedes the onset of microalbuminuria and its progression to macro-
albuminuria. Diabetes Care. 2014;37(1):226–34.
11. Vistisen D, Andersen GS, Hulman A, Persson F, Rossing P, Jorgensen ME. Progressive
decline in estimated glomerular filtration rate in patients with diabetes after moderate loss in
kidney function-even without albuminuria. Diabetes Care. 2019;42(10):1886–94.
12. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, Group US. Risk factors
for renal dysfunction in type 2 diabetes: U.K. prospective diabetes study 74. Diabetes.
2006;55(6):1832–9.
13. Thomas MC, Macisaac RJ, Jerums G, Weekes A, Moran J, Shaw JE, et al. Nonalbuminuric
renal impairment in type 2 diabetic patients and in the general population (national evaluation
of the frequency of renal impairment cO-existing with NIDDM [NEFRON] 11). Diabetes
Care. 2009;32(8):1497–502.
14. Caramori ML, Fioretto P, Mauer M. Low glomerular filtration rate in normoalbumin-
uric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes.
2003;52(4):1036–40.
15. Caramori ML, Kim Y, Huang C, Fish AJ, Rich SS, Miller ME, et al. Cellular basis of diabetic
nephropathy: 1. Study design and renal structural-functional relationships in patients with
long-standing type 1 diabetes. Diabetes. 2002;51(2):506–13.
16. Mauer M, Caramori ML, Fioretto P, Najafian B. Glomerular structural-functional relation-
ship models of diabetic nephropathy are robust in type 1 diabetic patients. Nephrol Dial
Transplant. 2015;30(6):918–23.
17. Mazzucco G, Bertani T, Fortunato M, Bernardi M, Leutner M, Boldorini R, et al. Different
patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biop-
sies. American Journal of Kidney Diseases: The Official Journal of the National Kidney
Foundation. 2002;39(4):713–20.
18. Chong YB, Keng TC, Tan LP, Ng KP, Kong WY, Wong CM, et al. Clinical predictors of non-
diabetic renal disease and role of renal biopsy in diabetic patients with renal involvement: a
single Centre review. Ren Fail. 2012;34(3):323–8.
19. Sharma SG, Bomback AS, Radhakrishnan J, Herlitz LC, Stokes MB, Markowitz GS, et al.
The modern spectrum of renal biopsy findings in patients with diabetes. Clinical Journal of
the American Society of Nephrology: CJASN. 2013;8(10):1718–24.
20. Kidney Disease: Improving Global Outcomes Diabetes Work G. KDIGO 2020 Clinical
Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Inter.
2020;98(4S):S1–115.
21. Gansevoort RT, Brinkman J, Bakker SJ, De Jong PE, de Zeeuw D. Evaluation of measures of
urinary albumin excretion. Am J Epidemiol. 2006;164(8):725–7.
22. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new
equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.
23. Mauer SM. Structural-functional correlations of diabetic nephropathy. Kidney Int.
1994;45(2):612–22.
24. Mauer SM, Steffes MW, Brown DM. The kidney in diabetes. Am J Med. 1981;70(3):603–12.
25. Lane PH, Steffes MW, Fioretto P, Mauer SM. Renal interstitial expansion in insulin-dependent
diabetes mellitus. Kidney Int. 1993;43(3):661–7.
162 M. L. Caramori and P. Rossing
26. Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M. Podocyte detachment and reduced
glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes.
2007;56(8):2155–60.
27. Ellis EN, Steffes MW, Goetz FC, Sutherland DE, Mauer SM. Glomerular filtration surface in
type I diabetes mellitus. Kidney Int. 1986;29(4):889–94.
28. Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC. Structural-
functional relationships in diabetic nephropathy. J Clin Invest. 1984;74(4):1143–55.
29. Mauer SM, Sutherland DE, Steffes MW. Relationship of systemic blood pressure to nephro-
pathology in insulin-dependent diabetes mellitus. Kidney Int. 1992;41(4):736–40.
30. Caramori ML, Parks A, Mauer M. Renal lesions predict progression of diabetic nephropathy in
type 1 diabetes. Journal of the American Society of Nephrology: JASN. 2013;24(7):1175–81.
31. Harris RD, Steffes MW, Bilous RW, Sutherland DE, Mauer SM. Global glomerular scle-
rosis and glomerular arteriolar hyalinosis in insulin dependent diabetes. Kidney Int.
1991;40(1):107–14.
32. Ellis EN, Steffes MW, Chavers B, Mauer SM. Observations of glomerular epithelial cell
structure in patients with type I diabetes mellitus. Kidney Int. 1987;32(5):736–41.
33. Bjorn SF, Bangstad HJ, Hanssen KF, Nyberg G, Walker JD, Viberti GC, et al. Glomerular epithe-
lial foot processes and filtration slits in IDDM patients. Diabetologia. 1995;38(10):1197–204.
34. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG,
et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest.
1997;99(2):342–8.
35. Harindhanavudhi T, Parks A, Mauer M, Caramori ML. Podocyte structural parameters do not
predict progression to diabetic nephropathy in normoalbuminuric type 1 diabetic patients.
Am J Nephrol. 2015;41(4–5):277–83.
36. Nordwall M, Abrahamsson M, Dhir M, Fredrikson M, Ludvigsson J, Arnqvist HJ. Impact
of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy
and nephropathy: the VISS study (vascular diabetic complications in Southeast Sweden).
Diabetes Care. 2015;38(2):308–15.
37. Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complica-
tions in type 1 diabetes: data from the diabetes control and complications trial. Diabetes Care.
2008;31(11):2198–202.
38. Rotbain Curovic V, Theilade S, Winther SA, Tofte N, Tarnow L, Jorsal A, et al. Visit-to-visit
variability of clinical risk markers in relation to long-term complications in type 1 diabetes.
Diabet Med. 2021;38(5):e14459.
39. Hsu CC, Chang HY, Huang MC, Hwang SJ, Yang YC, Lee YS, et al. HbA1c variability
is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective
cohort study. Diabetologia. 2012;55(12):3163–72.
40. Dost A, Klinkert C, Kapellen T, Lemmer A, Naeke A, Grabert M, et al. Arterial hypertension
determined by ambulatory blood pressure profiles: contribution to microalbuminuria risk in
a multicenter investigation in 2,105 children and adolescents with type 1 diabetes. Diabetes
Care. 2008;31(4):720–5.
41. Hypertension in Diabetes Study (HDS): I. Prevalence of hypertension in newly presenting
type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic
complications. J Hypertens. 1993;11(3):309–17.
42. Daousi C, Bain SC, Barnett AH, Gill GV. Hypertriglyceridaemia is associated with an
increased likelihood of albuminuria in extreme duration (>50 years) type 1 diabetes. Diabet
Med. 2008;25(10):1234–6.
43. Thomas MC, Rosengard-Barlund M, Mills V, Ronnback M, Thomas S, Forsblom C,
et al. Serum lipids and the progression of nephropathy in type 1 diabetes. Diabetes Care.
2006;29(2):317–22.
44. Tolonen N, Forsblom C, Thorn L, Waden J, Rosengard-Barlund M, Saraheimo M, et al.
Relationship between lipid profiles and kidney function in patients with type 1 diabetes.
Diabetologia. 2008;51(1):12–20.
7 Diabetic Kidney Disease: Identification, Prevention, and Treatment 163
45. Tofte N, Suvitaival T, Ahonen L, Winther SA, Theilade S, Frimodt-Moller M, et al. Lipidomic
analysis reveals sphingomyelin and phosphatidylcholine species associated with renal impair-
ment and all-cause mortality in type 1 diabetes. Sci Rep. 2019;9(1):16398.
46. Rossing P, Hougaard P, Parving HH. Risk factors for development of incipient and overt
diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study.
Diabetes Care. 2002;25(5):859–64.
47. Bjornstad P, Snell-Bergeon JK, Rewers M, Jalal D, Chonchol MB, Johnson RJ, et al. Early
diabetic nephropathy: a complication of reduced insulin sensitivity in type 1 diabetes.
Diabetes Care. 2013;36(11):3678–83.
48. Hsu CC, Chang HY, Huang MC, Hwang SJ, Yang YC, Tai TY, et al. Association between
insulin resistance and development of microalbuminuria in type 2 diabetes: a prospective
cohort study. Diabetes Care. 2011;34(4):982–7.
49. Hovind P, Rossing P, Tarnow L, Johnson RJ, Parving HH. Serum uric acid as a predictor for
development of diabetic nephropathy in type 1 diabetes: an inception cohort study. Diabetes.
2009;58(7):1668–71.
50. Thorn LM, Forsblom C, Waden J, Saraheimo M, Tolonen N, Hietala K, et al. Metabolic
syndrome as a risk factor for cardiovascular disease, mortality, and progression of diabetic
nephropathy in type 1 diabetes. Diabetes Care. 2009;32(5):950–2.
51. Allawi J, Rao PV, Gilbert R, Scott G, Jarrett RJ, Keen H, et al. Microalbuminuria in non-
insulin-dependent diabetes: its prevalence in Indian compared with Europid patients. Br Med
J (Clin Res Ed). 1988;296(6620):462–4.
52. Sinha SK, Shaheen M, Rajavashisth TB, Pan D, Norris KC, Nicholas SB. Association of race/
ethnicity, inflammation, and albuminuria in patients with diabetes and early chronic kidney
disease. Diabetes Care. 2014;37(4):1060–8.
53. Nelson RG, Knowler WC, Pettitt DJ, Hanson RL, Bennett PH. Incidence and determi-
nants of elevated urinary albumin excretion in Pima Indians with NIDDM. Diabetes Care.
1995;18(2):182–7.
54. Joshy G, Dunn P, Fisher M, Lawrenson R. Ethnic differences in the natural progression of
nephropathy among diabetes patients in New Zealand: hospital admission rate for renal
complications, and incidence of end-stage renal disease and renal death. Diabetologia.
2009;52(8):1474–8.
55. Collins VR, Dowse GK, Finch CF, Zimmet PZ, Linnane AW. Prevalence and risk factors for
micro- and macroalbuminuria in diabetic subjects and entire population of Nauru. Diabetes.
1989;38(12):1602–10.
56. Sandholm N, Van Zuydam N, Ahlqvist E, Juliusdottir T, Deshmukh HA, Rayner NW, et al.
The genetic landscape of renal complications in type 1 diabetes. Journal of the American
Society of Nephrology: JASN. 2017;28(2):557–74.
57. van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, et al. A
genome-wide association study of diabetic kidney Disease in subjects with type 2 diabetes.
Diabetes. 2018;67(7):1414–27.
58. Seaquist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease.
Evidence for genetic susceptibility to diabetic nephropathy [see comments]. N Engl J Med.
1989;320(18):1161–5.
59. Fagerudd JA, Pettersson-Fernholm KJ, Gronhagen-Riska C, Groop PH. The impact of a
family history of type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic
nephropathy in patients with type I (insulin-dependent) diabetes mellitus. Diabetologia.
1999;42(5):519–26.
60. Thorn LM, Forsblom C, Fagerudd J, Pettersson-Fernholm K, Kilpikari R, Groop PH, et al.
Clustering of risk factors in parents of patients with type 1 diabetes and nephropathy. Diabetes
Care. 2007;30(5):1162–7.
61. Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, et al. A catalog of genetic
loci associated with kidney function from analyses of a million individuals. Nat Genet.
2019;51(6):957–72.
164 M. L. Caramori and P. Rossing
62. Keating ST, van Diepen JA, Riksen NP, El-Osta A. Epigenetics in diabetic nephropathy,
immunity and metabolism. Diabetologia. 2018;61(1):6–20.
63. Pilemann-Lyberg S, Hansen TW, Tofte N, Winther SA, Theilade S, Ahluwalia TS, et al. Uric
acid is an independent risk factor for decline in kidney function, cardiovascular events, and
mortality in patients with type 1 diabetes. Diabetes Care. 2019;42(6):1088–94.
64. Murussi M, Campagnolo N, Beck MO, Gross JL, Silveiro SP. High-normal levels of
albuminuria predict the development of micro- and macroalbuminuria and increased
mortality in Brazilian type 2 diabetic patients: an 8-year follow-up study. Diabet Med.
2007;24(10):1136–42.
65. de Zeeuw D, Ramjit D, Zhang Z, Ribeiro AB, Kurokawa K, Lash JP, et al. Renal risk and
renoprotection among ethnic groups with type 2 diabetic nephropathy: a post hoc analysis of
RENAAL. Kidney Int. 2006;69(9):1675–82.
66. Babazono T, Nyumura I, Toya K, Hayashi T, Ohta M, Suzuki K, et al. Higher levels of urinary
albumin excretion within the normal range predict faster decline in glomerular filtration rate
in diabetic patients. Diabetes Care. 2009;32(8):1518–20.
67. Zoppini G, Targher G, Chonchol M, Ortalda V, Negri C, Stoico V, et al. Predictors of esti-
mated GFR decline in patients with type 2 diabetes and preserved kidney function. Clinical
Journal of the American Society of Nephrology: CJASN. 2012;7(3):401–8.
68. Rossing P, Hommel E, Smidt UM, Parving HH. Reduction in albuminuria predicts a benefi-
cial effect on diminishing the progression of human diabetic nephropathy during antihyper-
tensive treatment. Diabetologia. 1994;37(5):511–6.
69. Heerspink HJL, Greene T, Tighiouart H, Gansevoort RT, Coresh J, Simon AL, et al. Change
in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of
treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 2019;7(2):128–39.
70. Kramer CK, Retnakaran R. Concordance of retinopathy and nephropathy over time in type 1
diabetes: an analysis of data from the diabetes control and complications trial. Diabet Med.
2013;30(11):1333–41.
71. Penno G, Solini A, Zoppini G, Orsi E, Zerbini G, Trevisan R, et al. Rate and determinants of
association between advanced retinopathy and chronic kidney disease in patients with type 2
diabetes: the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study.
Diabetes Care. 2012;35(11):2317–23.
72. Margolis DJ, Hofstad O, Feldman HI. Association between renal failure and foot ulcer or
lower-extremity amputation in patients with diabetes. Diabetes Care. 2008;31(7):1331–6.
73. Ko SH, Park SA, Cho JH, Song KH, Yoon KH, Cha BY, et al. Progression of cardiovascular
autonomic dysfunction in patients with type 2 diabetes: a 7-year follow-up study. Diabetes
Care. 2008;31(9):1832–6.
74. Nielsen FS, Hansen HP, Jacobsen P, Rossing P, Smidt UM, Christensen NJ, et al. Increased
sympathetic activity during sleep and nocturnal hypertension in type 2 diabetic patients with
diabetic nephropathy. Diabet Med. 1999;16(7):555–62.
75. Tahrani AA, Dubb K, Raymond NT, Begum S, Altaf QA, Sadiqi H, et al. Cardiac autonomic
neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study.
Diabetologia. 2014;57(6):1249–56.
76. Amin AP, Whaley-Connell AT, Li S, Chen SC, McCullough PA, Kosiborod MN, et al. The
synergistic relationship between estimated GFR and microalbuminuria in predicting long-
term progression to ESRD or death in patients with diabetes: results from the kidney early
evaluation program (KEEP). American Journal of Kidney Diseases: The Official Journal of
the National Kidney Foundation. 2013;61(4 Suppl 2):S12–23.
77. McCullough PA, Jurkovitz CT, Pergola PE, McGill JB, Brown WW, Collins AJ, et al.
Independent components of chronic kidney disease as a cardiovascular risk state: results from
the kidney early evaluation program (KEEP). Arch Intern Med. 2007;167(11):1122–9.
78. So WY, Kong AP, Ma RC, Ozaki R, Szeto CC, Chan NN, et al. Glomerular filtration rate,
cardiorenal end points, and all-cause mortality in type 2 diabetic patients. Diabetes Care.
2006;29(9):2046–52.
7 Diabetic Kidney Disease: Identification, Prevention, and Treatment 165
79. Bruno G, Merletti F, Bargero G, Novelli G, Melis D, Soddu A, et al. Estimated glomerular
filtration rate, albuminuria and mortality in type 2 diabetes: the Casale Monferrato study.
Diabetologia. 2007;50(5):941–8.
80. Groop PH, Thomas MC, Moran JL, Waden J, Thorn LM, Makinen VP, et al. The presence and
severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes.
2009;58(7):1651–8.
81. Orchard TJ, Secrest AM, Miller RG, Costacou T. In the absence of renal disease, 20 year mor-
tality risk in type 1 diabetes is comparable to that of the general population: a report from the
Pittsburgh epidemiology of diabetes complications study. Diabetologia. 2010;53(11):2312–9.
82. Deckert T, Yokoyama H, Mathiesen E, Ronn B, Jensen T, Feldt-Rasmussen B, et al. Cohort
study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in
patients with insulin dependent diabetes. BMJ. 1996;312(7035):871–4.
83. Tuomilehto J, Borch-Johnsen K, Molarius A, Forsen T, Rastenyte D, Sarti C, et al. Incidence
of cardiovascular disease in type 1 (insulin-dependent) diabetic subjects with and without
diabetic nephropathy in Finland. Diabetologia. 1998;41(7):784–90.
84. Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic
fatty liver disease: causal effect or epiphenomenon? Diabetologia. 2008;51(11):1947–53.
85. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-
dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med.
1997;157(13):1413–8.
86. Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity:
the WHO Mutinational study of vascular disease in diabetes. Diabetologia. 2001;44(Suppl
2):S54–64.
87. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and pro-
gression of nephropathy in type 2 diabetes: the United Kingdom prospective diabetes study
(UKPDS 64). Kidney Int. 2003;63(1):225–32.
88. de Boer IH, Caramori ML, Chan JCN, Heerspink HJL, Hurst C, Khunti K, et al. Executive
summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based
advances in monitoring and treatment. Kidney Int. 2020;98(4):839–48.
89. Forouhi NG, Koulman A, Sharp SJ, Imamura F, Kroger J, Schulze MB, et al. Differences in
the prospective association between individual plasma phospholipid saturated fatty acids and
incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diabetes Endocrinol.
2014;2(10):810–8.
90. Kwakernaak AJ, Krikken JA, Binnenmars SH, Visser FW, Hemmelder MH, Woittiez AJ, et al.
Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic
nephropathy: a randomised clinical trial. Lancet Diabetes Endocrinol. 2014;2(5):385–95.
91. Lambers Heerspink HJ, Holtkamp FA, Parving HH, Navis GJ, Lewis JB, Ritz E, et al.
Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of
angiotensin receptor blockers. Kidney Int. 2012;82(3):330–7.
92. Nezu U, Kamiyama H, Kondo Y, Sakuma M, Morimoto T, Ueda S. Effect of low-protein diet
on kidney function in diabetic nephropathy: meta-analysis of randomised controlled trials.
BMJ Open. 2013;3(5).
93. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of dietary protein restriction on
prognosis in patients with diabetic nephropathy. Kidney Int. 2002;62(1):220–8.
94. Tirosh A, Golan R, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Rudich A, et al. Renal
function following three distinct weight loss dietary strategies during 2 years of a randomized
controlled trial. Diabetes Care. 2013;36(8):2225–32.
95. Jackson S, le Roux CW, Docherty NG. Bariatric surgery and microvascular complications of
type 2 diabetes mellitus. Curr Atheroscler Rep. 2014;16(11):453.
96. Bjornstad P, Nehus E, Jenkins T, Mitsnefes M, Moxey-Mims M, Dixon JB, et al. Five-year
kidney outcomes of bariatric surgery differ in severely obese adolescents and adults with and
without type 2 diabetes. Kidney Int. 2020;97(5):995–1005.
166 M. L. Caramori and P. Rossing
97. The effect of intensive treatment of diabetes on the development and progression of long-
term complications in insulin-dependent diabetes mellitus. The Diabetes Control and
Complications Trial Research Group. N Engl J Med. 1993;329(14):977–86.
98. The absence of a glycemic threshold for the development of long-term complications: the per-
spective of the Diabetes Control and Complications Trial. Diabetes. 1996;45(10):1289–98.
99. Group DER, de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, et al. Intensive diabetes
therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med. 2011;365(25):2366–76.
100. Beck RW, Bergenstal RM, Riddlesworth TD, Kollman C, Li Z, Brown AS, et al. Validation
of time in range as an outcome measure for diabetes clinical trials. Diabetes Care.
2019;42(3):400–5.
101. Ranjan AG, Rosenlund SV, Hansen TW, Rossing P, Andersen S, Norgaard K. Improved
time in range over 1 year is associated with reduced albuminuria in individuals with sensor-
augmented insulin pump-treated type 1 diabetes. Diabetes Care. 2020;43(11):2882–5.
102. Intensive blood-glucose control with sulphonylureas or insulin compared with conven-
tional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK
Prospective Diabetes Study (UKPDS) Group [published erratum appears in Lancet 1999 Aug
14;354(9178):602] [see comments]. Lancet. 1998;352(9131):837–53.
103. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of
glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS
35): prospective observational study. BMJ. 2000;321(7258):405–12.
104. Group AC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood
glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med.
2008;358(24):2560–72.
105. Perkovic V, Heerspink HL, Chalmers J, Woodward M, Jun M, Li Q, et al. Intensive glu-
cose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int.
2013;83(3):517–23.
106. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive
treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the
ACCORD randomised trial. Lancet. 2010;376(9739):419–30.
107. Papademetriou V, Lovato L, Doumas M, Nylen E, Mottl A, Cohen RM, et al. Chronic kidney
disease and intensive glycemic control increase cardiovascular risk in patients with type 2
diabetes. Kidney Int. 2015;87(3):649–59.
108. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, car-
diovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
109. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al.
Empagliflozin and progression of kidney Disease in type 2 diabetes. N Engl J Med.
2016;375(4):323–34.
110. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al.
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med.
2019;380(24):2295–306.
111. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al.
Dapagliflozin in patients with chronic kidney Disease. N Engl J Med. 2020;383(15):1436–46.
112. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 update to:
Management of Hyperglycemia in type 2 diabetes, 2018. A consensus report by the American
Diabetes Association (ADA) and the European Association for the Study of diabetes (EASD).
Diabetes Care. 2020;43(2):487–93.
113. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. Erratum. 2019
Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report
by the American Diabetes Association (ADA) and the European Association for the Study of
Diabetes (EASD). Diabetes Care 2020;43:487–93. Diabetes Care. 2020;43(7):1670.
114. Tuttle KR, Lakshmanan MC, Rayner B, Busch RS, Zimmermann AG, Woodward DB, et al.
Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe
7 Diabetic Kidney Disease: Identification, Prevention, and Treatment 167
132. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, et al. Randomised
controlled trial of dual blockade of renin-angiotensin system in patients with hypertension,
microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril micro-
albuminuria (CALM) study. BMJ. 2000;321(7274):1440–4.
133. Jacobsen P, Andersen S, Rossing K, Jensen BR, Parving HH. Dual blockade of the renin-
angiotensin system versus maximal recommended dose of ACE inhibition in diabetic
nephropathy. Kidney Int. 2003;63(5):1874–80.
134. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes
with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a
multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):547–53.
135. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD,
et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med.
2012;367(23):2204–13.
136. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined
angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med.
2013;369(20):1892–903.
137. Ren F, Tang L, Cai Y, Yuan X, Huang W, Luo L, et al. Meta-analysis: the efficacy and
safety of combined treatment with ARB and ACEI on diabetic nephropathy. Ren Fail.
2015;37(4):548–61.
138. Currie G, Taylor AH, Fujita T, Ohtsu H, Lindhardt M, Rossing P, et al. Effect of mineralo-
corticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a
systematic review and meta-analysis. BMC Nephrol. 2016;17(1):127.
139. Tofte N, Lindhardt M, Adamova K, Bakker SJL, Beige J, Beulens JWJ, et al. Early detection
of diabetic kidney disease by urinary proteomics and subsequent intervention with spirono-
lactone to delay progression (PRIORITY): a prospective observational study and embedded
randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2020;8(4):301–12.
140. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of Finerenone
on chronic kidney Disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219–29.
141. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular events
with Finerenone in kidney Disease and type 2 diabetes. N Engl J Med. 2021;385(24):2252–63.
142. Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, et al. Atrasentan
and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a
double-blind, randomised, placebo-controlled trial. Lancet. 2019;393(10184):1937–47.
143. Jun M, Zhu B, Tonelli M, Jardine MJ, Patel A, Neal B, et al. Effects of fibrates in kidney
disease: a systematic review and meta-analysis. J Am Coll Cardiol. 2012;60(20):2061–71.
144. Kreutz R, Camm AJ, Rossing P. Concomitant diabetes with atrial fibrillation and anticoagula-
tion management considerations. Eur Heart J Suppl. 2020;22(Suppl O):O78–86.
145. Hernandez AV, Bradley G, Khan M, Fratoni A, Gasparini A, Roman YM, et al. Rivaroxaban
vs. warfarin and renal outcomes in non-valvular atrial fibrillation patients with diabetes. Eur
Heart J Qual Care Clin Outcomes. 2020;6(4):301–7.
146. Petrie JR, Rossing PR, Campbell IW. Metformin and cardiorenal outcomes in diabetes: a
reappraisal. Diabetes Obes Metab. 2020;22(6):904–15.
147. Mathiesen ER. Diabetic nephropathy in pregnancy: new insights from a retrospective cohort
study. Diabetologia. 2015;58(4):649–50.
148. Klemetti MM, Laivuori H, Tikkanen M, Nuutila M, Hiilesmaa V, Teramo K. Obstetric and
perinatal outcome in type 1 diabetes patients with diabetic nephropathy during 1988-2011.
Diabetologia. 2015;58(4):678–86.
149. Damm JA, Asbjornsdottir B, Callesen NF, Mathiesen JM, Ringholm L, Pedersen BW,
et al. Diabetic nephropathy and microalbuminuria in pregnant women with type 1 and type
2 diabetes: prevalence, antihypertensive strategy, and pregnancy outcome. Diabetes Care.
2013;36(11):3489–94.
7 Diabetic Kidney Disease: Identification, Prevention, and Treatment 169
150. Lim LL, Lau ESH, Ozaki R, Chung H, Fu AWC, Chan W, et al. Association of technologically
assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the pro-
spective JADE program: a retrospective cohort analysis. PLoS Med. 2020;17(10):e1003367.
151. Tu ST, Chang SJ, Chen JF, Tien KJ, Hsiao JY, Chen HC, et al. Prevention of diabetic nephrop-
athy by tight target control in an asian population with type 2 diabetes mellitus: a 4-year
prospective analysis. Arch Intern Med. 2010;170(2):155–61.
152. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention
on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580–91.
153. Chan JC, So WY, Yeung CY, Ko GT, Lau IT, Tsang MW, et al. Effects of structured versus
usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter
translational study. Diabetes Care. 2009;32(6):977–82.
154. Gaede P, Oellgaard J, Carstensen B, Rossing P, Lund-Andersen H, Parving HH, et al.
Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus
and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia.
2016;59(11):2298–307.
155. Gaede P, Oellgaard J, Kruuse C, Rossing P, Parving HH, Pedersen O. Beneficial impact of
intensified multifactorial intervention on risk of stroke: outcome of 21 years of follow-up in
the randomised Steno-2 study. Diabetologia. 2019;62(9):1575–80.
156. Oellgaard J, Gaede P, Rossing P, Persson F, Parving HH, Pedersen O. Intensified multifacto-
rial intervention in type 2 diabetics with microalbuminuria leads to long-term renal benefits.
Kidney Int. 2017;91(4):982–8.
157. Oellgaard J, Gaede P, Rossing P, Rorth R, Kober L, Parving HH, et al. Reduced risk of
heart failure with intensified multifactorial intervention in individuals with type 2 diabetes
and microalbuminuria: 21 years of follow-up in the randomised Steno-2 study. Diabetologia.
2018;61(8):1724–33.
158. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clicical
practice guideline for the evaluation and management of chronic kidney disease. Kidney Inter
Suppl. 2013;3:1–150.
Chapter 8
Precision Medicine for Diabetic
Neuropathy
Evolution of Understanding
The entity referred to as diabetic peripheral neuropathy (DPN) was historically con-
sidered a single entity tied to glycemic index. Data accumulated over the last several
decades has produced a more precise understanding, one grounded in animal mod-
els, which paved the way for more targeted therapies. As early as the 1990s, it was
first noted by clinicians that many patients with cryptogenic sensory peripheral neu-
ropathy (CSPN) shared phenotypic features with diabetic patients, particularly with
regard to obesity and metabolic syndrome (MetS). Robust international epidemio-
logical data followed, confirming that obesity and MetS, even in the absence of
frank diabetes, were associated with peripheral neuropathy [1–6]. It is now clear
that type 1 diabetic peripheral neuropathy (T1DPN) and type 2 diabetic peripheral
neuropathy (T2DPN) are two separate disease entities [7, 8]. In addition, MetS itself
is a bona fide cause of peripheral neuropathy and accelerates the development of
peripheral neuropathy, particularly in type 2 diabetes (T2D) [3, 9, 10]. Most recently,
murine models have emerged, demonstrating a pathophysiologic foundation for
Table 8.1 Drug trials on peripheral neuropathy associated with T1DM and T2DM from
2010 to 2020
Disease or Clinical trial
pain Diabetes outcome for
Drug modifying Mechanism of action type neuropathy Reference
OnabotulintoxinA Pain Inhibits neurogenic T2DM Improved tactile [139]
(BoNT/A) inflammation from and mechanical
peripheral nociceptive pain perception
nerve terminals in painful DPN
Botulin toxin Pain Potent neurotoxin, T2DM Intradermal [140]
(BTX-A) used in treatment of injection of
dystonia, muscle BTX-A
hyperactivity, and significantly
glandular improved painful
hyperactivity. BTX-A DPN
may have analgesic
properties
Monochromatic Disease Increases blood T2DM No improvement [141]
infrared energy circulation
(MIRE)
L-arginine Disease Substrate for nitric T2DM No effect DPN [142]
oxide synthesis to
improve
microcirculation
Minocycline Disease Anti-inflammatory T2DM Improved [143]
and pain and antiapoptotic vibration
properties, perception
suppression of threshold,
microglial activation reduced
neuropathic
symptoms, and
pain disability
index
Benfotiamine Disease Modulates advanced T1DM No effect on [144]
glycation end peripheral nerve
products function
Reproduced with permission from Stino et al. [15]
Clinical Approach
DPN often presents with acral pain, numbness, tingling, or dysesthesias involving
the feet, which often progresses, if unchecked, to involve the distal upper limbs as
well. The Toronto consensus criteria laid out an objective and reproducible frame-
work for diagnosing DPN, applicable in both the clinical and research settings, and
predicated upon demonstrating (a) neuropathic signs and symptoms and (b) impair-
ment in validated measures of large and/or small fiber function, namely, nerve con-
duction studies (NCS) and skin biopsy evaluation of intraepidermal nerve fiber
density (IENFD), respectively [30]. NCS are quite useful clinically for evaluating
the severity of large fiber DPN; however, normal values do not exclude the presence
of small fiber neuropathy. Furthermore, NCS are of limited value in DPN research,
174 L. Davalos et al.
while IENFD has emerged as the gold standard outcome measure. MetS and diabe-
tes both preferentially target small nerve fibers early in the disease course. Data has
also shown that obesity and hypertriglyceridemia, both MetS components, preferen-
tially target small unmyelinated fibers, while hyperglycemia renders more damage
to large myelinated fibers [31]. IENFD testing is now considered the gold standard
for diagnosing small fiber DPN and involves immunohistochemical staining and
quantitation of unmyelinated axons using an antibody against protein end product
9.5 (PGP 9.5), a neuronal biomarker. IENFD testing is also invaluable to DPN ther-
apeutic development, as it allows sensitive detection of nerve healing and regrowth,
given the unique regenerative capacity of small fibers [32, 33].
While our chapter focuses on evaluating and testing somatic DPN, it is worth
noting that diabetic autonomic neuropathy represents another equally important
area of research. Autonomic neuropathy is tested by the autonomic reflex screen,
which encompasses quantitative sudomotor axon reflex testing, Valsalva blood pres-
sure analysis, heart rate variation to deep breathing, heart rate variation to Valsalva,
and tilt table testing [34].
Alongside obesity, prediabetes is another MetS component that has been the focus
of much epidemiologic research. Different studies have suggested an association
between prediabetes and neuropathy, although, conversely, a few reports have ques-
tioned this association.
The San Luis Valley study showed a neuropathy prevalence of 25.8% in diabetic
patients, 11.2% in those with impaired glucose tolerance (IGT), and 3.9% in the
control group [47]. The MONICA/KORA study reported a 13.3% prevalence of
painful neuropathy in diabetic individuals, 8.7% in the IGT group, 4.2% in the
impaired fasting glucose (IFG) group, and 1.2% in normoglycemic patients [49].
The longitudinal PROMISE study supported these prior findings, showing a preva-
lence of 49% in prediabetes patients. Furthermore, the progression to glucose intol-
erance over 3 years predicted a higher risk of peripheral neuropathy and nerve
dysfunction, and, compared to normoglycemic subjects, prediabetic patients had
higher Michigan Neuropathy Symptom Inventory (MNSI) scores and vibration
detection thresholds [50]. Likewise, a cohort of 32 patients with IGT and neuro-
pathic symptoms exhibited abnormalities in the distal skin biopsy of all subjects,
indicating that small fiber damage occurs quite frequently in the prediabetic popula-
tion [42]. All these studies support the role of prediabetes as a cause of neuropathy.
In addition, patients with preexisting CSPN seem more likely to have prediabetes.
In a cohort of CSPN patients, 56% were found to have IFG, and 36% had IGT, with
the IGT group showing primarily small nerve fiber involvement [51].
Despite the evidence linking prediabetes to neuropathy, there are some studies
that do not support this association [39, 52]. One recent single-center study showed
that there was no difference between prediabetic and normoglycemic patients
regarding small fiber structure and function [53]. Likewise, two studies of a popula-
tion in Olmsted County, Minnesota, showed that prediabetes did not increase neu-
ropathy risk [54, 55]. Nevertheless, these studies did suggest that other features of
MetS increased the likelihood of neuropathy. Adding to the complexity of interpret-
ing the findings is that despite adjusting for obesity, some of the studies used NCS
(rather than IENFD) as the primary outcome measure.
176 L. Davalos et al.
The conflicting conclusions of these published studies are most likely related to
the different criteria used to diagnose prediabetes and neuropathy. It is well-known
that a large proportion of prediabetic individuals develop T2D, and there is growing
data suggesting that MetS components are independent neuropathy risk factors.
Therefore, interventions that prevent prediabetes progression to diabetes, as well as
those that treat MetS, should be expected to reduce neuropathy incidence in predia-
betic patients.
In the pediatric population, T1D is the most prevalent diabetes type, accounting for
98% of diabetic cases in children younger than 10 years, and 87% of those aged
10–19 years [56]. The incidence and prevalence of both T1D and T2D in the pedi-
atric population have increased markedly, along with an associated rise in DPN
incidence [57–63].
Estimating the real prevalence of pediatric DPN can be challenging due variabil-
ity in tests and criteria, as well as the high prevalence of asymptomatic neuropathy.
In pediatric and youth patients with T1D, neuropathy prevalence ranges from 3 to
62%. The Epidemiology of Diabetes Complications (EDC) study found T1DPN in
3% of patients ≤18 years old using a standardized neurological exam and clinical
history as a tool to detect neuropathy. The EURODIAB insulin-dependent diabetes
mellitus (IDDM) complications study assessed symptoms, deep tendon reflexes,
vibration perception threshold (VPT), and autonomic function and reported T1DPN
in 19% of patients aged 15 to 29 [64, 65]. Conversely, a population-based longitu-
dinal Danish study reported a T1DPN prevalence of 62% in patients aged 12 to 27
using VPT [66]. Likewise, a cohort of 73 patients with a mean age of 13.6 years and
a T1D duration ≥5 years found neuropathic symptoms in only 4% but abnormal
neurological exam, NCS, and VPT in 36%, 57%, and 51% of subjects, respectively
[67]. In these studies, the prevalence was higher with older age and longer disease
duration. Pediatric DPN prevalence generally appears to be higher in T2D than T1D
patients in studies that have compared both groups, with estimates indicating a prev-
alence of 17–22% for T2D versus 7–12% for T1D [62, 68, 69]. As previously dis-
cussed, the wide range in stated prevalence is the result of testing modalities
employed to define DPN.
DPN is infrequently reported in pediatric practice, likely due to a lack of volun-
tary reporting from children and adolescents and the high rates of asymptomatic
manifestations. The DPN symptom profile in this population differs from the one in
adults and often consists of paresthesias and fewer intense pain experiences [70]. In
terms of risk factors, hyperglycemia is the major T1DPN driver, but there is no data
supporting this in T2DPN for pediatric patients [71]. Obesity and dyslipidemia have
emerged as potential risk factors, suggesting a multifactorial etiology similar to the
adult population. This is alarming considering that approximately one-third of chil-
dren and adolescents in most resource-rich countries are either overweight or obese,
8 Precision Medicine for Diabetic Neuropathy 177
which has fuelled the increase in DPN incidence and prevalence [57, 58, 72, 73].
Management should target glycemic control, as well as focus on weight loss, exer-
cise, and nutrition counseling in order to improve obesity and insulin resistance
[74]. Diagnosing DPN early and appropriate interventions in children and adoles-
cents are crucial, since it may improve or even reverse subclinical DPN.
Genetic risk factors in DPN development are the focus of much study. Despite
numerous potential variants of interest, it is still unclear how such variants impact
or associate with DPN development. Nevertheless, certain single-nucleotide poly-
morphisms of interest, which have gained attention in both adult and pediatric
patients, include variants affecting the polyol pathway (aldose reductase gene
(AKR1B1)) [75], cholesterol transport (apolipoprotein E (APOE)) [76], mitochon-
drial uncoupling (UCP2 and UCP3) [77], oxidative stress defense (superoxide dis-
mutase (SOD2 and SOD3)) [78], catalase (CAT) [79], and glutathione peroxidase-1
(GPX1) [79].
Epigenetics is another area of active research. A recent genome-wide methyla-
tion study explored alterations in the sural nerve DNA methylome and transcrip-
tome, demonstrating differentially methylated genes and differentially expressed
genes between T2DPN human subjects with the highest and lowest levels of hemo-
globin A1c. Differential gene methylation and expression were enriched in path-
ways critical to the immune system, extracellular matrix, and axon guidance [80].
Animal Models
Murine models of DPN now include leptin (ob/ob) and leptin receptor (db/db)
mutant mice, as well as a C57BL/6 J mice fed high-fat diet as a prediabetes model
and C57BL/6 J mice fed high-fat diet and administered low-dose streptozotocin as
a T2D model [11–14]. Mitochondrial dysfunction, dysregulated substrate uptake,
and inflammation underlie peripheral nerve DPN pathology, especially in T2DPN
and MetS-associated peripheral neuropathy [81]. Long-chain fatty acids alter mito-
chondrial size, morphology, and motility, contributing to compromised mitochon-
drial bioenergetics [82]. Nerve-lipid signaling is impaired in both murine models
and human sural nerve, as shown using transcriptomic and lipidomic analyses [83].
Transport and substrate uptake is also dysregulated in the MetS. Long-chain fatty
acid overexposure produces long-chain acylcarnitine, a trigger of mitochondrial
178 L. Davalos et al.
Mitochondrial β-oxidation
Pioglitazone PGC-1α–PPARγ
LXR
Acipimox NF-κB axon
SFA + MUFA/Dietary Reversal
Inflammatory modulation
LDs FFAs
LDs Acylcarnitines
LDs Pro-inflammatory
Signals
TNF-α COX-2
Oxidative phosphorylation
Abbreviations:
SFA= saturated fatty acid
Mitochondrial axonal trafficking
MUFA= monounsaturated fatty acid ROS
FFAs= free fatty acids
ROS= reactive oxygen species ATP
Functional mitochondria
LDs= lipid droplets
Fusion
Fig. 8.1 Therapeutic targets identified by dietary intervention and inflammatory pathway studies.
Molecular targets were identified in preclinical studies using murine models of dyslipidemia and
DPN. Dietary intervention with MUFA supplementation reverses DPN progression potentially
through the sequestration of SFAs into LDs in sensory neurons. Dietary reversal from a high-fat
diet to a standard diet reduces the level of SFAs in sensory neurons. Subsequent to both dietary
intervention paradigms, reduced levels of acylcarnitine improve mitochondrial function and pre-
vent apoptosis. Similarly, stimulation of PGC-1α, PPARγ, and LXR transcription factors by piogli-
tazone activates FFA β-oxidation, improving mitochondrial function and nerve function.
Pioglitazone and acipimox both inhibit NF-κB activation of pro-inflammatory pathways. The
reduction in pro-inflammatory TNF-α, IL-6, COX-2, and ROS production prevents downstream
mitochondrial dysfunction and sensory neuron apoptosis. (Reproduced with permission from
Stino et al. [15])
derivative that inhibits the enzyme triglyceride lipase and reduces fatty acid concen-
tration in the blood. In addition, COX-2 pathway inhibition and COX-2 gene inacti-
vation as well as heat-shock chaperone protein modulation are other therapies with
promising animal model data [94, 95].
Painful DPN is highly prevalent in patients with diabetes and often refractory, caus-
ing substantial disability and deterioration in quality of life. Much effort has gone
into identifying distinguishing risk factors and predispositions between painful and
non-painful DPN, including three cross-sectional studies in Britain, Germany/
Czech Republic, and Italy, but data was mixed at best [96–100]. The British Pain in
Neuropathy Study (PiNS) showed no dependence on BMI, sex, age, or waist-to-hip
180 L. Davalos et al.
circumference but did suggest that painful DPN had more profound large and small
fiber sensory loss [97]. Patients also tended to be younger and have higher hemoglo-
bin A1c levels.
With regard to managing painful DPN, pharmacotherapy is the treatment main-
stay, but the best which can be achieved for a monotherapy is 50% pain relief in only
a third of patients [101]. This wide variability in treatment response may in part be
due to an underlying heterogeneity in clinical pain phenotypes [102]. This could be
one reason several recent randomized clinical trials of painful DPN failed, despite
encouraging preclinical and early clinical results [101]. Moreover, most studies use
crude summative measures of pain (e.g., numeric rating scales) as primary end-
points. This approach is unlikely to capture the complex and multidimensional
nature of pain. The question arises whether it is possible to select more homogenous
phenotypic subgroups and/or use an alternative and more salient primary outcome
measure, which might increase sensitivity and reveal a positive response in future
clinical trials [103]. Currently, there are no biomarkers qualified by the US Food
and Drug Administration (FDA) or the European Medicines Agency (EMA) for use
in analgesic clinical trials requiring regulatory review [103]. Three types of assess-
ments with established roles in pain research – namely, sensory profile testing, skin
biopsy, and brain imaging – could serve as potential candidate biomarkers in anal-
gesic randomized controlled trials.
Sensory Profiling
For many years, sensory profiling has been the mainstay for identifying a homoge-
nous subgroup of neuropathic pain patients in clinical pain research. The basis of
this approach is that painful symptoms reflect specific pathophysiological mecha-
nisms, which are present to varying degrees in individual patients [102]. Detailed
sensory profiling using quantitative sensory testing (QST) can be used to subgroup
patients into more homogenous cohorts (pain phenotypes), which could then be
targeted with treatments known to act specifically on pathophysiological pathways
underlying the phenotypes [104]. QST refers to a battery of standardized, psycho-
physical tests (e.g., thermal testing, pin prick, pressure algometry, and von Frey fila-
ments) used to assess central and peripheral nervous system sensory function [105].
In DPN, QST has been used for several decades mainly for diagnosing and quanti-
fying the extent of small and large nerve fiber impairment in individuals predomi-
nantly with painless DPN. In the context of pain somatosensory phenotyping, a
standardized QST protocol was developed by the German Research Network on
Neuropathic Pain (DFNS), which includes 12 sensory testing parameters (i.e., cold
and warm detection thresholds, paradoxical heat sensations, thermal sensory limen
procedure, cold and heat pain thresholds, mechanical detection threshold, mechani-
cal pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia,
8 Precision Medicine for Diabetic Neuropathy 181
wind-up ratio, vibration detection threshold, and pressure pain threshold) [106].
The positive and negative results of individual patients are obtained by comparison
against a normative QST reference dataset, comprised of age- and sex-stratified
healthy individuals [106].
Application of the QST technique has shown that there are two distinct subgroups
of patients who have particular patterns of sensory symptoms and signs: (1) a pre-
dominant differentiation with loss of sensory function (nonirritable nociceptor phe-
notype) and (2) a relatively preserved small fiber function associated with thermal/
mechanical hypersensitivity (irritable nociceptor phenotype) [104]. Using the
DFNS protocol, the PiNS reported that the nonirritable nociceptor was the predomi-
nant phenotype in painful DPN, while only a minority of patients had the irritable
nociceptor phenotype (6.3%) [97]. Nevertheless, a small but significant proportion
of patients (15%) did demonstrate signs of sensory gain with dynamic mechanical
allodynia, often in combination with hyposensitivity across a range of small and
large nerve fiber sensory assessments. The presence of allodynia would suggest that
aberrant central processing of sensory inputs has an important role in these patients.
Recent studies have demonstrated proof of concept for using sensory profiling to
improve clinical trial efficiency by demonstrating that some treatments are more
effective in patients with the irritable versus the nonirritable nociceptor phenotype
[107–110]. However, most of these studies examined patients with peripheral neu-
ropathy of diverse causes.
treatment response based on sensory profiling using the Neuropathic Pain Symptom
Inventory (NPSI) questionnaire from the Combination vs Monotherapy of Pregabalin
and Duloxetine in Diabetic Neuropathy (COMBO-DN) study [113]. This study
examined the effect of high-dose duloxetine, a serotonin noradrenaline reuptake
inhibitor, or pregabalin, a calcium channel blocker, as monotherapy versus com-
bined pregabalin and duloxetine for painful DPN. The investigators showed that
adding pregabalin (300 mg) to duloxetine (60 mg) improved the dimensions of
“pressing pain” and “evoked pain” more significantly. On the other hand, increasing
duloxetine from 60 mg to 120 mg daily improved the dimension “paraesthesia/
dysesthesia” to a greater extent.
–1
–2
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Week Week
Fig. 8.2 Effect of oxcarbazepine in painful DPN depends on pain phenotype based on detailed
quantitative sensory testing. Nonirritable nociceptor phenotype comprise of patients with deaffer-
entiation dominated by sensory loss. Patients with the irritable nociceptor have preserved small
fiber function (cold, warm, and pinprick sensation) and contact hypersensitivity (e.g., allodynia).
(Adapted from Demant [114])
8 Precision Medicine for Diabetic Neuropathy 183
Drug Endpoint
Baseline profiling Randomisation VAS/Effect on
Placebo symptoms
Retrospective analysis of
responders
Drug
subgroup A
Endpoint
Stratification/Randomisation Drug
Baseline profiling VAS/Effect on
subgroup B
symptoms
Placebo
Fig. 8.3 Designing studies to inform personalized pharmacological treatment of neuropathic pain
Recent advances in neuroimaging provide us with unique insights into the human
central nervous system in chronic pain conditions (Fig. 8.4) [118]. We now have a
better understanding how the brain modulates nociceptive inputs to generate the
pain experience and how this is disrupted in patients with painful DPN. However, to
date, brain imaging serves mainly as a research tool, with minimal direct application
in clinical trials for pain or clinical practice. While mechanistic approaches that
require carefully evaluating specific responses to guide therapy have significant
appeal (e.g., cold, heat, von Frey, etc.), in practice, these are time-consuming and
may be difficult to implement in busy clinical practices. Furthermore, these are
psychophysical measures which rely on patient responses and may be subjective
and biased. Sensory profiling methods also do not capture the complex and multidi-
mensional pain experience, which affects emotional and cognitive processing in
addition to sensory processing. For example, chronic pain patients often undergo
neuropsychological changes, which include changes in emotion and motivation or
changes in cognition [119]. Chronic pain may also arise after the onset of depres-
sion, even in patients without a prior history of pain or depression. Collectively,
these clinical insights suggest a better strategy for assessing and treating painful
DPN, given it is a chronic disease of dynamic process (e.g., evolution of comorbid
phenotypes such as anxiety or depression), which is not easily reversed in most
patients. It is important to determine specific targets that are relevant to pain across
individuals, because modulating activation in these targets may provide evidence
that a compound engages a target or attenuates nociceptive processing.
Structural and functional cortical plasticity is a fundamental property of the
human central nervous system, which can adjust to nerve injury. However, it can
have maladaptive consequences, possibly resulting in chronic pain. Studies using
structural magnetic resonance (MR) neuroimaging have demonstrated a clear reduc-
tion in both spinal cord cross-sectional area [120] and primary somatosensory cor-
tex (S1) gray matter volume in patients with DPN [121]. These findings are
supported by studies in other pain conditions, which have also reported dynamic
structural and functional plasticity with profound effects on the brain in patients
with neuropathic pain. More recently, it has been demonstrated how brain structural
and functional changes are related to painful DPN clinical phenotypes [122].
Patients with the painful insensate phenotype have a more pronounced reduction in
S1 cortical thickness and a remapping of S1 sensory processing compared to painful
DPN subjects with relatively preserved sensation [122]. Furthermore, the extent to
which S1 cortical structure and function is altered is related to the severity of neu-
ropathy and the magnitude of self-reported pain. These data suggest a dynamic plas-
ticity of the brain in DPN driven by the neuropathic process and may ultimately
determine an individual’s clinical pain phenotypes.
Over the last decade, resting-state functional MR imaging (RS-fMRI) – a quick
and simple noninvasive technique – has become an increasingly appealing way to
examine spontaneous brain activity in individuals, without relying on external
8 Precision Medicine for Diabetic Neuropathy 185
a Ectopic activity
Periphery Cell body
Axon
Sympathetic
Sympathetic postganglionic
postganglionic fibres fibres
Limbic pathway Spinoreticular and Spinothalamic pathway Noradrenaline pathway Pain facilitation pathway
Thalamic relay dorsal column pathways Sensory and autonomic fibres Pain suppression pathway Changes induced
Fig. 8.4 Central and peripheral mechanisms contributing to neuropathic pain in diabetic neuropa-
thy. (a) Several alterations to peripheral and central neurons contribute to the pathophysiology of
painful diabetic neuropathy. Ion channels at the terminals of nociceptors can undergo glycation
through the addition of methylglyoxal to form advanced glycation end products (AGEs), which
can contribute to gain of function of these channels and neuronal hyperexcitability. Changes at the
perikaryon include increased expression of voltage-gated sodium channels, such as Nav1.8, which
can lead to hyperexcitability. In myelinated axons, the expression of shaker-type potassium (Kv)
channels is reduced, which can also contribute to hyperexcitability. Hyperexcitability of neurons
leads to increased stimulus responses and ectopic neuronal activity, leading to excessive nocicep-
tive input to the spinal cord. In the spinal cord, microglia become activated and further enhance
excitability within the dorsal horn. (b) Several ascending pathways are involved in pain perception
and the psychological changes associated with pain, for example, the spinothalamic pathway (1),
which is involved in pain perception, and the spinoreticular tract. In addition, ascending pathways
that travel via the parabrachial nucleus (2) to the hypothalamus and amygdala (3) are involved in
autonomic function, fear, and anxiety. Descending pathways inhibit or facilitate the transmission
of nociceptive information at the spinal level (4). Changes induced by peripheral neuropathy are
shown in boxes. (Reproduced with permission from Feldman et al. [117])
186 L. Davalos et al.
R R Thal-Post CG FC R Thal-IC FC
PostCG R PostCG
0.4
0.1
Effect size
Effect size
0.3
0.0
IC IC 0.2
Thalamus Thalamus
–0.1
0.1
–0.2 0
IR NIR IR NIR
a b c d
Responders Non-Responders
IC-Forb FC
R R IC-Amy FC
0.5 0.4
Effect size
Effect size
AC 0.3 AC
0.2
IC IC
–0.1
0.0
Amy FOrb Amy FOrb
–0.2
Res N-Res Res N-Res
High IC to cortical limbic connectivity Low IC to cortical limbic connectivity
e f g h
Fig. 8.5 Right view of resting-state functional connectivity in painful diabetic peripheral neuropa-
thy (DPN) patients with the nonirritable nociceptor phenotype (a) and irritable nociceptor pheno-
type (c); R, right; IC, insula cortex. Bar charts demonstrating effect size of differences in
thalamic-insula (d) and thalamic-postcentral (b) cortical functional connectivity between study
groups. (IR irritable nociceptor, NIR nonirritable nociceptor. Adapted from Teh et al. Somatosensory
network functional connectivity differentiates clinical pain phenotypes in diabetic neuropathy.
Diabetologia. 2021;64(6):1412–21). Right view of insula cortical resting-state functional connec-
tivity in responders (e) and nonresponders (g) to intravenous lidocaine treatment. IC insula cortex;
Amy amygdala; AC anterior cingulate gyrus; FOrb orbital frontal cortex. Bar charts demonstrating
the effect size of differences in resting-state functional connectivity in intravenous lidocaine
responders and nonresponders between the insula cortex and the orbital frontal cortex (f) and
amygdala (h) on the right. (Adapted from Wilkinson et al. [111])
8 Precision Medicine for Diabetic Neuropathy 187
both the somatic and non-somatic assessments of painful DPN. In one study, using
a machine learning approach to integrate anatomical and functional connectivity
data achieved an accuracy of 92% and sensitivity of 90%, indicating good overall
performance [111]. Multimodal MR imaging combining structural and RS-fMRI
has also been used to predict treatment response in painful DPN. Responders to
intravenous lidocaine treatment have significantly greater S1 cortical volume and
greater functional connectivity between the insular cortex and corticolimbic system
compared to nonresponders (Fig. 8.5) [111]. The insular cortex plays a pivotal role
in processing the emotion and cognitive dimensions of the chronic pain experience.
The corticolimbic circuits have also long been implicated in reward, decision-
making, and fear learning. Hence, these findings suggest that this network may have
a role in determining treatment response in painful DPN.
Using advanced multimodal MR neuroimaging, a number of studies have dem-
onstrated alterations in pain processing brain regions, which relate to clinical pain
phenotype, treatment response, and behavioral/psychological factors impacted by
pain. Taken together, these assessments could serve as a possible central pain signa-
ture for painful DPN. The challenge now is to apply this potential pain biomarker at
an individual level in order to demonstrate clinical utility. To this end, applying
machine learning [124] to leverage brain imaging features from a quick 6-minute
RS-fMRI scan to classify individual patients into different clinical pain phenotypes
is appealing. Future studies should externally validate and optimize current models
in larger patient cohorts to examine if/how such models can be used as biomarkers
in clinical trials of pain therapeutics. Although many of the findings described are
consistent with neuroimaging studies in other chronic pain conditions, it is difficult
to assess convergence of findings across a number of relatively small cohort studies
employing different analytical methods to derive complex models involving a large
number of distributed brain regions [125]. These are important limitations that are
being addressed with (1) a number of large-scale multicenter studies in progress or
in preparation (MAPP consortium [126] and placebo imaging consortium [127])
and (2) several consensus statements by key stakeholders, promoting standardized
approaches and reporting and transparent/sharable models.
The gap between pathogenic animal models and human data is large (and growing),
and how it all fits together to form a coherent, cumulative understanding of DPN is
complex and multifaceted. To promote convergence, human studies should increas-
ingly use results and concepts from animal studies, and vice versa, to constrain and
corroborate clinical study findings to move the field toward biomarkers with trans-
lational applications. Moreover, despite the recent aforementioned advances in
therapeutic avenues, it is becoming increasingly clear that one approach alone will
188 L. Davalos et al.
not capture all the variance in diagnostic, prognostic, and biomarkers in DPN. A
precision medicine approach, rather, will improve the development of multimodal
DPN biomarkers, which can enable earlier diagnosis, before irreversible nerve dam-
age occurs, and improve the overall sensitivity and specificity of preventive and
treatment strategies (Fig. 8.6).
Precision medicine leverages an individual’s variation in genes, environment,
and lifestyle to define more personalized approaches of disease prevention and man-
agement. Initial insight into this strategy in diabetes derives from recent efforts in
diabetic kidney disease, because kidney disease standard of care often involves col-
lecting blood, urine, and biopsy tissue, which are amenable to pathologic, transcrip-
tomic, proteomic, and metabolomic analyses [128–130]. As such, the Kidney
Precision Initiative was launched to combine these assessments with deep clinical
phenotyping over a 10-year period for individuals with kidney diseases, including
diabetic nephropathy, to ultimately inform diagnosis, risk assessment, and personal-
ized treatment opportunities [131].
Applying a similar precision medicine strategy to DPN will require developing
high-throughput profiling datasets, such as the currently available genome-wide
association studies (GWAS) from well-characterized clinical cohorts like DCCT/
EDIC, which supported recent nephropathy risk assessments [132, 133]. DPN
likewise has been the focus of recent GWAS [134, 135] and epigenomic assess-
ments [136] to establish and understand polygenic risk and mechanisms. Pairing
such data with robust deep clinical phenotyping and advanced machine learning has
the power to offer precision medicine-based metadata to support personalized phar-
macologic therapies and improve diagnostic and prognostic strategies, risk assess-
ment, and clinical trial designs, which account for both DPN genetics and clinical
classification. Importantly, the value of subject stratification based on clinical sub-
types, neuroimaging, and genetic data is beginning to be explored in painful DPN
[137, 138], as discussed above. Thus, given the dichotomy of pathogenic differ-
ences in T1DPN and T2DPN, the prevalence and variability of neuropathy in obe-
sity, prediabetes, and MetS and the occurrence of both painful and painless
phenotypes, precision medicine holds great promise for more targeted, effective
treatments for DPN.
Acknowledgements LD, AMS, SAS, and ELF are supported by the NeuroNetwork for Emerging
Therapies at the University of Michigan
References
1. Callaghan BC, Gao L, Li Y, Zhou X, Reynolds E, Banerjee M, et al. Diabetes and obe-
sity are the main metabolic drivers of peripheral neuropathy. Ann Clin Transl Neurol.
2018;5(4):397–405.
2. Callaghan BC, Xia R, Reynolds E, Banerjee M, Rothberg AE, Burant CF, et al. Association
between metabolic syndrome components and polyneuropathy in an obese population. JAMA
Neurol. 2016;73(12):1468–76.
3. Callaghan BC, Xia R, Banerjee M, de Rekeneire N, Harris TB, Newman AB, et al. Metabolic
syndrome components are associated with symptomatic polyneuropathy independent of gly-
cemic status. Diabetes Care. 2016;39(5):801–7.
4. Hanewinckel R, Drenthen J, Ligthart S, Dehghan A, Franco OH, Hofman A, et al. Metabolic
syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective
population-based cohort study. J Neurol Neurosurg Psychiatry. 2016;87(12):1336–42.
5. Lu B, Hu J, Wen J, Zhang Z, Zhou L, Li Y, et al. Determination of peripheral neuropa-
thy prevalence and associated factors in Chinese subjects with diabetes and pre-diabetes -
ShangHai diabetic neuRopathy epidemiology and molecular genetics study (SH-DREAMS).
PLoS One. 2013;8(4):e61053.
6. Schlesinger S, Herder C, Kannenberg JM, Huth C, Carstensen-Kirberg M, Rathmann W,
et al. General and abdominal obesity and incident distal sensorimotor polyneuropathy:
insights into inflammatory biomarkers as potential mediators in the KORA F4/FF4 cohort.
Diabetes Care. 2019;42(2):240–7.
7. Callaghan BC, Hur J, Feldman EL. Diabetic neuropathy: one disease or two? Curr Opin
Neurol. 2012;25(5):536–41.
8. Eid S, Sas KM, Abcouwer SF, Feldman EL, Gardner TW, Pennathur S, et al. New insights into
the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia.
2019;62(9):1539–49.
9. Kazamel M, Stino AM, Smith AG. Metabolic syndrome and peripheral neuropathy. Muscle
Nerve. 2021;63(3):285–93.
10. Smith AG, Rose K, Singleton JR. Idiopathic neuropathy patients are at high risk for meta-
bolic syndrome. J Neurol Sci. 2008;273(1–2):25–8.
190 L. Davalos et al.
11. Hinder LM, O’Brien PD, Hayes JM, Backus C, Solway AP, Sims-Robinson C, et al. Dietary
reversal of neuropathy in a murine model of prediabetes and metabolic syndrome. Dis Model
Mech. 2017;10(6):717–25.
12. Hur J, Dauch JR, Hinder LM, Hayes JM, Backus C, Pennathur S, et al. The metabolic syn-
drome and microvascular complications in a murine model of type 2 diabetes. Diabetes.
2015;64(9):3294–304.
13. McGregor BA, Eid S, Rumora AE, Murdock B, Guo K, de Anda-Jáuregui G, et al. Conserved
transcriptional signatures in human and murine diabetic peripheral neuropathy. Sci Rep.
2018;8(1):17678.
14. O’Brien PD, Hinder LM, Rumora AE, Hayes JM, Dauch JR, Backus C, et al. Juvenile
murine models of prediabetes and type 2 diabetes develop neuropathy. Dis Model Mech.
2018;18:11(12).
15. Stino AM, Rumora AE, Kim B, Feldman EL. Evolving concepts on the role of dyslipidemia,
bioenergetics, and inflammation in the pathogenesis and treatment of diabetic peripheral neu-
ropathy. J Peripher Nerv Syst JPNS. 2020;25(2):76–84.
16. Kobayashi M, Zochodne DW. Diabetic polyneuropathy: bridging the translational gap. J
Peripher Nerv Syst JPNS. 2020;25(2):66–75.
17. Malik RA, Calcutt NA. Translating diabetic peripheral neuropathy. J Peripher Nerv Syst
JPNS. 2020;25(2):64–5.
18. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged
severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-
based cohort: the Rochester diabetic neuropathy study. Neurology. 1993;43(4):817–24.
19. Franklin GM, Kahn LB, Baxter J, Marshall JA, Hamman RF. Sensory neuropathy in non-
insulin-dependent diabetes mellitus. The San Luis Valley diabetes study. Am J Epidemiol.
1990;131(4):633–43.
20. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M. Natural history
of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J
Med. 1995;333(2):89–94.
21. Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic
neuropathy: a position statement by the American Diabetes Association. Diabetes Care.
2017;40(1):136–54.
22. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons
from recent large clinical trials. Curr Diab Rep. 2014;14(9):528.
23. Martin CL, Albers JW, Pop-Busui R, DCCT/EDIC Research Group. Neuropathy and related
findings in the diabetes control and complications trial/epidemiology of diabetes interven-
tions and complications study. Diabetes Care. 2014;37(1):31–8.
24. Boulton AJ, Knight G, Drury J, Ward JD. The prevalence of symptomatic, diabetic neuropa-
thy in an insulin-treated population. Diabetes Care. 1985;8(2):125–8.
25. Control D, Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P,
Crofford O, et al. The effect of intensive treatment of diabetes on the development and pro-
gression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med.
1993;329(14):977–86.
26. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of
prior intensive insulin treatment during the diabetes Control and complications trial (DCCT)
on peripheral neuropathy in type 1 diabetes during the epidemiology of diabetes interventions
and complications (EDIC) study. Diabetes Care. 2010;33(5):1090–6.
27. Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for prevent-
ing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;6:CD007543.
28. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose
control and vascular complications in veterans with type 2 diabetes. N Engl J Med.
2009;360(2):129–39.
8 Precision Medicine for Diabetic Neuropathy 191
29. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive
treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the
ACCORD randomised trial. Lancet Lond Engl. 2010;376(9739):419–30.
30. Tesfaye S, Vileikyte L, Rayman G, Sindrup SH, Perkins BA, Baconja M, et al. Painful dia-
betic peripheral neuropathy: consensus recommendations on diagnosis, assessment and man-
agement. Diabetes Metab Res Rev. 2011;27(7):629–38.
31. Smith AG, Singleton JR. Obesity and hyperlipidemia are risk factors for early diabetic neu-
ropathy. J Diabetes Complicat. 2013;27(5):436–42.
32. Andersson C, Guttorp P, Särkkä A. Discovering early diabetic neuropathy from epidermal
nerve fiber patterns. Stat Med. 2016;35(24):4427–42.
33. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The diagnostic criteria
for small fibre neuropathy: from symptoms to neuropathology. Brain J Neurol. 2008;131(Pt
7):1912–25.
34. Vinik AI, Erbas T. Diabetic autonomic neuropathy. Handb Clin Neurol. 2013;117:279–94.
35. Moore JX, Chaudhary N, Akinyemiju T. Metabolic syndrome prevalence by race/ethnicity
and sex in the United States, National Health and nutrition examination survey, 1988-2012.
Prev Chronic Dis. 2017;14:E24.
36. Christensen DH, Knudsen ST, Gylfadottir SS, Christensen LB, Nielsen JS, Beck-Nielsen H,
et al. Metabolic factors, lifestyle habits, and possible polyneuropathy in early type 2 diabetes:
a Nationwide study of 5,249 patients in the Danish Centre for Strategic Research in type 2
diabetes (DD2) cohort. Diabetes Care. 2020;43(6):1266–75.
37. Callaghan BC, Reynolds E, Banerjee M, Chant E, Villegas-Umana E, Feldman
EL. Central obesity is associated with neuropathy in the severely obese. Mayo Clin Proc.
2020;95(7):1342–53.
38. Reynolds EL, Callaghan BC, Banerjee M, Feldman EL, Viswanathan V. The metabolic driv-
ers of neuropathy in India. J Diabetes Complicat. 2020;34(10):107653.
39. Hughes RAC, Umapathi T, Gray IA, Gregson NA, Noori M, Pannala AS, et al. A controlled
investigation of the cause of chronic idiopathic axonal polyneuropathy. Brain J Neurol.
2004;127(Pt 8):1723–30.
40. Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AAF, Feldman EL. Elevated triglyc-
erides correlate with progression of diabetic neuropathy. Diabetes. 2009;58(7):1634–40.
41. Callaghan BC, Feldman E, Liu J, Kerber K, Pop-Busui R, Moffet H, et al. Triglycerides
and amputation risk in patients with diabetes: ten-year follow-up in the DISTANCE study.
Diabetes Care. 2011;34(3):635–40.
42. Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S, et al. Lifestyle intervention
for pre-diabetic neuropathy. Diabetes Care. 2006;29(6):1294–9.
43. Look AHEAD Research Group. Effects of a long-term lifestyle modification programme on
peripheral neuropathy in overweight or obese adults with type 2 diabetes: the look AHEAD
study. Diabetologia. 2017;60(6):980–8.
44. Kristensen FP, Christensen DH, Callaghan BC, Kahlert J, Knudsen ST, Sindrup SH, et al.
Statin therapy and risk of polyneuropathy in type 2 diabetes: a Danish cohort study. Diabetes
Care. 2020;43(12):2945–52.
45. Rajamani K, Colman PG, Li LP, Best JD, Voysey M, D’Emden MC, et al. Effect of fenofi-
brate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespeci-
fied analysis of a randomised controlled trial. Lancet Lond Engl. 2009;373(9677):1780–8.
46. Müller-Stich BP, Fischer L, Kenngott HG, Gondan M, Senft J, Clemens G, et al. Gastric
bypass leads to improvement of diabetic neuropathy independent of glucose normalization-
-results of a prospective cohort study (DiaSurg 1 study). Ann Surg. 2013;258(5):760–5; dis-
cussion 765-766.
47. Davis TME, Yeap BB, Davis WA, Bruce DG. Lipid-lowering therapy and peripheral sensory
neuropathy in type 2 diabetes: the Fremantle diabetes study. Diabetologia. 2008;51(4):562–6.
192 L. Davalos et al.
48. Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H, et al. Bariatric
surgery and long-term cardiovascular events. JAMA. 2012;307(1):56–65.
49. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group.
Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/
KORA Augsburg surveys S2 and S3. Pain Med Malden Mass. 2009;10(2):393–400.
50. Lee CC, Perkins BA, Kayaniyil S, Harris SB, Retnakaran R, Gerstein HC, et al. Peripheral
neuropathy and nerve dysfunction in individuals at high risk for type 2 diabetes: the PROMISE
cohort. Diabetes Care. 2015;38(5):793–800.
51. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy
in diabetes and impaired glucose tolerance. Neurology. 2003;60(1):108–11.
52. Pourhamidi K, Dahlin LB, Englund E, Rolandsson O. No difference in small or large nerve
fiber function between individuals with normal glucose tolerance and impaired glucose toler-
ance. Diabetes Care. 2013;36(4):962–4.
53. Thaisetthawatkul P, Lyden E, Americo Fernandes J, Herrmann DN. Prediabetes, diabetes,
metabolic syndrome, and small fiber neuropathy. Muscle Nerve. 2020;61(4):475–9.
54. Dyck PJ, Clark VM, Overland CJ, Davies JL, Pach JM, Dyck PJB, et al. Impaired glycemia
and diabetic polyneuropathy: the OC IG survey. Diabetes Care. 2012;35(3):584–91.
55. Kassardjian CD, Dyck PJB, Davies JL, Carter RE, Dyck PJ. Does prediabetes cause small
fiber sensory polyneuropathy? Does it matter? J Neurol Sci. 2015;355(1–2):196–8.
56. American Diabetes Association. 13. children and adolescents: standards of medical care in
diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S163–82.
57. Divers J, Mayer-Davis EJ, Lawrence JM, Isom S, Dabelea D, Dolan L, et al. Trends in inci-
dence of type 1 and type 2 diabetes among youths - selected counties and Indian reservations,
United States, 2002-2015. MMWR Morb Mortal Wkly Rep. 2020;69(6):161–5.
58. Pettitt DJ, Talton J, Dabelea D, Divers J, Imperatore G, Lawrence JM, et al. Prevalence of
diabetes in U.S. youth in 2009: the SEARCH for diabetes in youth study. Diabetes Care.
2014;37(2):402–8.
59. Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, et al. Prevalence
of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009.
JAMA. 2014;311(17):1778–86.
60. Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, et al. Incidence trends of
type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med. 2017;376(15):1419–29.
61. Patterson CC, Gyürüs E, Rosenbauer J, Cinek O, Neu A, Schober E, et al. Trends in child-
hood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over
time in rates of increase. Diabetologia. 2012;55(8):2142–7.
62. Zeitler P. Progress in understanding youth-onset type 2 diabetes in the United States: recent
lessons from clinical trials. World J Pediatr WJP. 2019;15(4):315–21.
63. Imperatore G, Boyle JP, Thompson TJ, Case D, Dabelea D, Hamman RF, et al. Projections
of type 1 and type 2 diabetes burden in the U.S. population aged <20 years through
2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care.
2012;35(12):2515–20.
64. Maser RE, Steenkiste AR, Dorman JS, Nielsen VK, Bass EB, Manjoo Q, et al. Epidemiological
correlates of diabetic neuropathy. Report from Pittsburgh epidemiology of diabetes compli-
cations study. Diabetes. 1989;38(11):1456–61.
65. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C,
et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic con-
trol and potential risk factors: the EURODIAB IDDM complications study. Diabetologia.
1996;39(11):1377–84.
66. Olsen BS, Johannesen J, Sjølie AK, Borch-Johnsen K, Hougarrdss P, Thorsteinsson B, et al.
Metabolic control and prevalence of microvascular complications in young Danish patients
with type 1 diabetes mellitus. Danish study Group of Diabetes in childhood. Diabet Med J Br
Diabet Assoc. 1999;16(1):79–85.
8 Precision Medicine for Diabetic Neuropathy 193
67. Nelson D, Mah JK, Adams C, Hui S, Crawford S, Darwish H, et al. Comparison of con-
ventional and non-invasive techniques for the early identification of diabetic neuropathy in
children and adolescents with type 1 diabetes. Pediatr Diabetes. 2006;7(6):305–10.
68. Eppens MC, Craig ME, Cusumano J, Hing S, Chan AKF, Howard NJ, et al. Prevalence of
diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes
Care. 2006;29(6):1300–6.
69. Jaiswal M, Divers J, Dabelea D, Isom S, Bell RA, Martin CL, et al. Prevalence of and risk
factors for diabetic peripheral neuropathy in youth with type 1 and type 2 diabetes: SEARCH
for diabetes in youth study. Diabetes Care. 2017;40(9):1226–32.
70. Moser J, Lipman T, Langdon DR, Bevans KB. Development of a youth-report measure
of DPN symptoms: conceptualization and content validation. J Clin Transl Endocrinol.
2017;9:55–60.
71. Arslanian S, Bacha F, Grey M, Marcus MD, White NH, Zeitler P. Evaluation and Management
of Youth-Onset Type 2 diabetes: a position statement by the American Diabetes Association.
Diabetes Care. 2018;41(12):2648–68.
72. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, under-
weight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-
based measurement studies in 128·9 million children, adolescents, and adults. Lancet Lond
Engl. 2017;390(10113):2627–42.
73. Janssen I, Katzmarzyk PT, Boyce WF, Vereecken C, Mulvihill C, Roberts C, et al. Comparison
of overweight and obesity prevalence in school-aged youth from 34 countries and their rela-
tionships with physical activity and dietary patterns. Obes Rev Off J Int Assoc Study Obes.
2005;6(2):123–32.
74. Akinci G, Savelieff MG, Gallagher G, Callaghan BC, Feldman EL. Diabetic neuropathy in
children and youth: new and emerging risk factors. Pediatr Diabetes. 2021;22(2):132–47.
75. Thamotharampillai K, Chan AKF, Bennetts B, Craig ME, Cusumano J, Silink M, et al.
Decline in neurophysiological function after 7 years in an adolescent diabetic cohort and the
role of aldose reductase gene polymorphisms. Diabetes Care. 2006;29(9):2053–7.
76. Monastiriotis C, Papanas N, Trypsianis G, Karanikola K, Veletza S, Maltezos E. The ε4 allele
of the APOE gene is associated with more severe peripheral neuropathy in type 2 diabetic
patients. Angiology. 2013;64(6):451–5.
77. Rudofsky G, Schroedter A, Schlotterer A, Voron’ko OE, Schlimme M, Tafel J, et al.
Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of
diabetic neuropathy in patients with type 1 diabetes. Diabetes Care. 2006;29(1):89–94.
78. Strokov IA, Bursa TR, Drepa OI, Zotova EV, Nosikov VV, Ametov AS. Predisposing genetic
factors for diabetic polyneuropathy in patients with type 1 diabetes: a population-based case-
control study. Acta Diabetol. 2003;40(Suppl 2):S375–9.
79. Chistiakov DA, Zotova EV, Savost’anov KV, Bursa TR, Galeev IV, Strokov IA, et al. The
262T>C promoter polymorphism of the catalase gene is associated with diabetic neuropathy
in type 1 diabetic Russian patients. Diabetes Metab. 2006;32(1):63–8.
80. Guo K, Eid SA, Elzinga SE, Pacut C, Feldman EL, Hur J. Genome-wide profiling of DNA
methylation and gene expression identifies candidate genes for human diabetic neuropathy.
Clin Epigenetics. 2020;12(1):123.
81. Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate
metabolic events. Curr Diab Rep. 2015;15(11):89.
82. Rumora AE, Lentz SI, Hinder LM, Jackson SW, Valesano A, Levinson GE, et al. Dyslipidemia
impairs mitochondrial trafficking and function in sensory neurons. FASEB J Off Publ Fed
Am Soc Exp Biol. 2018;32(1):195–207.
83. O’Brien PD, Guo K, Eid SA, Rumora AE, Hinder LM, Hayes JM, et al. Integrated lipidomic
and transcriptomic analyses identify altered nerve triglycerides in mouse models of prediabe-
tes and type 2 diabetes. Dis Model Mech. 2020;24:13(2).
194 L. Davalos et al.
84. Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, et al. Aberrant Schwann cell
lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy.
Neuron. 2013;77(5):886–98.
85. Hur J, Sullivan KA, Pande M, Hong Y, Sima AAF, Jagadish HV, et al. The identification of
gene expression profiles associated with progression of human diabetic neuropathy. Brain J
Neurol. 2011;134(Pt 11):3222–35.
86. Vincent AM, Hayes JM, McLean LL, Vivekanandan-Giri A, Pennathur S, Feldman
EL. Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes.
2009;58(10):2376–85.
87. Nowicki M, Müller K, Serke H, Kosacka J, Vilser C, Ricken A, et al. Oxidized low-density
lipoprotein (oxLDL)-induced cell death in dorsal root ganglion cell cultures depends
not on the lectin-like oxLDL receptor-1 but on the toll-like receptor-4. J Neurosci Res.
2010;88(2):403–12.
88. Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, Lastoskie C, et al. Receptor for
advanced glycation end products activation injures primary sensory neurons via oxidative
stress. Endocrinology. 2007;148(2):548–58.
89. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest.
2006;116(7):1793–801.
90. Elzinga S, Murdock BJ, Guo K, Hayes JM, Tabbey MA, Hur J, et al. Toll-like receptors
and inflammation in metabolic neuropathy; a role in early versus late disease? Exp Neurol.
2019;320:112967.
91. Shevalye H, Yorek MS, Coppey LJ, Holmes A, Harper MM, Kardon RH, et al. Effect of
enriching the diet with menhaden oil or daily treatment with resolvin D1 on neuropathy in a
mouse model of type 2 diabetes. J Neurophysiol. 2015;114(1):199–208.
92. Hinder LM, Park M, Rumora AE, Hur J, Eichinger F, Pennathur S, et al. Comparative RNA-
Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney
disease. J Cell Mol Med. 2017;21(9):2140–52.
93. Eid SA, O’Brien PD, Hinder LM, Hayes JM, Mendelson FE, Zhang H, et al. Differential
effects of Empagliflozin on microvascular complications in murine models of type 1 and type
2 diabetes. Biology. 2020;22:9(11).
94. Kellogg AP, Wiggin TD, Larkin DD, Hayes JM, Stevens MJ, Pop-Busui R. Protective effects
of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepider-
mal nerve fiber loss in experimental diabetes. Diabetes. 2007;56(12):2997–3005.
95. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, et al. HSP70
stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual
role as a chaperone and cytokine. Nat Med. 2000;6(4):435–42.
96. Truini A, Spallone V, Morganti R, Tamburin S, Zanette G, Schenone A, et al. A cross-sectional
study investigating frequency and features of definitely diagnosed diabetic painful polyneu-
ropathy. Pain. 2018;159(12):2658–66.
97. Themistocleous AC, Ramirez JD, Shillo PR, Lees JG, Selvarajah D, Orengo C, et al. The pain
in neuropathy study (PiNS): a cross-sectional observational study determining the somato-
sensory phenotype of painful and painless diabetic neuropathy. Pain. 2016;157(5):1132–45.
98. Raputova J, Srotova I, Vlckova E, Sommer C, Üçeyler N, Birklein F, et al. Sensory phenotype
and risk factors for painful diabetic neuropathy: a cross-sectional observational study. Pain.
2017;158(12):2340–53.
99. Shillo P, Sloan G, Greig M, Hunt L, Selvarajah D, Elliott J, et al. Painful and painless diabetic
neuropathies: what is the difference? Curr Diab Rep. 2019;19(6):32.
100. Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of dia-
betic sensorimotor peripheral neuropathy. Nat Rev End. In Press.
101. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al.
Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.
Lancet Neurol. 2015;14(2):162–73.
8 Precision Medicine for Diabetic Neuropathy 195
102. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, et al. Towards a
mechanism-based classification of pain? Pain. 1998;77(3):227–9.
103. Edwards RR, Dworkin RH, Turk DC, Angst MS, Dionne R, Freeman R, et al. Patient phe-
notyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain.
2016;157(9):1851–71.
104. Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative sen-
sory testing in the German research network on neuropathic pain (DFNS): somatosen-
sory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain.
2010;150(3):439–50.
105. Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, et al. Quantitative
sensory testing: report of the therapeutics and technology assessment Subcommittee of the
American Academy of neurology. Neurology. 2003;60(6):898–904.
106. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, et al. Quantitative
sensory testing: a comprehensive protocol for clinical trials. Eur J Pain Lond Engl.
2006;10(1):77–88.
107. Tesfaye S, Boulton AJM, Dickenson AH. Mechanisms and management of diabetic painful
distal symmetrical polyneuropathy. Diabetes Care. 2013;36(9):2456–65.
108. Birbaumer N, Lutzenberger W, Montoya P, Larbig W, Unertl K, Töpfner S, et al. Effects of
regional anesthesia on phantom limb pain are mirrored in changes in cortical reorganization.
J Neurosci. 1997;17(14):5503–8.
109. Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, et al. Phantom-limb
pain as a perceptual correlate of cortical reorganization following arm amputation. Nature.
1995;375(6531):482–4.
110. Wrigley PJ, Press SR, Gustin SM, Macefield VG, Gandevia SC, Cousins MJ, et al.
Neuropathic pain and primary somatosensory cortex reorganization following spinal cord
injury. Pain. 2009;141(1–2):52–9.
111. Wilkinson ID, Teh K, Heiberg-Gibbons F, Awadh M, Kelsall A, Shillo P, et al. Determinants
of treatment response in painful diabetic peripheral neuropathy: a combined deep sensory
phenotyping and multimodal brain MRI study. Diabetes. 2020;69(8):1804–14.
112. Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, et al. Randomized
control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain.
2012;153(9):1815–23.
113. Bouhassira D, Wilhelm S, Schacht A, Perrot S, Kosek E, Cruccu G, et al. Neuropathic pain
phenotyping as a predictor of treatment response in painful diabetic neuropathy: data from
the randomized, double-blind. COMBO-DN study Pain. 2014;155(10):2171–9.
114. Demant et al. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain
phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain.
2014;155(11):2263–73.
115. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned
pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain.
2012;153(6):1193–8.
116. Haroutounian S, Nikolajsen L, Bendtsen TF, Finnerup NB, Kristensen AD, Hasselstrøm JB,
et al. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropa-
thy. Pain. 2014;155(7):1272–9.
117. Feldman et al. Diabetic neuropathy. Nature reviews disease primers. 2019;5(1):1–8.
118. Wager TD, Atlas LY, Lindquist MA, Roy M, Woo C-W, Kross E. An fMRI-based neurologic
signature of physical pain. N Engl J Med. 2013;368(15):1388–97.
119. Tracey I. “Seeing” how our drugs work brings translational added value. Anesthesiology.
2013;119(6):1247–8.
120. Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ, Witte DR, et al. Early involve-
ment of the spinal cord in diabetic peripheral neuropathy. Diabetes Care. 2006;29(12):2664–9.
196 L. Davalos et al.
121. Selvarajah D, Wilkinson ID, Maxwell M, Davies J, Sankar A, Boland E, et al. Magnetic reso-
nance neuroimaging study of brain structural differences in diabetic peripheral neuropathy.
Diabetes Care. 2014;37(6):1681–8.
122. Selvarajah D, Wilkinson ID, Fang F, Sankar A, Davies J, Boland E, et al. Structural and func-
tional abnormalities of the primary somatosensory cortex in diabetic peripheral neuropathy:
a multimodal MRI study. Diabetes. 2019;68(4):796–806.
123. Buxton RB. Interpreting oxygenation-based neuroimaging signals: the importance and the
challenge of understanding brain oxygen metabolism. Front Neuroenerg. 2010;2:8.
124. Pereira F, Mitchell T, Botvinick M. Machine learning classifiers and fMRI: a tutorial over-
view. NeuroImage. 2009;45(1 Suppl):S199–209.
125. Wager TD, Lindquist MA, Nichols TE, Kober H, Van Snellenberg JX. Evaluating the con-
sistency and specificity of neuroimaging data using meta-analysis. NeuroImage. 2009;45(1
Suppl):S210–21.
126. Alger JR, Ellingson BM, Ashe-McNalley C, Woodworth DC, Labus JS, Farmer M, et al.
Multisite, multimodal neuroimaging of chronic urological pelvic pain: methodology of the
MAPP research network. NeuroImage Clin. 2016;12:65–77.
127. Zunhammer M, Bingel U, Wager TD. Placebo imaging consortium. Placebo effects on the
neurologic pain signature: a meta-analysis of individual participant functional magnetic reso-
nance imaging data. JAMA Neurol. 2018;75(11):1321–30.
128. Eddy S, Mariani LH, Kretzler M. Integrated multi-omics approaches to improve classifica-
tion of chronic kidney disease. Nat Rev Nephrol. 2020;16(11):657–68.
129. Heerspink HJL, de Zeeuw D. Treating diabetic complications; from large randomized clini-
cal trials to precision medicine. Diabetes Obes Metab. 2018;20(Suppl 3):3–5.
130. Idzerda NMA, Pena MJ, Heerspink HJL. Personalized medicine in diabetic kidney disease: a
novel approach to improve trial design and patient outcomes. Curr Opin Nephrol Hypertens.
2018;27(6):426–32.
131. de Boer IH, Alpers CE, Azeloglu EU, Balis UGJ, Barasch JM, Barisoni L, et al. Rationale and
design of the kidney precision medicine project. Kidney Int. 2021;99(3):498–510.
132. van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, et al. A
genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes.
Diabetes. 2018;67(7):1414–27.
133. Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, et al.
Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabe-
tes. Diabetes. 2009;58(6):1403–10.
134. Lan D, Jiang H-Y, Su X, Zhao Y, Du S, Li Y, et al. Transcriptome-wide association study iden-
tifies genetically dysregulated genes in diabetic neuropathy. Comb Chem High Throughput
Screen. 2021;24(2):319–25.
135. Ustinova M, Peculis R, Rescenko R, Rovite V, Zaharenko L, Elbere I, et al. Novel suscepti-
bility loci identified in a genome-wide association study of type 2 diabetes complications in
population of Latvia. BMC Med Genet. 2021;14(1):18.
136. Guo K, Elzinga S, Eid S, Figueroa-Romero C, Hinder LM, Pacut C, et al. Genome-wide
DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2
diabetes mellitus. Epigenetics. 2019;14(8):766–79.
137. Yang H, Sloan G, Ye Y, Wang S, Duan B, Tesfaye S, et al. New perspective in diabetic neu-
ropathy: from the periphery to the brain, a call for early detection, and precision medicine.
Front Endocrinol. 2019;10:929.
138. Themistocleous AC, Crombez G, Baskozos G, Bennett DL. Using stratified medicine to
understand, diagnose, and treat neuropathic pain. Pain. 2018;159(Suppl 1):S31–42.
139. Chen W-T, Yuan R-Y, Chiang S-C, Sheu J-J, Yu J-M, Tseng I-J, et al. OnabotulinumtoxinA
improves tactile and mechanical pain perception in painful diabetic polyneuropathy. Clin J
Pain. 2013;29(4):305–10.
8 Precision Medicine for Diabetic Neuropathy 197
140. Ghasemi M, Ansari M, Basiri K, Shaigannejad V. The effects of intradermal botulinum toxin
type a injections on pain symptoms of patients with diabetic neuropathy. J Res Med Sci Off J
Isfahan Univ Med Sci. 2014;19(2):106–11.
141. Nawfar SA, Yacob NBM. Effects of monochromatic infrared energy therapy on dia-
betic feet with peripheral sensory neuropathy: a randomised controlled trial. Singap Med
J. 2011;52(9):669–72.
142. Jude EB, Dang C, Boulton AJM. Effect of L-arginine on the microcirculation in the neu-
ropathic diabetic foot in type 2 diabetes mellitus: a double-blind, placebo-controlled study.
Diabet Med J Br Diabet Assoc. 2010;27(1):113–6.
143. Syngle A, Verma I, Krishan P, Garg N, Syngle V. Minocycline improves peripheral and auto-
nomic neuropathy in type 2 diabetes: MIND study. Neurol Sci Off J Ital Neurol Soc Ital Soc
Clin Neurophysiol. 2014;35(7):1067–73.
144. Fraser DA, Diep LM, Hovden IA, Nilsen KB, Sveen KA, Seljeflot I, et al. The effects of
long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory
markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-
controlled trial. Diabetes Care. 2012;35(5):1095–7.
Chapter 9
Inpatient Precision Medicine for Diabetes
Introduction
Cell stress
Proteolysis Lipolysis Inflammation Immune System Activation
Pro-thrombosis
Ceramides,
BCAA Acyl-carnitines
TNF-a, IL-6
Fig. 9.1 Multiple factors influence glucose metabolism in acutely ill patients. Patient-specific fac-
tors including the metabolic phenotype (normoglycemia, obesity, prediabetes, type 1 or type 2
diabetes), the severity of disease (counterregulatory response and the severity of disease), as well
as hospital factors (medical nutrition therapy, steroids, vasopressors). Potential mediators of dys-
glycemia include metabolites originating from catabolism and inflammation during the acute ill-
ness that have been associated with increase hepatic glucose output, insulin resistance, and
beta-cell dysfunction including BCAA (branched-chain amino acids), ceramides, and
acylcarnitines
social factors, and patient preferences may further facilitate the generation of pre-
cise recommendations to improve care at the individual and population level
(Fig. 9.2). Furthermore, the integration of systems biology and the digital revolution
are transforming healthcare toward a P7 medicine concept [14, 15] where care is
more personalized, predictive, precise, preventive, pervasive, participatory, and
protective (Table 9.1).
Optimizing glycemic control in the inpatient setting has been limited by infrequent
glucose testing, most often relying on point-of-care finger-stick blood samples. In
utilizing this method of glucose monitoring, a desire for increased frequency of
glucose testing increases the work burden of staff responsible for the POC glucose
testing. Even with an increased number of POC glucose values, the glycemic
202 G. Davis et al.
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Se
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ve
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Bio ity o nt s
in ic
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g
ma f Ill a
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P re
ab ta
rke nes e
ef
et
rs s pr
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os Data input to
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Precision inpatient
Diabetes Care
Fig. 9.2 Integrating multidimensional data for precision medicine in the hospital. Advances in
bioinformatics that integrate multidimensional data and the use of artificial intelligence with deep
learning techniques may facilitate personalized and adaptive diabetes management
Table 9.1 Adapting the elements of the P7 concept to the future of inpatient diabetes care [14, 15]
Personalized Individualized inpatient therapy strategies that work should be standardized
medicine
Predictive Development of risk prediction tools using EHR data and -omics data may
help determine susceptibility to additional diseases and hospital complications
in patients with diabetes
Precise The information obtained from multidimensional data may be used to
precisely determine inpatient regimens and appropriate transitions of care
Preventive Personalized approaches using machine learning and decision analytical tools
can be used to develop strategies to prevent severe glycemic excursions and
medication interactions and reduce the risk of readmissions
Pervasive The information for inpatient care utilizing dynamic metrics should be
available at any time and at any location
Participatory Patient preferences should be included in the decision-making for inpatient
care and at time of discharge
Protective Cybersecurity measures should be implemented to ensure confidentiality of all
patient data
9 Inpatient Precision Medicine for Diabetes 203
control data generated still provides only a limited snapshot of glucose trends and
fluctuations. Accordingly, there has been much interest in moving continuous glu-
cose monitoring (CGM) into the hospital setting. During the coronavirus 2019
(COVID-19) pandemic, efforts to implement real-time CGM (rt-CGM) for inpatient
use were rapidly put in place to minimize viral exposures while maintaining ade-
quate monitoring of glycemic control. While these devices were able to be used in
the hospital without objection from the Food and Drug Administration during a
public health crisis [4, 16], there are limited studies and data on the use of CGM in
the inpatient setting, with ongoing studies continuing to investigate reliability and
functionality of CGM in hospitalized patients. However, the rapid and widespread
implementation of hospital CGM use during COVID-19 has provided a snapshot of
the potential benefits of CGM for hospital monitoring of glucose values and trends
[16–18]. The most frequently used CGM systems employ subcutaneous monitoring
of interstitial glucose values every few minutes with a corresponding glucose trend
arrow, as well as alerts that can be set to detect hypoglycemia, hyperglycemia, and
rapid changes in glucose trend. Real-time CGM generates exponentially more gly-
cemic control data than that from POC glucose testing alone and addresses prior
limitations in hospital glucose monitoring through closer observation of glucose
values and the use of glucose trends and alerts to prevent severe glycemic excur-
sions and hypoglycemic events [4, 19].
Though inpatient rt-CGM implementation is a crucial step forward in guiding
personalized diabetes management in the hospital, further consideration on how
CGM data can be accurately and meaningfully recorded for incorporation into
larger diverse data sets will be required to move toward precision diabetes care. As
CGM data from hospitalized patients becomes available, infrequent discrete glu-
cose measurements are being replaced by glucose values every few minutes during
hospitalization. This wealth of glucose data affords the opportunity to aggregate
data on hospital glucose measurements and glycemic control metrics (time in glu-
cose ranges, glycemic variability) for the creation of comprehensive databases with
information on individual-level inpatient glycemic control [20]. Previous studies
have proposed that more comprehensive subtyping of diabetes classification is
needed to inform precision diabetes care [21], with one study suggesting the use of
individual-level CGM data related to other glucose control and clinical characteris-
tics to classify patterns and underlying mechanisms of glucose dysregulation (“glu-
cotypes”) potentially associated with early type 2 diabetes or cardiovascular risk
[22]. However, this glucose excursion-based classification from CGM data com-
bined with other risk stratification phenotypes, inpatient clinical metrics and phar-
macotherapeutic data, could be a powerful technique to help predict treatment
responses and individualize glucose monitoring. Current efforts to translate CGM to
the hospital setting are allowing an opportunity to define patterns of glycemia in
heterogeneous populations with acute illnesses. A detailed assessment of glucose
patterns with CGM integrated with other clinical parameters, such as ECG, may in
the near future continue to facilitate optimal individualized glucose monitoring and
prevention of hypoglycemia [23].
204 G. Davis et al.
Current recommended glycemic targets for both noncritical and critical care set-
tings have been derived from clinical trials and observational studies with the goal
of limiting hyperglycemic and hypoglycemic excursions known to be associated
with poor hospital outcomes [24]. Some of the largest studies from which the rec-
ommendations are derived included heterogeneous populations that did not account
for individual-level patient characteristics, including a diagnosis of diabetes, which
could impact determination of clinically appropriate target glucose ranges [25, 26].
Still, it is not well-known (a) who are the most vulnerable patients to extreme glu-
cose fluctuations, (b) how diabetes phenotypes and severity of illness impact glyce-
mic control patterns, (c) the actual biological impact and reversibility of both
hyperglycemia- and hypoglycemia-associated complications, and (d) the most opti-
mal diabetes treatment strategies during acute illness for diverse populations.
Recent clinical trials have shown that even in controlled hospital settings not all
patients are able to reach recommended glucose targets [27, 28] and worse control
is expected in real-world inpatient scenarios. The landscape of available therapies
for the management of diabetes has significantly expanded in the last decade, and
new agents have emerged as potential alternatives to insulin, considered for many
years the ideal treatment strategy in the hospital. Recent data documented with
CGM has shown that even with subcutaneous insulin therapy, the proportion of time
spent in target glucose range (defined as 70–180 mg/dL) is often suboptimal [18,
27–30]. Additionally, data from inpatient hospitalizations, nursing homes, and reha-
bilitation facilities have consistently shown increased hypoglycemia risk with insu-
lin therapy [25, 31–33]. Recent studies including vulnerable patients with diabetes
(such as those with older age and/or renal failure) have shown, as expected, that less
insulin is associated with a lower risk of hypoglycemia and that the use of non-
insulin agents may be appropriate in certain circumstances to achieve glycemic con-
trol in the inpatient setting [4].
The individualization of inpatient diabetes management strategies is evolving to
include new pharmacotherapeutic agents, insulin delivery systems, and glucose
monitoring strategies. In choosing patient-specific therapy, glycemic targets will
also be personalized based on patient factors as well as risks associated with these
individualized therapeutic strategies. Recent clinical trials have started to delineate
the characteristics of patients more likely to benefit from insulin and non-insulin
therapy regimens. Figure 9.3 shows a framework utilizing clinical patient data,
admission biometrics, and severity of disease to individualized therapy with insulin
and non-insulin agents.
Even though insulin therapy with fixed insulin dosing regimens has been consid-
ered standard of care for patients with type 2 diabetes in the hospital, recent obser-
vational studies have shown that oral agents (i.e., metformin or sulfonylureas) are
commonly used in the hospital. A basal-bolus insulin regimen [with a total daily
dose usually delivered as basal insulin (50%) along with scheduled prandial insulin
9
Non-critically ill patients with diabetes Critically ill patients or hyperglycaemic crises
Transition to
subcutaneous
Moderate hyperglycaemia Basal insulin with or without correction* Continuous insulin Severe DKA or HHS
subcutaneous
Type 2 diabetes • BG 201–300 mg/dL • Start at 0·2–0·3 U/kg per day‡ infusion
insulin regimen
(100-180 mg/dL) • Multiple antidiabetic agents† • Correction doses with rapid-acting insulin
• Insulin TDD <0·6 U/kg before meals or every 6 h
per day
• BG >300 mg/dL • Reduce home insulin TDD by 20% or start Subcutaneous insulin Mild-to-moderate DKA
• Multiple antidiabetic agents† 0·3 U/kg per day (TDD given half basal, half DKA protocol
• Insulin TDD >0·6 U/kg per bolus)
day • Adjust as needed
• Withhold prandial insulin if poor oral intake
• Or continue insulin pump (type 1 diabetes)
Type 1 diabetes following hospital regulations
(100-180 mg/dL)
Fig. 9.3 Individualized antihyperglycemic therapy in hospitalized patients with diabetes. In critically ill patients, continuous insulin infusion is recommended
followed by transition to subcutaneous insulin regimens once patients are stable and close to discharge from the intensive care unit. Subcutaneous insulin DKA
protocols might be considered in patients with mild-to-moderate DKA (subcutaneous insulin protocol examples adapted for COVID-19 are available online).
We discourage the widespread use of premixed insulin regimens in the hospital setting. (BG, blood glucose. DKA, diabetic ketoacidosis. HHS, hyperosmolar
hyperglycemic state. OAD, oral antidiabetic drug. TDD, total daily dose. U, units. *Consider OAD if no contraindications (only DPP-4 inhibitors have been
studied in randomized controlled trials); metformin is commonly used in the hospital setting but might be associated with lactic acidosis in high-risk patients
(e.g., sepsis, shock, renal or liver failure). †Antidiabetic agents include OADs and GLP-1 receptor agonists. ‡In patients with hypoglycemia risk (frail, elderly,
acute kidney injury), reduce starting dose to 0·15 U/kg per day (basal alone) or TDD 0·3 U/kg per day (basal-bolus). From Pasquel FJ et al. with permission [4])
205
206 G. Davis et al.
before meals (50% divided in three doses)] can lead to lower average BG levels
compared to sliding-scale insulin (SSI). This approach, however, is labor-intensive,
requiring multiple injections per day, and is associated with increased risk of iatro-
genic hypoglycemia [34]. More recently, RCTs have consistently shown that DPP-4
inhibitors with SSI are safe in hospitalized patients with mild hyperglycemia
(<200 mg/dl) [35]. For patients with BG 140–400 mg/dL treated at home with oral
agents or insulin at a dose <0.6 units/kg/day, a DPP-4 inhibitor and basal insulin
combination is as effective as a basal-bolus regimen [35]. Currently, individualiza-
tion of care approaches unfortunately demand clinical experience of inpatient pro-
viders familiar with the field. Data integration using technology for systematic
decision-making with precise regimens may alleviate the burden for providers tak-
ing care of patients with diabetes in the hospital.
Diabetes technology may become an integral part of diabetes care in the future.
In addition to rt-CGM, other technologies are emerging in the inpatient setting.
These technologies include various computerized decision support systems and
EHR enhancements for glucose management implemented to systematically initiate
therapy in patients with diabetes or hyperglycemia [36]. In addition, current tech-
nology allows for individualized care (CGM-based insulin delivery) along with
population health management (cloud-based platforms). We recently showed feasi-
bility of integrating remote rt-CGM technology with a protocol incorporating EHR
validation of glucose values (confirmation of sensor accuracy compared to POC)
with a computerized algorithm for continuous insulin infusion to care for critically
ill patients with COVID-19 [17].
Furthermore, the use of automated insulin delivery (AID) systems, or artificial
pancreas technology, has been rapidly expanding in the outpatient setting and is
becoming more common in the hospital; however, the infrastructure is not readily
available for the inpatient use of AID. Initial studies with AID have shown improve-
ment in glycemic control in diverse populations of noncritically ill patients [29, 30].
A recent retrospective analyses of inpatient studies with closed-loop showed a high
variability of exogenous insulin requirements in hospitalized patients, particularly
overnight, confirming the need for personalized glucose-responsive approaches to
achieve glucose targets while minimizing hypoglycemia risk [37]. Further develop-
ment of this technology for inpatient therapy will likely integrate more individual-
ized algorithms through the use of artificial intelligence to adapt care during acute
illness.
Conclusions
References
1. Fradkin JE, Hanlon MC, Rodgers GP. NIH precision medicine initiative: implications for dia-
betes research: table 1. Diabetes Care. 2016;39(7):1080–4.
2. Meyer RJ. Precision medicine, diabetes, and the U.S. Food and Drug Administration. Diabetes
Care. 2016;39(11):1874–8.
3. Klonoff DC. Precision medicine for managing diabetes. J Diabetes Sci Technol. 2015;9(1):3–7.
4. Pasquel FJ, Lansang MC, Dhatariya K, Umpierrez GE. Management of diabetes and hypergly-
caemia in the hospital. Lancet Diabetes Endocrinol. 2021;9(3):174–88.
5. Reyes-Umpierrez D, Davis G, Cardona S, et al. Inflammation and oxidative stress in car-
diac surgery patients treated to intensive vs. conservative glucose targets. J Clin Endocrinol
Metabol. 2016:jc.2016–3197.
6. Hotamisligil G. Molecular mechanisms of insulin resistance and the role of the adipocyte. Int
J Obes. 2000;24(S4):S23–7.
7. Guasch-Ferre M, Hruby A, Toledo E, et al. Metabolomics in prediabetes and diabetes: a sys-
tematic review and meta-analysis. Diabetes Care. 2016;39(5):833–46.
8. Menni C, Fauman E, Erte I, et al. Biomarkers for type 2 diabetes and impaired fasting glucose
using a nontargeted metabolomics approach. Diabetes. 2013;62(12):4270–6.
9. Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes.
Nat Med. 2011;17(4):448–53.
10. Batchuluun B, Al Rijjal D, Prentice KJ, et al. Elevated medium chain-Acylcarnitines are asso-
ciated with gestational diabetes, and early progression to Type-2 diabetes, and induce pancre-
atic beta-cell dysfunction. Diabetes. 2018.
11. Sun L, Liang L, Gao X, et al. Early prediction of developing type 2 diabetes by plasma
Acylcarnitines: a population-based study. Diabetes Care. 2016;39(9):1563–70.
12. Ruiz-Canela M, Toledo E, Clish CB, et al. Plasma branched-chain amino acids and incident
cardiovascular disease in the PREDIMED trial. Clin Chem. 2016;62(4):582–92.
208 G. Davis et al.
13. Ardila D, Kiraly AP, Bharadwaj S, et al. End-to-end lung cancer screening with
three-dimensional deep learning on low-dose chest computed tomography. Nat Med.
2019;25(6):954–61.
14. Hood L, Flores M. A personal view on systems medicine and the emergence of proac-
tive P4 medicine: predictive, preventive, personalized and participatory. New Biotechnol.
2012;29(6):613–24.
15. Sriram RD, Reddy SSK. Artificial intelligence and digital tools. Clin Geriatr Med.
2020;36(3):513–25.
16. Galindo RJ, Aleppo G, Klonoff DC, et al. Implementation of continuous glucose monitoring
in the hospital: emergent considerations for remote glucose monitoring during the COVID-19
pandemic. J Diabetes Sci Technol. 2020;14(4):822–32.
17. Davis GM, Faulds E, Walker T, et al. Remote continuous glucose monitoring with a computer-
ized insulin infusion protocol for critically ill patients in a COVID-19 medical ICU: proof of
concept. Diabetes Care. 2021;44(4):1055–8.
18. Agarwal S, Mathew J, Davis GM, et al. Continuous glucose monitoring in the intensive care
unit during the COVID-19 pandemic. Diabetes Care. 2021;44(3):847–9.
19. Singh LG, Satyarengga M, Marcano I, et al. Reducing inpatient hypoglycemia in the general
wards using real-time continuous glucose monitoring: the glucose telemetry system, a ran-
domized clinical trial. Diabetes Care. 2020;43(11):2736–43.
20. Vettoretti M, Cappon G, Acciaroli G, Facchinetti A, Sparacino G. Continuous glucose moni-
toring: current use in diabetes management and possible future applications. J Diabetes Sci
Technol. 2018;12(5):1064–71.
21. Ahlqvist E, Storm P, Käräjämäki A, et al. Novel subgroups of adult-onset diabetes and their
association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes
Endocrinol. 2018;6(5):361–9.
22. Hall H, Perelman D, Breschi A, et al. Glucotypes reveal new patterns of glucose dysregulation.
PLoS Biol. 2018;16(7):e2005143.
23. Porumb M, Stranges S, Pescapè A, Pecchia L. Precision medicine and artificial intelligence:
a pilot study on deep learning for hypoglycemic events detection based on ECG. Sci Rep.
2020;10(1):170.
24. 15. Diabetes care in the hospital: standards of medical care in diabetes—2021. Diabetes Care.
2021;44(Supplement 1):S211–20.
25. Intensive versus conventional glucose control in critically ill patients. New England J Med.
2009;360(13):1283–97.
26. Moghissi ES, Korytkowski MT, Dinardo M, et al. American Association of Clinical
Endocrinologists and American Diabetes Association Consensus Statement on inpatient gly-
cemic control. Diabetes Care. 2009;32(6):1119–31.
27. Fortmann AL, Spierling Bagsic SR, Talavera L, et al. Glucose as the fifth vital sign: a random-
ized controlled trial of continuous glucose monitoring in a non-ICU hospital setting. Diabetes
Care. 2020;43(11):2873–7.
28. Pasquel FJ, Lansang MC, Khowaja A, et al. A randomized controlled trial comparing glargine
U300 and glargine U100 for the inpatient Management of Medicine and Surgery Patients with
Type 2 diabetes: glargine U300 hospital trial. Diabetes Care. 2020;43(6):1242–8.
29. Bally L, Thabit H, Hartnell S, et al. Closed-loop insulin delivery for glycemic control in non-
critical care. N Engl J Med. 2018;379(6):547–56.
30. Boughton CK, Bally L, Martignoni F, et al. Fully closed-loop insulin delivery in inpatients
receiving nutritional support: a two-Centre, open-label, randomised controlled trial. Lancet
Diabetes Endocrinol. 2019;7(5):368–77.
31. Pasquel FJ, Powell W, Peng L, et al. A randomized controlled trial comparing treatment with
oral agents and basal insulin in elderly patients with type 2 diabetes in long-term care facilities.
BMJ Open Diabetes Res Care. 2015;3(1):e000104.
32. Umpierrez GE, Cardona S, Chachkhiani D, et al. A randomized controlled study comparing
a DPP4 inhibitor (Linagliptin) and basal insulin (Glargine) in Patients with type 2 diabetes
9 Inpatient Precision Medicine for Diabetes 209
in long-term care and skilled nursing facilities: linagliptin-LTC trial. J Am Med Directors
Associat. 2018;19(5):399–404.e393.
33. Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with Detemir
plus Aspart versus neutral protamine Hagedorn plus regular in medical patients with type 2
diabetes. J Clin Endocrinol Metabol. 2009;94(2):564–9.
34. Umpierrez GE, Hellman R, Korytkowski MT, et al. Management of hyperglycemia in hospital-
ized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin
Endocrinol Metab. 2012;97(1):16–38.
35. Pasquel FJ, Gianchandani R, Rubin DJ, et al. Efficacy of sitagliptin for the hospital manage-
ment of general medicine and surgery patients with type 2 diabetes (Sita-Hospital): a multi-
centre, prospective, open-label, non-inferiority randomised trial. Lancet Diabetes Endocrinol.
2017;5(2):125–33.
36. Davis GM, Galindo RJ, Migdal AL, Umpierrez GE. Diabetes Technology in the Inpatient
Setting for Management of Hyperglycemia. Endocrinol Metab Clin N Am. 2020;49(1):79–93.
37. Boughton CK, Daly A, Thabit H, et al. Day-to-day variability of insulin requirements in the
inpatient setting: observations during fully closed-loop insulin delivery. Diabetes Obesity
Metabol. 2021.
Chapter 10
Precision Medical Management Strategies
for Diabetes Remission
S. R. Kashyap (*)
Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
e-mail: [email protected]
S. M. Borgan
Endocrinology and Metabolism Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
the level of muscles and hepatic fat deposition cause reduced uptake of glucose
from the blood, as well as abnormally increased hepatic glucose production [4]. In
response to hyperglycemia, pancreatic B cells produce excess amounts of insulin
which further lead to the favored processing of triacylglycerol in the liver into either
storage (leading to worsened fatty liver, hepatic insulin resistance, and increased
hepatic glucose production) or transportation in blood (which contributes to fatty
acid deposition in the pancrease, eventually contributing to permanent reduced
B-cell function and reduced sensitivity in response to hyperglycemia) [3].
Peripheral insulin resistance and hepatic glucose production occur early in the
pathophysiological state, usually spanning years before clinical diabetes becomes
evident [5]. In the years of hyperinsulinemia, elevated plasma triacylglycerol leads
to progressive decompensation of beta cells. In fact, there is evidence that this B-cell
dysfunction begins before the development of diabetes, as defined by our thresholds
[5]. It is not thought to become irreversible until at least 2–3 years from the initial
diagnosis [3]. While the exact duration is unclear, based on clinical data from pro-
spective studies, 50% of patients with type 2 diabetes will require insulin at 10 years,
likely reflecting irreversible B-cell loss [6].
Inducing remission early is important for a number of reasons. Firstly, the dura-
tion of hyperglycemia has a linear relationship with the development of microvas-
cular and macrovascular complications of diabetes [6]. Additionally, as described
earlier, the likelihood of remission success relies on the reversibility of B-cell dys-
function, which is time-dependent. Recognizing this narrow time window is impor-
tant for successful attempts to induce remission. Unfortunately, clinical inertia is
widely prevalent among physicians treating type 2 diabetes, especially early in dia-
betes [7]. This may stem from physicians’ historic perspective that type 2 diabetes
is a chronic lifelong disorder, in which Hba1c control is achieved by addition of
anti-hyperglycemic agents in a stepwise reactive fashion.
associated with the rate or extent of the weight loss, but rather associated with a
reduction in hepatic glucose output. While this study did not evaluate diabetes
remission per se, it does provide important insight into the effect of low-calorie diet
on hepatic glucose output and the speed of improvement of plasma glucose. A more
recent study using a less restrictive diet (600 calorie/day diet) has subsequently
confirmed these findings, including normalization of fasting plasma levels within
1 week of diet initiation, reduction of hepatic glucose output, reduced hepatic triac-
ylglycerol content, and improved first-phase insulin response at week 8 [12]. While
these studies show short-term changes in glycemic indices with very low-calorie
diets, they do not confirm longitudinal remission of type 2 diabetes, especially after
return to long-term isocaloric feeding.
To address this, a prospective study measured the maintenance of remission of
type 2 diabetes 6 months after resumption of isocaloric feeding. Thirty patients with
type 2 diabetes (duration 0.5–23 years) underwent an 8-week course of very low
caloric diet (624–700 calorie per day through liquid meal replacement with 240 g of
non-starchy vegetables) followed by 2-week gradual reintroduction of solid food
and then a 6-month weight loss management program. At 6 months’ follow-up visit,
13 out of 30 patients (40%) had achieved remission (partial or complete). Duration
of diabetes was significantly shorter in responders compared to nonresponders
(M3.8 (±1) vs M9.8 (±1.6)), while weight loss was similar between both groups
[13]. Another study randomized 83 patients with recently diagnosed type 2 diabetes
(<3 year duration) into 8- and 16-week “intensive metabolic intervention” (negative
500–750 calories from daily requirement and exercise) or standard care and estab-
lished a 21.4% and 40.7% remission rates at the 3-month follow-up visit in the two
intervention groups [14].
A less restrictive diet may be unhelpful in terms of remission especially in those
with more prolonged diabetes duration, as shown in a parallel arm study of 215
patients with type 2 diabetes (mean duration 5.1 years) randomized either to low-
carb Mediterranean diet (1500 cal/day for females, 1800 cal/day for males) or to
low-fat diet. Remission rates were 4.6% and 0.9% at 1 year, respectively [15]. In a
retrospective analysis of 88 obese patients with type 2 diabetes who underwent a
12-week multidisciplinary weight loss program (“Why WAIT”; 1200–1800 calories
per day, along with exercise and other interventions), many had improved glycemic
control, but only four were able to meet criteria for partial or complete remission at
1-year follow-up visit [16]. The “Look AHEAD study” randomized 5145 patients
with type 2 diabetes (median duration 5 years) into either “intensive lifestyle inter-
vention” (target calorie consumption 1200–1800 per day, exercise, counseling, and
twice monthly contact) or diabetes support and education, with complete remission
prevalence being 1.3% at 1 year in the intensive lifestyle intervention group (any
remission prevalence 11.5%) [17].
Considering the need for very low-calorie diet, the real-world applicability of
inducing remission in type 2 diabetics in the ambulatory setting, aside from bariatric
surgery or intensive clinical trials, has come into question. The latest of the remis-
sion trials was meant to address this. The “DiRECT” study randomized 306
214 S. R. Kashyap and S. M. Borgan
participants with type 2 diabetes across 49 primary centers to either “weight loss
management program” or best practice (control). The intervention group received
meal replacement through formula (825–853 calorie/day for 3–5 months), followed
by a gradual reintroduction of food spanning 2–8 weeks and monthly visits to main-
tain weight loss, with a total of 8 hours of structured counseling by dieticians/nurses
trained in “Counterweight-Plus” weight management program. Remission of diabe-
tes at 12 months was achieved in 46% (n = 68) of patients in the intervention group
(mean duration of diabetes 3.0 years, SD 1.7), with mean weight loss of 10.0 kg
(SD = 8) [18]. In a subsequent durability measure of that study, patients were fol-
lowed for an additional of 12 months, and while the intervention group continued to
receive 30-minute monthly counseling sessions, they were offered a “rescue” partial
meal replacement course for 2–4 weeks if they had gained more than 2 kg and full
meal replacement course for 4 weeks if they gained more than 4 kg. At 24 months,
remission rates dropped to 36% (n = 53) in the intervention group, with remission
being directly linked to the extent of sustained weight loss among participants [19].
A subset of patients who achieved remission underwent functional B-cell capacity
testing and were shown to have normalization of indices, confirming remission at
the physiological as well as the clinical levels [20].
The use of pharmacotherapy and insulin to induce remission from type 2 diabetes
has been investigated, with mixed but perhaps promising results. Theoretically,
eliminating glucotoxicity early through intensive control of plasma glucose is
expected to reduce B-cell decompensation. Pharmacological interventions in these
settings were performed alongside weight loss management. A multicenter study in
China investigated the utility of intensive glucose management in early diabetes on
long-term remission rates. Patients (n = 382) with newly diagnosed type 2 diabetes
were randomized to intensive insulin therapy through continuous subcutaneous
infusion (CSI), multiple daily insulin (MDI) injections, or oral hypoglycemics
(either metformin, gliclazide, or a combination of both upon escalation) with a goal
of reducing fasting glucose to <6.1 mmol/L (<110 mg/dL) dubbed “euglycemia.”
Two weeks after attainment of euglycemia, treatments were discontinued, and
patients were asked to continue diet and exercise. Mean duration to euglycemia was
less than 10 days in all groups but significantly shorter in the insulin groups.
Remission rates at 12 months were 51.1% in the CSI group, 44.9% in the MDI
group, and 26.7% in the oral hypoglycemic group [21]. While the glycemic goals
reached in the insulin and oral hypoglycemic groups were similar, the reason for
improved remission rates in the insulin groups was postulated to be secondary to
insulin-induced “B-cell rest,” among other insulin-induced effects [21]. In another
intensive therapy study, the REMIT-DAPA study from Canada, 154 patients with
10 Precision Medical Management Strategies for Diabetes Remission 215
established type 2 diabetes, most of whom were already on oral hypoglycemics with
a mean diabetes duration of 3 years, were randomized into “intensive intervention”
or standard care. The intensive intervention group stopped their home oral hypogly-
cemic and received a 12-week course of “induction” treatment with basal insulin
(titration for morning glucose of 70–95), maximal doses of metformin and dapa-
gliflozin, as well as weight reduction and exercise counseling. Intervention contin-
ued until attainment of Hba1c of <7.3%, at which point all their hypoglycemic
agents and insulin were stopped and they were asked to continue diet and exercise
and were followed for 64 weeks. By 12 weeks, 49% of the intensive group reached
morning glucose of <95, and all of them had Hba1c of <7.3% and stopped therapy,
compared to 5.2% and 68.8% in the standard care group, respectively. Remission
rates at 24 weeks not significantly different between the two groups [22]. While
more research is needed to confirm the utility of intensive glucose management on
type 2 diabetes remission, previous studies challenge the dogma of the stepwise
approach that is usually used to manage uncontrolled diabetes [2].
There is a paucity of studies evaluating the utility of using pharmacological
weight loss agents to induce remission from type 2 diabetes. In one study evaluating
glycemic indices with orlistat treatment, 39 patients with type 2 diabetes were ran-
domized to nutritional counseling (500 calorie negative balance) with orlistat or
with placebo. At 6 months’ follow-up, both groups have similar rates of weight loss
and Hba1c reduction, but the orlistat group had statistically significant improvement
in free fatty acids and insulin sensitivity. The combination of weight loss medica-
tions phentermine and topiramate has been investigated in the “OB202” and
“DM-230”studies, each 28-week studies evaluating the safety and efficiency of
once-daily phentermine/topiramate in weight loss and glycemic control of patients
with type 2 diabetes. At the end of the 56-week intervention, patients on phenter-
mine/topiramate had lower weight (−9.6% vs −2.6%) and lower Hba1c compared
to placebo (−1.6% vs −1.2%) with 32% reaching target Hba1c <6.5% compared to
16% in the placebo group. However, the study was not meant to address remission,
and antidiabetic agents were not discontinued prior to study initiation.
In summary, remission of type 2 diabetes requires reversal of the conditions that
led to its development. Namely, a large negative energy balance early in the diagno-
sis is the most effective way to induce medical remission. The ability of pharmaco-
therapy to induce remission is an area of active research.
References
1. Buse JB, Caprio S, Cefalu WT, et al. How do we define cure of diabetes? Diabetes Care.
2009;32:2133–5.
2. Rasouli N. An escape from diabetes. J Clin Endocrinol Metab. 2020;105:3460–1.
3. Taylor R. Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause.
Diabetologia. 2008;51:1781–9.
4. Cersosimo E, Triplitt C, Mandarino LJ, DeFronzo RA. Pathogenesis of type 2 diabetes mel-
litus – endotext – NCBI Bookshelf. Endotext, Compr. Free online Endocrinol B. 2015.
216 S. R. Kashyap and S. M. Borgan
Introduction
remission in patients with obesity [5]. However, sustained weight loss with conser-
vative measures such as lifestyle interventions and medications is challenging to
achieve. Thus, bariatric surgeries, the gold standard treatment for achieving sus-
tained weight loss, have become accepted therapeutic options to treat DM2, espe-
cially when DM2 is refractory to lifestyle and pharmacologic interventions.
Furthermore, because of the progressive nature of DM2 resulting in multiple com-
plications and the overall improvement of the cardiovascular risk after bariatric sur-
gery, modeling analyses suggest that bariatric surgery may be a cost-saving and
practical therapeutic option for patients with DM2 [6, 7].
The beneficial effects of bariatric surgery on glycemic control have been known
for the past three decades [8]. Given the strong evidence surrounding the role of
bariatric surgery on DM2 remission, the American Diabetes Association in conjunc-
tion with many other international organizations has consistently recommended
bariatric surgery consideration for the treatment of DM2 in patients with a body
mass index (BMI) as low as 30 kg/m2 (27.5 kg/m2 for Asians), particularly when
DM2 control is not achieved with lifestyle or pharmacologic interventions [9–12].
In this chapter, first, we will define DM2 remission; second, we will briefly
describe the bariatric surgeries that have been associated with DM2 remission;
third, we will summarize the supporting evidence of the role of bariatric surgery on
DM2 remission; finally, we will discuss the mechanisms involved in DM2 remission.
Medical dictionaries define cure as the restoration of health. Remission, on the other
hand, is defined as a state or period during which the symptoms of a disease subside
but may recur [13]. With respect to DM2, the definitions of cure and remission have
not been consistently delineated over the years. Although therapies with curative
intent have been developed, evidence suggests that given the complex pathophysiol-
ogy of DM2, there is always a chance of relapse. Consequently, a consensus group
in 2009 concluded that for DM2, it would be more accurate to use the term remis-
sion than cure [14].
The consensus group defined DM2 remission based on:
1. Glucose levels below the diabetes range.
2. The absence of glucose-lowering medications and/or ongoing procedures to
maintain glucose homeostasis.
3. Sustainability over time (for at least 1 year).
Conventionally, complete remission is defined as an HbA1c below 6%
or <42 mmol/mol, and partial remission is defined by an HbA1c below 6.5%
or <48 mmol/mol. Prolonged remission is defined as complete remission for at least
5 years [14].
Although complete remission is the most coveted outcome, partial remission has
clinical significance. Partial remission has also been associated with a reduced risk
11 Surgical Management for Diabetes Remission 219
Figure 11.1 shows a schematic representation of the types of bariatric surgeries that
have been associated with DM2 remission which include laparoscopic adjustable
gastric banding (LAGB), vertical sleeve gastrectomy (VSG), Roux-en-Y gastric
bypass (RYGB), and biliopancreatic diversion (BPD) with or without duodenal
switch (BPD-DS).
The first two procedures, the LAGB and the VSG, are purely restrictive proce-
dures, i.e., they do not encompass rerouting of the food through the gastrointesti-
nal tract. The LAGB consists of a band like tube that encircles the upper part of
the stomach, immediately after the gastroesophageal junction. When the tube is
filled with saline solution, it creates a small gastric pouch that results in restriction
of the stomach volume. The VSG is characterized by the removal of the greater
curvature and fundus of the stomach that results in a significantly decreased gas-
tric capacity.
The RYGB, the BPD, and BPD-DS are all surgeries characterized by bypasses,
i.e., they encompass rerouting of the food through the gastrointestinal tract in addi-
tion to their restrictive component. The RYGB involves a partial horizontal gastrec-
tomy resulting in a small functional gastric pouch that is then connected to the
jejunum; consequently, food bypasses 95% of the stomach, the entire duodenum,
and a small portion of the jejunum. The BPD is similar to the RYGB as it involves
a partial horizontal gastrectomy leaving a variable sized functional gastric pouch
that is anastomosed to the ileum; thus, this procedure bypasses a significant part of
the stomach, the duodenum, and the jejunum and a portion of the ileum. The
BPD-DS is characterized by a vertical sleeve gastrectomy and preservation of the
© MAYO CLINIC
The beneficial effects of bariatric surgery on glucose control were first anecdotally
described in the 1970s. It was not until the mid-1990s that a seminal paper by Pories
et al. reported impressive DM2 remission rates after RYGB: at the end of the 14-year
follow-up (mean 7.6 years), 83% of patients with DM2 who had undergone RYGB
were in remission [8]. Since then, strong evidence has continued to emerge about
the role of bariatric surgery on DM2 remission and the underlying mechanisms that
are involved.
Among the different bariatric procedures, the BPD-DS results in a higher degree
and length of DM2 remission, followed by the RYGB, the VSG, and finally the
LAGB [18–20]. Multiple randomized controlled trials and observational studies
have consistently demonstrated remission rates of 30–95% between 1 and 5 years
postoperatively [21–39]. Table 11.1 summarizes the evidence to date on DM2
Table 11.1 Studies supporting the role of bariatric surgery on DM2 remission
Mean or median
Type of time of follow-up Rate of DM2
Study surgery Definition of DM2 remission time (years) remission
Pories et al. RYGB “Normal” FPG and HbA1c 7.6 82.9%
(1995) [8]
Schauer et al. RYGB FPG ≤110 mg/dL, a normal 5 82%
(2003) [19] HbA1c on no medications
Dixon et al. LAGB FPG <126 mg/dL, HbA1c 2 76%
(2008) [24] <6.2% on no medications
Iaconelli et al. BPD ADA criteria for complete 10 100%
(2011) [36] remissiona
Schauer et al. RYGB and ADA criteria for complete 1 42% for RYGB
(2012) [34] VSG remissiona 37% for VSG
Adams et al. RYGB “Normal” FPG and HbA1c 2 and 6 75% at 2 years
(2012) [37] on no medications 62% at 6 years
Mingrone et al. RYGB and ADA criteria for partial 2 75% for RYGB
(2012) [33] BPD remissiona 95% for BPD
Liang et al. RYGB “Normal” FPG and HbA1c 1 90%
(2013) [35] on no medications
Arterburn et al. RYGB ADA criteria for complete 1, 3, and 5 37% at 1 year
(2013) [45] remissiona 63% at 3 years
68% at 5 years
11 Surgical Management for Diabetes Remission 221
remission rates after bariatric surgery. Overall, the rate of partial remission is, on
average, 10% higher compared to the rate of complete remission in studies that have
reported both [40]. Several meta-analyses have echoed these findings [41, 42]. The
largest meta-analysis included 621 studies with a total of 135,246 patients, with
more than 3000 patients with DM2. This study showed that the overall DM2 remis-
sion rate after bariatric procedures was 78.1%, 95.1% after BPD-DS, 80.3% after
RYGB, and 56.7% after LAGB, with consistent rates among studies up to approxi-
mately 2 years after surgery [20].
In spite of the increasing evidence of the effect of bariatric surgery in patients
with DM2, there are data showing that postoperative DM2 remission is not always
durable. Studies have shown that the maximum cumulative incidence of DM2
remission occurs 3 years after bariatric surgery. After 3 years, relapses begin to
accumulate [21, 23, 30, 37, 39, 43, 44]. Studies estimate that at 5 years after RYGB,
35–50% of patients in remission experience a relapse [21, 45–47]. The rate of
relapse is higher after VSG and reported at 80% at 5 years [48].
Several preoperative and postoperative factors play a role in the probability of
postoperative DM2 remission. A Swedish nationwide register-based cohort study
including more than 8000 patients demonstrated that preoperative factors strongly
associated with a higher rate of DM2 remission after bariatric surgery included
shorter duration of DM2 and no insulin treatment [32]. Other preoperative factors
that have been shown to influence DM2 remission include younger age, male sex,
higher BMI, glycemic control, and higher education [22, 32, 43, 45, 49–55]. Among
Asians, visceral fat has also been found to be an important predictor [56].
Postoperative factors include higher amount of weight loss after surgery and the
type of procedure, with RYGB associated with a higher rate of remission [32].
Because bariatric surgery is not a treatment without risk, the rates of DM2 after
bariatric surgery are widely variable, and the risk of DM2 recurrence over time is
not irrelevant, researchers have developed scoring systems to help identify the most
suitable candidates for bariatric surgery aimed at DM2 remission. The most com-
monly used score systems are the ABCD and the DiaRem (Table 11.2). The former
takes into consideration age, BMI, C-peptide, and duration of DM2. The latter takes
into consideration age, HbA1c, and the use of antidiabetic medications [57, 58].
Both scoring systems have their own limitations, but validation studies suggest that
the ABCD scoring system may be better predictive tool for DM2 remission after
bariatric surgery [59].
The effects of bariatric surgery on glucose homeostasis are intricate, and not all the
mechanisms involved are completely understood. Bariatric surgery overall results in
enhanced β-cell function, decreased hepatic glucose production, increased insulin
sensitivity, and improved peripheral glucose uptake. The significant weight loss
achieved after bariatric surgery is undoubtedly an important factor for DM2
11 Surgical Management for Diabetes Remission 223
Table 11.2 Scoring systems to predict the remission of DM2 after bariatric surgery
DiaRem score
Factor Points
Age
<40 0
40–49 1
50–59 2
≥60 3
HbA1c
<6.5% 0
6.5–6.9% 2
7.0–8.9% 4
≥9.0% 6
Diabetes drugs
No medication or metformin only 0
Sulfonylureas and insulin-sensitizing 3
agents other than metformin
Treatment with insulin
No 0
Yes 10
Total score calculated by adding each of the four variables 0–22
Lower DiaRem scores predict a higher probability of DM2 remission after RYGB
ABCD score
Factor Points
Age (years)
<40 1
≥40 0
BMI (kg/m2)
<27 0
27–34.9 1
35–41.9 2
≥42 3
C-peptide (ng/mL)
<2 0
2–2.9 1
3–3.9 2
≥5 3
Duration of DM2 (years)
>8 0
4–8 1
1–3.9 2
<1 3
Total score calculated by adding each of the four variables 0–10
Higher ABCD scores predict a higher probability of DM2 remission after RYGB
Abbreviations used: BMI body mass index, DM2, type 2 diabetes mellitus, HbA1c hemoglobin
A1c, RYGB Roux-en-Y gastric bypass
224 A. Maria Daniela Hurtado and M. Collazo-Clavell
remission. However, a strong body of evidence suggests that there are weight loss-
independent mechanisms that play a crucial role in DM2 remission as well.
The massive weight loss associated with bariatric procedures promotes glucose
transport into the muscle and overall whole-body glucose disposal [60]. The mecha-
nisms behind this phenomenon include increased levels of adiponectin which is an
insulin-sensitizing hormone, increased insulin receptor concentration at the level of
the muscle, and decreased concentrations of intramuscular lipids and fatty acyl-
CoA molecules [61–63].
The following facts support the role of weight loss-independent mechanisms of
DM2 remission:
1. The remission of DM2 occurs before significant and sustained weight loss
occurs, generally within days to weeks after RYGB or BPD-DS, phenomenon
not seen after LAGB or SVG [8, 19, 64, 65].
2. DM2 remission rate is higher in patients after RYGB compared to other inter-
ventions that result in similar weight loss such as lifestyle interventions, VSG,
and LAGB [66–68].
3. Certain GI bypass procedures, such as the duodenal-jejunal bypass and the endo-
luminal duodenal bypass, improve glucose control disproportionately to weight
loss [69–72].
4. The existence of the rare hyperinsulinemic hypoglycemia, which is a late com-
plication of the RYGB [73].
Mechanistically, these factors are thought to play a major role in weight loss-
independent DM2:
1. Significant and rapid reduction in hepatic and pancreatic fat content precipitated
by caloric restriction and resulting in a rapid improvement of insulin secretion
[74, 75].
2. Increased secretion of gastrointestinal peptides, mainly GLP-1 and PYY, result-
ing from the anatomical rearrangement and the consequent nutrient and bile
acid-mediated stimulation of the distal intestinal tract (also known as hindgut
hypothesis) [76, 77].
3. Intestinal adaptation characterized by mucosal hypertrophy and hyperplasia
(particularly of GLP-1 and GIP producing L-enteroendocrine cells), enhanced
expression of glucose transporters, and increased glucose uptake in the intestinal
epithelium [78].
4. Decreased secretion of the orexigenic and prodiabetic hormone ghrelin.
5. Increase in circulating bile acids that induce GLP-1, GIP, and PYY secre-
tion [79].
6. Alterations in the gut microbiome [80, 81].
7. Reduction of yet to be defined anti-incretins, substances secreted by the duode-
num and possibly jejunum, whose role would be to counteract the effect of
incretins (GLP-1 and GIP) to prevent postprandial hypoglycemia (foregut
hypothesis).
11 Surgical Management for Diabetes Remission 225
Although bariatric surgery is a safe surgical intervention with a low mortality rate,
it is an invasive and costly procedure with potential complications. Over the last
several years, less invasive endoscopic procedures have been developed and are
considered cost-effective alternatives to bariatric surgery. These include the intra-
gastric balloon, the endoscopic sleeve gastroplasty, the duodenal-jejunal bypass
liner, and the gastro-duodeno-jejunal bypass sleeve. The intragastric balloon is a
mechanical device that is inflated in the stomach, thereby decreasing gastric capac-
ity. The endoscopic sleeve gastroplasty mimics the anatomic changes of the VSG by
stapling the anterior and posterior walls of the stomach to decrease its size. The
duodenal-jejunal bypass liner consists of an impermeable liner anchored to the duo-
denal bulb that extends through the proximal part of the small intestine covering the
intestinal mucosa. This procedure mimics the intestinal bypass portion of the RYGB
by excluding the proximal small intestine from the alimentary flow. The gastro-
duodeno-jejunal bypass sleeve is a flexible plastic device anchored to the gastro-
esophageal junction that extends into the proximal intestine. This procedure
excludes the stomach and proximal small intestine from the alimentary flow.
Although these procedures and devices have demonstrated encouraging weight loss
results, there is a paucity of data on safety and long-term efficacy, particularly in
relation to DM2 outcomes [82–85].
Although not aimed at weight loss, the duodenal mucosal resurfacing is a novel
endoscopic procedure involving the thermal ablation, and subsequent regeneration,
of the duodenal mucosa with the goal of improving glucose metabolism. The duo-
denal mucosa has been implicated as an important regulator of glucose homeostasis,
and data so far suggest a promising potential therapeutic target in DM2 control [86].
Conclusions
For a long time, DM2 had been seen as a chronic, progressive, and incurable dis-
ease. With the advent of bariatric surgery, DM2 remission has become a reality.
Extensive evidence has demonstrated that bariatric surgery is the most efficient and
effective therapeutic modality to achieve DM2 remission compared with any other
nonsurgical modality. The rate of complete DM2 remission after bariatric surgery
varies but has been overall consistently robust among studies. The BPD-DS and the
RYGB have been associated with the highest DM2 remission rates (70–90%),
whereas the LAGB is associated with the lowest rates of remission. There are pre-
operative and postoperative predictors of DM2 remission after bariatric surgery that
must be taken into consideration when discussing this possible outcome with
patients. It is also important to disclose that DM2 recidivism has been described
after all procedures over time.
226 A. Maria Daniela Hurtado and M. Collazo-Clavell
References
14. Buse JB, Caprio S, Cefalu WT, Ceriello A, Del Prato S, Inzucchi SE, et al. How do we define
cure of diabetes? Diabetes Care. 2009;32(11):2133–5.
15. Coleman KJ, Haneuse S, Johnson E, Bogart A, Fisher D, O’Connor PJ, et al. Long-term micro-
vascular disease outcomes in patients with type 2 diabetes after bariatric surgery: evidence for
the legacy effect of surgery. Diabetes Care. 2016;39(8):1400–7.
16. Sheng B, Truong K, Spitler H, Zhang L, Tong X, Chen L. The Long-term effects of bariatric
surgery on type 2 diabetes remission, microvascular and macrovascular complications, and
mortality: a systematic review and meta-analysis. Obes Surg. 2017;27(10):2724–32.
17. Ponce J, DeMaria EJ, Nguyen NT, Hutter M, Sudan R, Morton JM. American Society for
Metabolic and Bariatric Surgery estimation of bariatric surgery procedures in 2015 and sur-
geon workforce in the United States. Surgery for Obesity and Related Diseases : Official
Journal of the American Society for Bariatric Surgery. 2016;12(9):1637–9.
18. Yska JP, van Roon EN, de Boer A, Leufkens HG, Wilffert B, de Heide LJ, et al. Remission of
type 2 diabetes mellitus in patients after different types of bariatric surgery: a population-based
cohort study in the United Kingdom. JAMA Surg. 2015;150(12):1126–33.
19. Schauer PR, Burguera B, Ikramuddin S, Cottam D, Gourash W, Hamad G, et al. Effect of lapa-
roscopic roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003;238(4):467–85.
20. Buchwald H, Estok R, Fahrbach K, Banel D, Jensen MD, Pories WJ, et al. Weight and
type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med.
2009;122(3):248–56.e5.
21. Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Nanni G, et al. Bariatric-
metabolic surgery versus conventional medical treatment in obese patients with type 2 dia-
betes: 5 year follow-up of an open-label, single-Centre, randomised controlled trial. Lancet.
2015;386(9997):964–73.
22. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, et al. Bariatric
surgery versus intensive medical therapy for diabetes - 5-year outcomes. N Engl J Med.
2017;376(7):641–51.
23. Ikramuddin S, Korner J, Lee W-J, Bantle JP, Thomas AJ, Connett JE, et al. Durability of addi-
tion of roux-en-Y gastric bypass to lifestyle intervention and medical management in achiev-
ing primary treatment goals for uncontrolled type 2 diabetes in mild to moderate obesity: a
randomized control trial. Diabetes Care. 2016;39(9):1510–8.
24. Dixon JB, O’Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, et al. Adjustable
gastric banding and conventional therapy for type 2 diabetesA randomized controlled trial.
JAMA. 2008;299(3):316–23.
25. Courcoulas AP, Goodpaster BH, Eagleton JK, Belle SH, Kalarchian MA, Lang W, et al.
Surgical vs medical treatments for type 2 diabetes mellitus: a randomized clinical trial. JAMA
Surg. 2014;149(7):707–15.
26. Halperin F, Ding S-A, Simonson DC, Panosian J, Goebel-Fabbri A, Wewalka M, et al. Roux-
en-Y gastric bypass surgery or lifestyle with intensive medical Management in Patients with
Type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg.
2014;149(7):716–26.
27. Wentworth JM, Playfair J, Laurie C, Ritchie ME, Brown WA, Burton P, et al. Multidisciplinary
diabetes care with and without bariatric surgery in overweight people: a randomised controlled
trial. Lancet Diabetes Endocrinol. 2014;2(7):545–52.
28. Ding S-A, Simonson DC, Wewalka M, Halperin F, Foster K, Goebel-Fabbri A, et al. Adjustable
gastric band surgery or medical management in patients with Type 2 diabetes: a randomized
clinical trial. J Clin Endocrinol Metabol. 2015;100(7):2546–56.
29. Cummings DE, Arterburn DE, Westbrook EO, Kuzma JN, Stewart SD, Chan CP, et al.
Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the
CROSSROADS randomised controlled trial. Diabetologia. 2016;59(5):945–53.
30. Courcoulas AP, Belle SH, Neiberg RH, Pierson SK, Eagleton JK, Kalarchian MA, et al. Three-
year outcomes of bariatric surgery vs lifestyle intervention for type 2 diabetes mellitus treat-
ment: a randomized clinical trial. JAMA Surg. 2015;150(10):931–40.
228 A. Maria Daniela Hurtado and M. Collazo-Clavell
31. Gloy VL, Briel M, Bhatt DL, Kashyap SR, Schauer PR, Mingrone G, et al. Bariatric sur-
gery versus non-surgical treatment for obesity: a systematic review and meta-analysis of ran-
domised controlled trials. BMJ: Br Med J. 2013;347:f5934.
32. Jans A, Näslund I, Ottosson J, Szabo E, Näslund E, Stenberg E. Duration of type 2 diabetes and
remission rates after bariatric surgery in Sweden 2007–2015: a registry-based cohort study.
PLoS Med. 2019;16(11):e1002985.
33. Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, et al.
Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med.
2012;366(17):1577–85.
34. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, et al. Bariatric
surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med.
2012;366(17):1567–76.
35. Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang X. Effect of laparoscopic roux-en-Y gastric
bypass surgery on type 2 diabetes mellitus with hypertension: a randomized controlled trial.
Diabetes Res Clin Pract. 2013;101(1):50–6.
36. Iaconelli A, Panunzi S, De Gaetano A, Manco M, Guidone C, Leccesi L, et al. Effects of
bilio-pancreatic diversion on diabetic complications: a 10-year follow-up. Diabetes Care.
2011;34(3):561–7.
37. Adams TD, Davidson LE, Litwin SE, Kolotkin RL, LaMonte MJ, Pendleton RC, et al. Health
benefits of gastric bypass surgery after 6 years. JAMA. 2012;308(11):1122–31.
38. Purnell JQ, Selzer F, Wahed AS, Pender J, Pories W, Pomp A, et al. Type 2 diabetes remission
rates after laparoscopic gastric bypass and gastric banding: results of the longitudinal assess-
ment of bariatric surgery study. Diabetes Care. 2016;39(7):1101–7.
39. Madsen LR, Baggesen LM, Richelsen B, Thomsen RW. Effect of roux-en-Y gastric bypass
surgery on diabetes remission and complications in individuals with type 2 diabetes: a Danish
population-based matched cohort study. Diabetologia. 2019;62(4):611–20.
40. Isaman DJM, Rothberg AE, Herman WH. Reconciliation of type 2 diabetes remission rates in
studies of roux-en-Y gastric bypass. Diabetes Care. 2016;39(12):2247–53.
41. Tice JA, Karliner L, Walsh J, Petersen AJ, Feldman MD. Gastric banding or bypass?
A systematic review comparing the two most popular bariatric procedures. Am J Med.
2008;121(10):885–93.
42. Chang SH, Stoll CR, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of
bariatric surgery: an updated systematic review and meta-analysis, 2003-2012. JAMA Surg.
2014;149(3):275–87.
43. Brethauer SA, Aminian A, Romero-Talamás H, Batayyah E, Mackey J, Kennedy L, et al. Can
diabetes be surgically cured? Long-term metabolic effects of bariatric surgery in obese patients
with type 2 diabetes mellitus. Ann Surg. 2013;258(4):628–36; discussion 36-7.
44. Gulliford MC, Booth HP, Reddy M, Charlton J, Fildes A, Prevost AT, et al. Effect of contem-
porary bariatric surgical procedures on type 2 diabetes remission. A population-based matched
cohort study. Obes Surg. 2016;26(10):2308–15.
45. Arterburn DE, Bogart A, Sherwood NE, Sidney S, Coleman KJ, Haneuse S, et al. A multisite
study of long-term remission and relapse of type 2 diabetes mellitus following gastric bypass.
Obes Surg. 2013;23(1):93–102.
46. Chikunguwo SM, Wolfe LG, Dodson P, Meador JG, Baugh N, Clore JN, et al. Analysis of fac-
tors associated with durable remission of diabetes after roux-en-Y gastric bypass. Surgery for
Obesity and Related Diseases: Official Journal of the American Society for Bariatric Surgery.
2010;6(3):254–9.
47. DiGiorgi M, Rosen DJ, Choi JJ, Milone L, Schrope B, Olivero-Rivera L, et al. Re-emergence
of diabetes after gastric bypass in patients with mid- to long-term follow-up. Surgery for
Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery.
2010;6(3):249–53.
48. Golomb I, Ben David M, Glass A, Kolitz T, Keidar A. Long-term metabolic effects of laparo-
scopic sleeve gastrectomy. JAMA Surg. 2015;150(11):1051–7.
11 Surgical Management for Diabetes Remission 229
e ffectiveness in patients with type 2 diabetes after roux-en-Y gastric bypass. Am J Physiol
Endocrinol Metabol. 2015;308(6):E535–E44.
66. Laferrère B, Teixeira J, McGinty J, Tran H, Egger JR, Colarusso A, et al. Effect of weight loss
by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients
with type 2 diabetes. J Clin Endocrinol Metabol. 2008;93(7):2479–85.
67. Lee W-J, Wang W, Lee Y-C, Huang M-T, Ser K-H, Chen J-C. Effect of laparoscopic mini-
gastric bypass for type 2 diabetes mellitus: comparison of BMI >35 and <35 kg/m2. J
Gastrointest Surg. 2008;12(5):945–52.
68. Pattou F, Beraud G, Arnalsteen L, Seguy D, Pigny P, Fermont C, et al. O47 La restauration de
l’insulinosécrétion après Gastric bypass chez le diabétique de type 2 est indépendante de la
perte de poids et corrélée à l’augmentation du GLP1. Diabetes Metab. 2008;34:H24.
69. Ramos AC, Galvão Neto MP, de Souza YM, Galvão M, Murakami AH, Silva AC, et al.
Laparoscopic duodenal–Jejunal exclusion in the treatment of type 2 diabetes mellitus in
patients with BMI <30 kg/m2 (LBMI). Obes Surg. 2009;19(3):307–12.
70. Cohen RV, Schiavon CA, Pinheiro JS, Correa JL, Rubino F. Duodenal-jejunal bypass for the
treatment of type 2 diabetes in patients with body mass index of 22–34 kg/m2: a report of 2
cases. Surg Obes Relat Dis. 2007;3(2):195–7.
71. Tarnoff M, Rodriguez L, Escalona A, Ramos A, Neto M, Alamo M, et al. Open label, prospec-
tive, randomized controlled trial of an endoscopic duodenal-jejunal bypass sleeve versus low
calorie diet for pre-operative weight loss in bariatric surgery. Surg Endosc. 2009;23(3):650–6.
72. Rodriguez L, Reyes E, Fagalde P, Oltra MS, Saba J, Aylwin CG, et al. Pilot clinical study of
an endoscopic, removable duodenal-Jejunal bypass liner for the treatment of type 2 diabetes.
Diabetes Technol Ther. 2009;11(11):725–32.
73. Service FJ. Hypoglycemic disorders. N Engl J Med. 1995;332(17):1144–52.
74. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2
diabetes: normalisation of beta cell function in association with decreased pancreas and liver
triacylglycerol. Diabetologia. 2011;54(10):2506–14.
75. Steven S, Hollingsworth KG, Small PK, Woodcock SA, Pucci A, Aribisala B, et al. Weight
loss decreases excess pancreatic triacylglycerol specifically in type 2 diabetes. Diabetes Care.
2016;39(1):158–65.
76. Purnell JQ, Johnson GS, Wahed AS, Dalla Man C, Piccinini F, Cobelli C, et al. Prospective
evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2
years after roux-en-Y gastric bypass. Diabetologia. 2018;61(5):1142–54.
77. Yousseif A, Emmanuel J, Karra E, Millet Q, Elkalaawy M, Jenkinson AD, et al. Differential
effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circu-
lating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans. Obes
Surg. 2014;24(2):241–52.
78. Cavin JB, Couvelard A, Lebtahi R, Ducroc R, Arapis K, Voitellier E, et al. Differences in ali-
mentary glucose absorption and intestinal disposal of blood glucose after roux-En-Y gastric
bypass vs sleeve gastrectomy. Gastroenterology. 2016;150(2):454–64.e9.
79. Penney NC, Kinross J, Newton RC, Purkayastha S. The role of bile acids in reducing the
metabolic complications of obesity after bariatric surgery: a systematic review. Int J Obes.
2015;39(11):1565–74.
80. Tremaroli V, Karlsson F, Werling M, Ståhlman M, Kovatcheva-Datchary P, Olbers T, et al.
Roux-en-Y gastric bypass and vertical banded gastroplasty induce Long-term changes on the
human gut microbiome contributing to fat mass regulation. Cell Metab. 2015;22(2):228–38.
81. Liou AP, Paziuk M, Luevano J-M, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts
in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Translat Med.
2013;5(178):178ra41.
82. Sharaiha RZ, Kumta NA, Saumoy M, Desai AP, Sarkisian AM, Benevenuto A, et al. Endoscopic
sleeve Gastroplasty significantly reduces body mass index and metabolic complications in
obese patients. Clin Gastroenterol Hepatol. 2017;15(4):504–10.
11 Surgical Management for Diabetes Remission 231
Introduction
The prevalence of diabetes is increasing worldwide, affecting more than 10% of the
global population, with the vast majority of cases classified as type 2 diabetes mel-
litus (T2DM) [1]. Substantial evidence indicates that T2DM can be largely pre-
vented by adherence to healthy lifestyles, which include high-quality healthy diets,
habitual exercise, and healthy body weight maintenance [2]. Once fully bloomed,
T2DM is clinically managed by healthy diets and lifestyles combined with glucose-
lowering pharmacological agents that aim to prevent or delay both acute symptoms
of hyperglycemia and long-term complications of the disease [3]. As recommended
by the Dietary Guidelines for Americans [4] and the American Diabetes Association
[5], a healthy dietary pattern that protects against T2DM is rich in fruits, vegetables
(except potatoes), whole grains, nuts, and legumes and low in refined grains, red or
processed meats, and sugar-sweetened beverages. However, these current dietary
recommendations are based on population averages and often do not take into
account interpersonal variability in response to specific foods and dietary compo-
nents. Although successful in reducing the population-level chronic disease burden
to some extent [6], dietary guidelines based on population averages may not be best
suited for a given individual, and personalization of interventions may be more
effective in changing behavior that will affect health outcomes [7, 8]. In addition,
O. Ben-Yacov (*)
Department of Computer Science and Applied Mathematics and Department of Molecular
Cell Biology, Weizmann Institute of Science, Rehovot, Israel
e-mail: [email protected]
M. Rein
Department of Computer Science and Applied Mathematics and Department of Molecular
Cell Biology, Weizmann Institute of Science, Rehovot, Israel
School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa,
Haifa, Israel
OTYPING
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prevention and
management of T2DM PH
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DE
N
PRECISIO
BIO M E
IE S
RO
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for T2D
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12 Precision Nutrition for Type 2 Diabetes 235
(e) an ability to provide personalized dietary and lifestyle guidance for more effec-
tive prevention and management per person [29].
This chapter is seeking to review the current evidence from population-based
studies on precision nutrition in T2DM using different technology axes and discuss
promises and challenges of applying such approaches for prevention and manage-
ment of T2DM in clinical practice.
The major increase in genome-wide association studies (GWAS) in the past decade
has contributed extensively to the knowledge about the genetic architecture of
T2DM [30]. GWAS, and more recently exome sequencing studies have identified
more than 100 loci reproducibly associated with risk of T2DM and glycemic traits
[31]. While most identified loci have a small effect size (risk of T2DM increased by
5–40%) and are common across populations, some causal variants have been identi-
fied for few loci [32, 33]. The GWAS loci collectively explain ~10% of the heritabil-
ity of the disease [34]. Gene-environment and gene-gene interactions along with
epigenetics are likely to contribute to the missing heritability of the disease.
Epigenetic factors, such as DNA methylations and histone modifications, are espe-
cially important because they might mediate the effects of environmental exposures,
including diet, on the risk of T2DM. Genome-wide DNA methylation studies com-
paring patients who have T2DM with healthy controls found varying levels of DNA
methylation in pancreatic islets for thousands of CpG sites, corresponding to a large
number of genes, including many known T2DM loci such as TCF7L2, FTO, and
PPARG [35–37]. Other gene-environment studies explored the distinctive effect of
dietary patterns on metabolic health depending on genetic makeup using a genetic
risk score (GRS). For example, in a recent case-control study with more than 7000
participants, with or without T2DM, issued from the PREDIMED study [38], a
significant interaction was observed between the adherence score to the MEDAS
(Mediterranean Diet Adherence Screener) 14-item questionnaire and a GRS formed
by two SNPs at the FTO and MC4R loci in determining T2DM risk (Pinteraction = 0.006).
Specifically, carriers of the rare alleles of these two loci had higher T2DM risk when
adherence to the Mediterranean diet was low, but this association disappeared as
adherence increased.
Overall, GWAS have not yet led to meaningful clinical advances in prevention or
management of T2DM, and findings in this field are still relatively far from giving
their fully expected potential in terms of translation and application of the genetic
knowledge to precision nutrition. Nevertheless, discoveries of specific genetic vari-
ants directly related to dietary intake and nutrient metabolism may partially help to
236 O. Ben-Yacov and M. Rein
Microbiome
plant-based foods. The authors further demonstrated that a panel of intestinal species
found to be associated with healthy dietary habits also overlapped with those associ-
ated with favorable cardio-metabolic and postprandial markers, suggesting potential
stratification of the gut microbiome into generalizable health levels even in individu-
als without clinically manifest disease [62]. With respect to diabetes, alterations in
gut microbiome composition and function, including changes in microbial richness,
diversity, and specific bacterial taxa, have been repeatedly linked to glycemic status
and T2DM [63–70]. Importantly, a recent study by Wu et al. indicated that overall
gut microbiota shifts in parallel with glycemic status in humans, independent of
diabetes medications. In addition, microbial functional changes of the gut microbi-
ota, such as biotin biosynthesis and butyrate production, within heterogeneous popu-
lations of glycemic status, also suggest potential interactions between the gut
microbiota and the diet that could be important for the onset of T2DM [71]. As such,
the gut microbiota represents an important modifiable factor to consider when devel-
oping precision nutrition approaches for prevention of T2DM.
Several recent studies incorporated multiple data sources, including microbiome
data, and applied big data analytics to inform personalized nutrition interventions
[12, 13, 72]. In a pioneering work by Zeevi et al., the researchers devised a machine
learning algorithm that integrates blood parameters, dietary habits, anthropomet-
rics, physical activity, and gut microbiota, measured in an 800-person cohort, to
predict personalized postprandial glycemic response (PPGR) to real-life meals.
Short-term personalized dietary interventions based on this algorithm successfully
lowered PPGRs in healthy individuals and individuals with prediabetes [13].
Following that study, a recently completed randomized clinical trial (RCT) for fur-
ther evaluating the long-term clinical efficacy of the algorithm-based diet in adults
with prediabetes showed that the personalized algorithm-based diet, aimed at lower-
ing PPGR, improved glycemic control more than a standard Mediterranean-style
diet, as measured by blood HbA1c levels and average daily time of glucose levels
above 140 mg/dl in a 6-month dietary intervention and additional follow-up at
12 months [73]. Additionally, in a small-scale dietary intervention in individuals
with newly diagnosed T2DM and naïve to diabetes medications, the personalized
algorithm-based diet improved multiple metabolic parameters, including glycemic
control, blood lipid profile, and body composition measurements, and resulted in
diabetes remission in 61% of the participants, as measured by HbA1c [74]. The
PREDICT 1 study, another large-scale and high-resolution study, also suggested
that part of the interindividual variability in postprandial responses is explained by
person-specific factors, including gut microbiome. Using gut microbiome data as
well as other informative personal and meal features, the researchers further devel-
oped machine learning models that were able to predict triglycerides and glycemic
responses to meals [12]. Lastly, a recent large-scale study (n = 4132) by Reitmeier
et al. demonstrated that specific microbiota members show 24-hour oscillations in
their relative abundance and identified 13 taxa with disrupted rhythmicity in T2DM
patients. The researchers applied cross-validation prediction models based on this
238 O. Ben-Yacov and M. Rein
Metabolomics
82]. Recently, metabolomics has emerged as a potential valuable tool for diabetes
prevention [83–85] and treatment [84, 86, 87]. The individual metabolomics finger-
print consists of some endogenously produced metabolites and some that have been
taken up from the environment [88, 89]. Specifically, it is affected by diet, suggest-
ing that metabolite profiles can be used to accurately and objectively characterize
short-term [90, 91] or long-term dietary patterns [85, 92–94], evaluate adherence to
dietary interventions [95], and unveil dietary biomarkers related to metabolic health
and diabetes progression. Therefore, metabolomics research has become an impor-
tant component in the field of precision nutrition [29, 96].
Some studies indicated that the metabolome responds to diet before other deep
phenotyping strategies, such as transcriptome and proteome [87], which suggests a
role for metabolomics in early diagnosis and enable targeted interventions for dia-
betes prevention, with dietary modifications and increased physical activity [81,
97]. For example, levels of 2-aminoadipic acid (2-AAA), an intermediate metabo-
lite of lysine metabolism associated with insulin resistance, were enriched up to
12 years before the onset of overt diabetes, in two long-term follow-up cohorts [98].
Furthermore, branched-chain amino acids, aromatic amino acids (BCAA/As), and
lipids (phospholipids and triglycerides) were suggested as promising biomarkers
for diagnosis of T2DM, as their serum concentrations have been found to be higher
in individuals with prediabetes and T2DM as compared to healthy individuals in
several studies [83, 84, 99, 100]. Notably, the positive associations of BCAA/As
levels with the risk of diabetes were attenuated after adjusting for clinical measures,
such as baseline body mass index (BMI) and fasting plasma glucose (FPG), in obese
subjects with increased risk for developing T2DM as reported in the Diabetes
Prevention Program (DPP) trial [100].
Interventional studies in mice or humans that investigated the metabolomics fin-
gerprint associated with a single metabolite supplementation or a full dietary plan
are particularly important as they improve our understanding of the molecular fac-
tors that mediate metabolic outcomes [69, 97, 101–103]. For example, in a study
originated from the DPP trial, it was suggested that serum levels of betaine, a
metabolite of choline that can also be obtained directly from the diet, were indepen-
dently associated with reduced incidence of T2DM and were able to predict a suc-
cessful response to prevention strategies [100]. Interestingly, 16 weeks of betaine
supplementation to mice improved metabolic status including glucose homeostasis
and hepatic lipid accumulation [101]. On a dietary intervention aimed for weight
loss in obese subjects, average protein diets (15% of total daily energy) lowered
BCAA/As concentration, more than high-protein diets (25% of total daily energy).
Importantly, the improved amino acid profiles, especially reductions in alanine and
the tyrosine levels, were related to reduced insulin resistance independent of weight
loss [103]. Another work by Thaiss et al. [102] investigated microbiome dynamics
in mice in response to post-dieting weight regain cycles, also known as the “yoyo
effect.” The authors suggested that the microbiome contributes to diminished post-
dieting levels of a flavonoid metabolite and reduced energy expenditure and further
demonstrate that flavonoid-based “post-biotic” intervention ameliorates excessive
secondary weight gain in susceptible mice [102].
240 O. Ben-Yacov and M. Rein
Deep Monitoring
studies, such as the studies by Zeevi et al. and Berry et al., previously described in
this chapter, utilized real-time self-recorded dietary intake using designated mobile
applications to accurately assess metabolic responses to food intakes, evaluate eat-
ing behaviors, and further use these data to predict personalized metabolic responses
to standardized and real-world meals [12, 13]. In other studies, such as several
dietary interventions, self-recording of dietary intake by study participants allowed
to both accurately characterize dietary habits prior to the intervention and during the
intervention and monitor participants’ compliance to dietary regimes and distin-
guish de facto between different dietary treatments. As such, it allowed to draw
more precise conclusions about health outcomes of different dietary changes for
different people [73, 107]. Notably, in the recently completed dietary interventions
for personalized nutrition by prediction of glycemic responses in subjects with pre-
diabetes and T2DM (previously described in this chapter), the utilization of a desig-
nated mobile application for delivering personalized dietary recommendations and
real-time feedback on predicted PPGRs to real-life meals was a unique feature in
study design that may have contributed to participants’ engagement with the dietary
treatment and high satisfaction [74].
Taken together, the utilization of mobile technologies to effectively collect per-
sonal data and provide feedback to individuals is emerging as a potential important
tool for implementation of precision nutrition in T2DM.
technologies have not yet provided clinically scalable biomarkers for predicting
both disease outcomes and interpersonal variability to specific dietary exposures.
For example, when biomarkers recently identified by GWAS and metabolomics
studies were added to a risk prediction model of traditional risk factors, the model
showed only a modest improvement in predicting risk of T2DM [116]. Likewise,
metabolomics and microbiome technologies are not yet incorporated into compre-
hensive frameworks for broad use in clinical and public health settings, although
they are rapidly evolving and might be incorporated in the future into personalized
nutrition in clinical care, as demonstrated by several proof-of-concept studies [12,
13, 74].
In the private sector, there are some direct-to-consumer nutrigenomics compa-
nies that advocate customized dietary recommendations, but scientific evidence
suggests that these approaches are not comprehensive enough and it is unlikely that
prediction algorithms using DNA variant data alone would be sufficiently effective
in improving metabolic outcomes. Broader approaches that integrate personal data
from other omics axes, such as microbiome and metabolomics, for tailoring dietary
recommendations, are still rare in the private sector, and the evidence regarding the
clinical efficacy of such commercial products for improving metabolic outcomes
among customers is limited. In that sense, one company that uses microbiome and
other personal data to guide personalized meal planning recommendations for con-
trolling postprandial glycemic responses [110] recently reported a mean reduction
of 0.97% in HbA1c among subjects with T2DM following a 3-month pilot interven-
tion conducted in real-world settings with five different employer groups (n = 125).
Another commercial company is offering personalized nutrition plans as well as
personal recommendations for probiotic and prebiotic supplementation based on
comprehensive gut microbiome activity profiling, using meta-transcriptomic meth-
ods [117]. According to the company website, there is an ongoing research con-
ducted to study the adherence of customers to their recommended personalized
nutrition programs and determine impacts on metabolic health and wellness.
Another resource for potential developments of precision nutrition solutions for
prevention and management of T2DM may rise from governments and/or industry-
backed biobank initiatives that contain in-depth genetic and other health informa-
tion in large population-based cohorts. The large-scale biological and physiological
datasets generated by these initiatives may be harnessed for precision nutritional
diagnostics and therapeutics. Pragmatic studies of decision support systems utiliz-
ing rich information in healthcare systems, particularly those with biobank-linked
electronic healthcare records, will be needed to guide implementation of precision
nutrition in diabetes into clinical practice and to generate the much needed cost-
efficacy data for broader adoption [118].
Taken together, the field of precision nutrition has rapidly evolved in recent
years, thanks to major advances in omics, mobile, and wearable technologies that
allow in-depth phenotyping and monitoring of individuals. Despite these advances,
major challenges exist in applying precision nutrition approaches for broad use in
clinical and public health settings for the prevention and management of T2DM. One
major challenge is the integration of high-dimensional data from multiple disparate
244 O. Ben-Yacov and M. Rein
sources and application of big data analytics, to provide valuable and clinically scal-
able biomarkers, along with expert knowledge for accurate interpretation and
assimilation of findings into clinical practice. This field is in its infancy and still
awaits clinically robust and reproducible results. Other important challenges that
need to be overcome in order to successfully translate basic nutritional science into
an effective precision nutrition care in T2DM include the high costs of omics tech-
nologies as well as feasibility and accessibility of technology-based services to
wide-range populations. Lastly, as demonstrated in the latest consensus report from
the American Diabetes Association (ADA) and the European Association for the
Study of Diabetes (EASD) about precision medicine in diabetes [118], there is a
need to establish partnerships between the scientific community, patients, health-
care systems, providers, payors, and industry and regulatory bodies involved in the
development, evaluation, approval, adoption, and implementation of precision
nutritional diagnostics, monitoring, and therapeutics that are deemed acceptable for
safe, efficacious, and cost-effective use in precision diabetes care.
Bibliography
37. Volkmar M, Dedeurwaerder S, Cunha DA, et al. DNA methylation profiling identi-
fies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO
J. 2012;31:1405–26.
38. Ortega-Azorín C, Sorlí JV, Asensio EM, et al. Associations of the FTO rs9939609 and the
MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher
when adherence to the Mediterranean diet pattern is low. Cardiovasc Diabetol. 2012;11:137.
39. Rasinperä H, Savilahti E, Enattah NS, Kuokkanen M, Tötterman N, Lindahl H, Järvelä I,
Kolho KL. A genetic test which can be used to diagnose adult-type hypolactasia in children.
Gut. 2004;53:1571–6.
40. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease:
guidelines from the British Society of Gastroenterology. Gut. 2014;63:1210–28.
41. DiLella AG, Huang WM, Woo SL. Screening for phenylketonuria mutations by DNA ampli-
fication with the polymerase chain reaction. Lancet. 1988;1:497–9.
42. Cornelis MC, El-Sohemy A, Campos H. Genetic polymorphism of the adenosine A2A recep-
tor is associated with habitual caffeine consumption. Am J Clin Nutr. 2007;86:240–4.
43. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and
risk of myocardial infarction. JAMA. 2006;295:1135–41.
44. Cornelis MC, Kacprowski T, Menni C, et al. Genome-wide association study of caffeine
metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption
behavior. Hum Mol Genet. 2016;25:5472–82.
45. Corella D, Peloso G, Arnett DK, et al. APOA2, dietary fat, and body mass index: replication of
a gene-diet interaction in 3 independent populations. Arch Intern Med. 2009;169:1897–906.
46. Corella D, Tai ES, Sorlí JV, Chew SK, Coltell O, Sotos-Prieto M, García-Rios A, Estruch R,
Ordovas JM. Association between the APOA2 promoter polymorphism and body weight in
Mediterranean and Asian populations: replication of a gene-saturated fat interaction. Int J
Obes. 2011;35:666–75.
47. Giner V, Poch E, Bragulat E, Oriola J, González D, Coca A, De La Sierra A. Renin-angiotensin
system genetic polymorphisms and salt sensitivity in essential hypertension. Hypertension.
2000;35:512–7.
48. Poch E, González D, Giner V, Bragulat E, Coca A, de La Sierra A. Molecular basis of salt
sensitivity in human hypertension. Evaluation of renin-angiotensin-aldosterone system gene
polymorphisms. Hypertension. 2001;38:1204–9.
49. Cauchi S, Del Guerra S, Choquet H, D’Aleo V, Groves CJ, Lupi R, McCarthy MI, Froguel
P, Marchetti P. Meta-analysis and functional effects of the SLC30A8 rs13266634 polymor-
phism on isolated human pancreatic islets. Mol Genet Metab. 2010;100:77–82.
50. Schumann G, Liu C, O’Reilly P, et al. KLB is associated with alcohol drinking, and its gene
product β-klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci
USA. 2016;113:14372–7.
51. Tanaka T, Ngwa JS, van Rooij FJA, et al. Genome-wide meta-analysis of observational stud-
ies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr.
2013;97:1395–402.
52. Goni L, Cuervo M, Milagro FI, Martínez JA. A genetic risk tool for obesity predisposition
assessment and personalized nutrition implementation based on macronutrient intake. Genes
Nutr. 2015;10:445.
53. Ferguson LR, De Caterina R, Görman U, Allayee H. Guide and position of the international
society of nutrigenetics/nutrigenomics on personalised nutrition: part 1-fields of precision
nutrition. J Nutrigenet Nutrigenomics. 2016;9(1):12–27.
54. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a
Mediterranean diet. N Engl J Med. 2013;368:1279–90.
55. Ryan NM, O’Donovan CB, Forster H. New tools for personalised nutrition: the Food4Me
project. Nutr Bull. 2015;40:134–9.
56. Allison DB, Bassaganya-Riera J, Burlingame B, et al. Goals in nutrition science 2015-2020.
Front Nutr. 2015;2:26.
12 Precision Nutrition for Type 2 Diabetes 247
57. Corella D, Coltell O, Mattingley G, Sorlí JV, Ordovas JM. Utilizing nutritional genomics to
tailor diets for the prevention of cardiovascular disease: a guide for upcoming studies and
implementations. Expert Rev Mol Diagn. 2017;17:1–19.
58. Srinivasan B, Lee S, Erickson D, Mehta S. Precision nutrition - review of methods for point-
of-care assessment of nutritional status. Curr Opin Biotechnol. 2017;44:103–8.
59. Kang JX. Gut microbiota and personalized nutrition. J Nutrigenet Nutrigenomics. 2013;6:I-II.
60. Hughes RL, Kable ME, Marco M, Keim NL. The role of the gut microbiome in predicting
response to diet and the development of precision nutrition models. Part II: results. Adv Nutr.
2019;10:979–98.
61. Mendes-Soares H, Raveh-Sadka T, Azulay S, et al. Assessment of a personalized approach
to predicting postprandial glycemic responses to food among individuals without diabetes.
JAMA Netw Open. 2019;2:e188102.
62. Asnicar F, Berry SE, Valdes AM, et al. Microbiome connections with host metabolism
and habitual diet from 1,098 deeply phenotyped individuals. Nat Med. 2021; https://doi.
org/10.1038/s41591-020-01183-8.
63. Janssen AWF, Kersten S. The role of the gut microbiota in metabolic health. FASEB
J. 2015;29:3111–23.
64. Allin KH, Tremaroli V, Caesar R, et al. Aberrant intestinal microbiota in individuals with
prediabetes. Diabetologia. 2018;61:810–20.
65. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, Nielsen J,
Bäckhed F. Gut metagenome in European women with normal, impaired and diabetic glucose
control. Nature. 2013;498:99–103.
66. Larsen N, Vogensen FK, van den Berg FWJ, Nielsen DS, Andreasen AS, Pedersen BK,
Al-Soud WA, Sørensen SJ, Hansen LH, Jakobsen M. Gut microbiota in human adults with
type 2 diabetes differs from non-diabetic adults. PLoS One. 2010;5:e9085.
67. Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2
diabetes. Nature. 2012;490:55–60.
68. Schüssler-Fiorenza Rose SM, Contrepois K, Moneghetti KJ, et al. A longitudinal big data
approach for precision health. Nat Med. 2019;25:792–804.
69. Zhao L, Zhang F, Ding X, et al. Gut bacteria selectively promoted by dietary fibers alleviate
type 2 diabetes. Science. 2018;359:1151–6.
70. Pallister T, Spector TD. Food: a new form of personalised (gut microbiome) medicine for
chronic diseases? J R Soc Med. 2016;109:331–6.
71. Wu H, Tremaroli V, Schmidt C, Lundqvist A, Olsson LM, Krämer M, Gummesson A, Perkins
R, Bergström G, Bäckhed F. The gut microbiota in prediabetes and diabetes: a population-
based cross-sectional study. Cell Metab. 2020;32:379–390.e3.
72. Price ND, Magis AT, Earls JC, et al. A wellness study of 108 individuals using personal,
dense, dynamic data clouds. Nat Biotechnol. 2017;35:747–56.
73. Ben-Yacov O, Godneva A, Rein M, et al. Personalized postprandial glucose response-
targeting diet versus Mediterranean diet for glycemic control in prediabetes. Diabetes Care.
2021;44(9):1980–91.
74. Rein M, Ben-Yacov O, Godneva A, et al. Effects of personalized diets by prediction of gly-
cemic responses on glycemic control and metabolic health in newly diagnosed T2DM: a
randomized dietary intervention pilot trial. BMC Med. 2022;20:56.
75. Reitmeier S, Kiessling S, Clavel T, et al. Arrhythmic gut microbiome signatures predict risk
of type 2 diabetes. Cell Host Microbe. 2020;28:258–272.e6.
76. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary Fiber to host physiol-
ogy: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165:1332–45.
77. Sawicki CM, Livingston KA, Obin M, Roberts SB, Chung M, McKeown NM. Dietary fiber
and the human gut microbiota: application of evidence mapping methodology. Nutrients.
2017; https://doi.org/10.3390/nu9020125.
78. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin
treatment signatures in the human gut microbiota. Nature. 2015;528:262–6.
248 O. Ben-Yacov and M. Rein
79. Hughes RL, Marco ML, Hughes JP, Keim NL, Kable ME. The role of the gut microbiome in
predicting response to diet and the development of precision nutrition models-part I: over-
view of current methods. Adv Nutr. 2019;10:953–78.
80. Kootte RS, Levin E, Salojärvi J, et al. Improvement of insulin sensitivity after lean donor
Feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell
Metab. 2017;26:611–619.e6.
81. Roberts LD, Koulman A, Griffin JL. Towards metabolic biomarkers of insulin resistance and
type 2 diabetes: progress from the metabolome. Lancet Diabetes Endocrinol. 2014;2:65–75.
82. Menni C, Zhai G, Macgregor A, et al. Targeted metabolomics profiles are strongly correlated
with nutritional patterns in women. Metabolomics. 2013;9:506–14.
83. Long J, Yang Z, Wang L, Han Y, Peng C, Yan C, Yan D. Metabolite biomarkers of type 2 dia-
betes mellitus and pre-diabetes: a systematic review and meta-analysis. BMC Endocr Disord.
2020;20:174.
84. Guasch-Ferré M, Hruby A, Toledo E, Clish CB, Martínez-González MA, Salas-Salvadó J,
Hu FB. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis.
Diabetes Care. 2016;39:833–46.
85. Eriksen R, Perez IG, Posma JM, et al. Dietary metabolite profiling brings new insight into
the relationship between nutrition and metabolic risk: an IMI DIRECT study. EBioMedicine.
2020;58:102932.
86. Gonzalez-Franquesa A, Burkart AM, Isganaitis E, Patti M-E. What have metabolomics
approaches taught us about type 2 diabetes? Curr Diab Rep. 2016;16:74.
87. O’Gorman A, Brennan L. The role of metabolomics in determination of new dietary bio-
markers. Proc Nutr Soc. 2017;76:295–302.
88. Bar N, Korem T, Weissbrod O, et al. A reference map of potential determinants for the human
serum metabolome. Nature. 2020; https://doi.org/10.1038/s41586-020-2896-2.
89. Tebani A, Bekri S. Paving the way to precision nutrition through metabolomics. Front Nutr.
2019;6:41.
90. Llorach R, Urpi-Sarda M, Tulipani S, Garcia-Aloy M, Monagas M, Andres-Lacueva
C. Metabolomic fingerprint in patients at high risk of cardiovascular disease by cocoa inter-
vention. Mol Nutr Food Res. 2013;57:962–73.
91. Garcia-Perez I, Posma JM, Gibson R, et al. Objective assessment of dietary patterns by
use of metabolic phenotyping: a randomised, controlled, crossover trial. Lancet Diabetes
Endocrinol. 2017;5:184–95.
92. Floegel A, von Ruesten A, Drogan D, Schulze MB, Prehn C, Adamski J, Pischon T, Boeing
H. Variation of serum metabolites related to habitual diet: a targeted metabolomic approach
in EPIC-Potsdam. Eur J Clin Nutr. 2013;67:1100–8.
93. O’Sullivan A, Gibney MJ, Brennan L. Dietary intake patterns are reflected in metabolomic
profiles: potential role in dietary assessment studies. Am J Clin Nutr. 2011;93:314–21.
94. Hernández-Alonso P, Papandreou C, Bulló M, et al. Plasma metabolites associated with fre-
quent red wine consumption: a metabolomics approach within the PREDIMED study. Mol
Nutr Food Res. 2019;63:e1900140.
95. Andersen M-BS, Rinnan Å, Manach C, Poulsen SK, Pujos-Guillot E, Larsen TM, Astrup A,
Dragsted LO. Untargeted metabolomics as a screening tool for estimating compliance to a
dietary pattern. J Proteome Res. 2014;13:1405–18.
96. Clish CB. Metabolomics: an emerging but powerful tool for precision medicine. Cold Spring
Harb Mol Case Stud. 2015;1:a000588.
97. Lee HJ, Jang HB, Kim W-H, Park KJ, Kim KY, Park SI, Lee H-J. 2-Aminoadipic acid
(2-AAA) as a potential biomarker for insulin resistance in childhood obesity. Sci Rep.
2019;9:13610.
98. Wang TJ, Ngo D, Psychogios N, et al. 2-Aminoadipic acid is a biomarker for diabetes risk. J
Clin Invest. 2013;123(10):4309–17.
99. Drogan D, Dunn WB, Lin W, et al. Untargeted metabolic profiling identifies altered serum
metabolites of type 2 diabetes mellitus in a prospective, nested case control study. Clin Chem.
2015;61:487–97.
12 Precision Nutrition for Type 2 Diabetes 249
100. Walford GA, Ma Y, Clish C, Florez JC, Wang TJ, Gerszten RE, Diabetes Prevention Program
Research Group. Metabolite profiles of diabetes incidence and intervention response in the
diabetes prevention program. Diabetes. 2016;65:1424–33.
101. Ejaz A, Martinez-Guino L, Goldfine AB, et al. Dietary betaine supplementation increases
fgf21 levels to improve glucose homeostasis and reduce hepatic lipid accumulation in mice.
Diabetes. 2016;65:902–12.
102. Thaiss CA, Itav S, Rothschild D, et al. Persistent microbiome alterations modulate the rate of
post-dieting weight regain. Nature. 2016;540:544–51.
103. Zheng Y, Ceglarek U, Huang T, et al. Weight-loss diets and 2-y changes in circulating amino
acids in 2 randomized intervention trials. Am J Clin Nutr. 2016;103:505–11.
104. Greenwood DA, Gee PM, Fatkin KJ, Peeples M. A systematic review of reviews evaluat-
ing technology-enabled diabetes self-management education and support. J Diabetes Sci
Technol. 2017;11:1015–27.
105. Powers MA, Bardsley JK, Cypress M, et al. Diabetes Self-management Education and Support
in Adults with Type 2 Diabetes: a consensus report of the American Diabetes Association,
the Association of Diabetes Care & Education Specialists, the Academy of Nutrition and
Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the
American Association of Nurse Practitioners, and the American Pharmacists Association.
Diabetes Care. 2020;43:1636–49.
106. American Diabetes Association. 5. Facilitating behavior change and well-being to improve
health outcomes: standards of medical care in diabetes-2021. Diabetes Care. 2021;44:S53–72.
107. Korem T, Zeevi D, Zmora N, et al. Bread affects clinical parameters and induces gut
microbiome-associated personal Glycemic responses. Cell Metab. 2017;25:1243–1253.e5.
108. Cassidy S, Chau JY, Catt M, Bauman A, Trenell MI. Cross-sectional study of diet, physi-
cal activity, television viewing and sleep duration in 233,110 adults from the UK biobank;
the behavioural phenotype of cardiovascular disease and type 2 diabetes. BMJ Open.
2016;6:e010038.
109. Hall H, Perelman D, Breschi A, Limcaoco P, Kellogg R, McLaughlin T, Snyder M. Glucotypes
reveal new patterns of glucose dysregulation. PLoS Biol. 2018;16:e2005143.
110. Mendes-Soares H, Raveh-Sadka T, Azulay S, et al. Model of personalized postprandial gly-
cemic response to food developed for an Israeli cohort predicts responses in Midwestern
American individuals. Am J Clin Nutr. 2019;110:63–75.
111. Yoo HJ, An HG, Park SY, et al. Use of a real time continuous glucose monitoring system
as a motivational device for poorly controlled type 2 diabetes. Diabetes Res Clin Pract.
2008;82:73–9.
112. Ehrhardt N, Al Zaghal E. Behavior modification in prediabetes and diabetes: potential use of
real-time continuous glucose monitoring. J Diabetes Sci Technol. 2019;13:271–5.
113. Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term
effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes
Care. 2012;35:32–8.
114. Kooiman TJM, de Groot M, Hoogenberg K, Krijnen WP, van der Schans CP, Kooy A. Self-
tracking of physical activity in people with type 2 diabetes: a randomized controlled trial.
Comput Inform Nurs. 2018;36:340–9.
115. Bailey TS, Ahmann A, Brazg R, Christiansen M, Garg S, Watkins E, Welsh JB, Lee
SW. Accuracy and acceptability of the 6-day Enlite continuous subcutaneous glucose sensor.
Diabetes Technol Ther. 2014;16:277–83.
116. Walford GA, Porneala BC, Dauriz M, Vassy JL, Cheng S, Rhee EP, Wang TJ, Meigs JB,
Gerszten RE, Florez JC. Metabolite traits and genetic risk provide complementary informa-
tion for the prediction of future type 2 diabetes. Diabetes Care. 2014;37:2508–14.
117. Tily H, Perlina A, Patridge E, et al. Gut microbiome activity contributes to individual varia-
tion in glycemic response in adults. BioRxiv. 2019; https://doi.org/10.1101/641019.
118. Chung WK, Erion K, Florez JC, et al. Precision medicine in diabetes: a consensus report from
the American Diabetes Association (ADA) and the European Association for the Study of
diabetes (EASD). Diabetologia. 2020;63:1671–93.
Chapter 13
Precision Exercise and Physical Activity
for Diabetes
N. G. Boulé
Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
Alberta Diabetes Institute, Edmonton, AB, Canada
J. E. Yardley (*)
Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
Alberta Diabetes Institute, Edmonton, AB, Canada
Augustana Faculty, University of Alberta, Edmonton, AB, Canada
Women’s and Children’s Health Research Institute, Edmonton, AB, Canada
e-mail: [email protected]
© Springer Nature Switzerland AG 2022 251
R. Basu (ed.), Precision Medicine in Diabetes,
https://doi.org/10.1007/978-3-030-98927-9_13
252 N. G. Boulé and J. E. Yardley
Precision Medicine
Type 1 Diabetes
subcutaneous infusion (insulin pump) of synthetic insulin. It has recently been rec-
ognized that what has generally been classified as “type 1” diabetes actually encom-
passes a spectrum, where some individuals continue to produce a certain amount of
insulin (usually measured by residual c-peptide), while others become completely
insulin-deficient [7, 8]. Latent autoimmune diabetes in adults (LADA) is another
insulin-requiring form of diabetes where patients tend to present at a slightly older
age, develop insulin deficiency at a much slower rate, and also tend to possess vary-
ing degrees of insulin resistance [9]. In addition, the term “double diabetes” [10]
has been used to describe a growing subpopulation of individuals with type 1 dia-
betes having clinical features of insulin resistance, often related to obesity, older
age, and longer diabetes duration [11]. As a result, each patient requires an indi-
vidualized insulin regimen in order to maintain blood glucose levels in as close to a
euglycemic range as possible, and, consequently, there is a great deal of variability
in individual responses to exercise [12].
In general, being physically active is associated with increased longevity [13, 14]
and a decreased risk of microvascular and macrovascular complications [13, 15–17]
in individuals with type 1 diabetes. In large longitudinal studies of individuals with
type 1 diabetes, performing physical activity with greater frequency and/or intensity
is associated with a lower risk and/or slower progression of complications such as
neuropathy [15], nephropathy [15, 18], and retinopathy [16, 19]. Training interven-
tion studies involving individuals with type 1 diabetes are few and have generally
failed to show any improvement in mean blood glucose levels (as measured by
hemoglobin A1c) although this could be due to overcompensation (in terms of insu-
lin adjustments and carbohydrate intake [20]) on the part of the participants or due
to inadequate exercise “dose” (frequency, intensity, duration) in many studies [21].
The vast majority of training studies involving participants with type 1 diabetes
have involved aerobic exercise with variable dosage timing, frequency, intensity,
and duration. Many of these studies have shown that aerobic training leads to an
increase in aerobic fitness in individuals with type 1 diabetes [22–27], along with
increases in capillary density [28] and improvements in endothelial function [25,
28, 29]. While not universal, some studies of aerobic training have resulted in a
decrease in insulin dosage [24, 25, 30] and/or insulin resistance [24, 26, 31] among
the participants. Similar to aerobic training in adults without diabetes, several
studies involving participants with type 1 diabetes show an improvement in blood
lipid levels as a result of performing regular aerobic exercise [22, 24, 25, 27, 31].
Finally, there are also data to support the role of aerobic training in ameliorating
body composition, either by decreasing waist circumference [32] or by increasing
bone density [33].
There are very few resistance training intervention studies involving individuals
with type 1 diabetes, and those that do exist tend to involve very small sample sizes.
From the limited evidence available, we know that resistance exercise increases
254 N. G. Boulé and J. E. Yardley
muscle strength [34, 35] in individuals with type 1 diabetes. Where body composition
is concerned, one study showed a decrease in fat mass along with an increase in lean
mass after 10 weeks of resistance training [34]. There is also evidence from a very
small study to indicate that resistance exercise may be beneficial in terms of reducing
A1c and improving triglycerides [35]. Training programs that combined both aerobic
(or high-intensity interval training) and resistance exercises have resulted in increased
aerobic fitness [36, 37], greater muscle strength [36, 37], improved lipid profiles [36,
37], lower A1c [34, 37], and reduction in insulin needs [34, 36].
Intervention studies of HIIE in individuals with type 1 diabetes are currently just
as rare as studies of resistance exercise and also involve small sample sizes. One of
the consistent findings is that this type of training increases aerobic capacity [29, 34,
38, 39]. There is also evidence to indicate that HIIE may decrease aortic stiffness (as
measured by pulse wave velocity) [38], improve endothelial function [29, 38],
reduce fat mass [34, 39], increase lean mass [34, 39], and lower fasting glucose
levels [39] in individuals with type 1 diabetes. Whether or not the improvements in
aerobic fitness and endothelial function are greater with HIIE than with aerobic
training are unclear, with one study finding HIIE to be superior [29], while another
found that gains in these areas were similar to aerobic training [38]. As the two stud-
ies differed with respect to the length of the intervention, matching (or not) of par-
ticipants within groups, duration/intensity/frequency of the intervals in the HIIE,
and aerobic exercise protocols, the data are difficult to interpret.
In spite of the many known benefits of various types of exercise and physical
activity for individuals with type 1 diabetes, a large proportion of adults with type 1
diabetes fail to meet the weekly recommendations of 150 minutes of moderate to
vigorous physical activity (MVPA) [16, 40]. Women with type 1 diabetes tend to
have lower activity levels than men with type 1 diabetes [2], and adolescents with
type 1 diabetes are less active than their nondiabetic counterparts [41]. In addition
to the regular barriers that exist where exercise and physical activity are concerned
(lack of time, lack of money, lack of resources, etc.), fear of hypoglycemia and fear
of losing control over diabetes management are major barriers to becoming more
active in this population [42]. As such, a great deal of research has gone into deter-
mining the acute effects of different types, timings, durations, and intensities of
exercise on blood glucose levels in individuals with type 1 diabetes in order to better
understand the risk of hypoglycemia both during and after exercise. To date, a great
amount of variability has been found, which may, to a certain extent, be due to indi-
vidual characteristics such as age, sex, and fitness level [43] in addition to the exer-
cise characteristics (type, intensity, duration) themselves.
While exercise and physical activity are highly recommended for individuals with
type 1 diabetes [44, 45], being physically active also complicates blood glucose
management, resulting in an increased risk for both hypoglycemia and
13 Precision Exercise and Physical Activity for Diabetes 255
While several generalities about exercise in individuals with type 1 diabetes have
been listed in section “The Right Treatment: Acute Glycemic Effects of Exercise in
Individuals with Type 1 Diabetes”, it is important to consider individual character-
istics when providing exercise and physical activity advice. Insulin regimens, physi-
ological/physical characteristics, and patient goals will all be relevant with respect
to the type, timing, and intensity of activities selected. They may also play a role in
the risk of hypoglycemia during and after exercise.
Insulin Management
There are currently three main ways that individuals with type 1 diabetes administer
their insulin to manage blood glucose levels, albeit a great deal of variability exists
within each category [69]. The first of these is multiple daily injections of insulin
13 Precision Exercise and Physical Activity for Diabetes 257
(MDI). This type of regimen generally involves one daily injection of long-lasting
(basal) insulin, plus several injections of short-acting (bolus) insulin to manage
blood glucose around meals and snacks or to correct for blood glucose levels in a
hyperglycemic range. The second type of treatment involves continuous subcutane-
ous insulin infusion (CSII) of fast-acting insulin via an insulin pump. Rates of basal
infusion can be programmed to vary throughout the day to manage diurnal varia-
tions in blood glucose. The user also has the ability to administer a bolus of insulin
to account for carbohydrate intake in meals and snacks (or to correct for high blood
glucose levels). The final and more recent type of system is referred to as a closed-
loop system, where insulin is administered via an insulin pump, with information
from a continuous glucose monitoring (CGM) sensor providing the data for an algo-
rithm to adjust insulin infusion based on interstitial glucose levels [70]. Adjusting
insulin dosages for exercise will vary depending on the type, timing, and intensity
of exercise but also on the type of insulin regimen being followed.
For individuals administering insulin via MDI, there are two main options for
adjusting insulin dosage prior to exercise. Where a weekly pattern of exercise days
is well established, decreasing the basal insulin injection by ~20% the night before
(or morning of depending on insulin management routines) the activity is recom-
mended [45]. Where exercise and physical activity are less predictable, individuals
with type 1 diabetes using MDI also have the option to decrease the size of their
meal bolus if exercise is to take place within a few hours after a meal [63]. Should
the activity be spontaneous and advance adjustments to insulin were not possible,
fast-acting carbohydrates can be consumed before, during, and after exercise to
maintain blood glucose levels in a euglycemic range. The size of the insulin adjust-
ment and/or the amount of carbohydrate intake will depend on the type, timing,
intensity, and duration of exercise, along with pre-exercise blood glucose levels
[45]. The 2017 consensus statement by Riddell et al. [45] provides a detailed and
comprehensive overview of exercise-related insulin adjustments and carbohydrate
intake for individuals using an MDI insulin regimen.
Insulin pumps are often preferred by physically active individuals with type 1
diabetes as using only fast-acting insulin and being able to alter basal insulin infu-
sion rates allow more flexibility for adjusting insulin before, during, and after exer-
cise. While one observational study comparing MDI and CSII users showed
comparable changes in blood glucose during exercise in both groups, those using
CSII were better able to prevent postexercise hyperglycemia with small correction
boluses, without increasing the occurrence of nocturnal hypoglycemia [71]. Current
recommendations call, once again, for one of two strategies to be used in adjusting
insulin delivery: either a decrease in basal rate (from 50% to 100%) at least 90 min-
utes before exercise or a reduced bolus with a meal or a snack prior to exercise (in
particular for aerobic exercise) [45]. Studies have recently shown that adjusting
basal rates closer to the start of exercise (either 40 or 20 minutes in advance) [72]
and suspending insulin completely at the start of exercise [55] are less effective at
preventing hypoglycemia during exercise than planning 90 minutes ahead. Where
insulin has not been adjusted in advance, once again, carbohydrates will probably
be required in order to maintain blood glucose levels in a euglycemic range during
exercise, especially if that exercise is aerobic in nature. A further advantage of CSII
258 N. G. Boulé and J. E. Yardley
was in the control participants, indicating that transplanted islets are generally able
to cope with the demands of exercise. More widespread use of this procedure is still
being limited by the need for lifelong immune suppression therapy posttransplant.
While methods to circumvent the need for this medication are being explored, many
experts are still leaning toward fully automated insulin delivery as the preferred
means of decreasing the burden of insulin management in individuals with type 1
diabetes [81].
Many individuals with type 1 diabetes whether using MDI or CSII will also use
CGM or intermittently scanned CGM (isCGM) to help monitor and manage blood
glucose levels throughout the day. As these monitors provide not only information
about current interstitial glucose levels but also about the rate of change of glucose
(in the form of trend arrows), they can be used to assist in making decisions around
insulin adjustments and carbohydrate intake before, during, and after exercise.
Recent studies of CGM [82–85] and isCGM [86, 87] show that there is a tendency
for most, but not all [88], of these systems to decrease in accuracy during exercise,
due to the time lag for plasma glucose and interstitial glucose levels to equilibrate
[89]. Users are therefore advised to consider trend arrows in addition to CGM glu-
cose values in making decisions during exercise. A recent consensus statement has
been published with recommendations on insulin adjustment and carbohydrate
intake before and during exercise based on the type, timing, and intensity of exer-
cise, along with starting CGM glucose values and trend arrows [90]. These recom-
mendations are not meant to be a set of rules, but rather a starting point for developing
individual management strategies.
Individual Characteristics
to have the lowest A1c and the smallest insulin dosage (IU/kg/day), along with a
tendency to be less obese/overweight, with a healthier lipid profile and a lower fre-
quency of diabetes complications such as retinopathy and nephropathy.
The same observational study found that women with type 1 diabetes were more
likely to be inactive than men with type 1 diabetes: 66% of women reported no
weekly physical activity, compared to 60.5% of men (p < 0.0001) [16]. This higher
level of inactivity may be related to the fact that women who were active in the
study also reported higher rates of severe hypoglycemia than those who were inac-
tive, whereas the opposite was found among men up to the age of 45 years.
These data conflict to a certain extent with the only study to date examining sex-
related differences in acute blood glucose responses to exercise. This secondary
analysis of resistance exercise found that male participants had a greater decline in
blood glucose during resistance exercise and a higher risk of postexercise hypogly-
cemia compared to female participants [91]. Another secondary analysis examining
the effects of aerobic fitness found that blood glucose levels decreased more during
aerobic exercise in individuals of higher aerobic fitness, compared to those of lower
aerobic fitness [92]. In both instances, the greater changes in glucose may have been
due to a greater amount of work performed or a higher lean body mass in the group
that experienced greater changes. The latter argument is supported by yet another
secondary analysis, showing that declines in blood glucose during exercise were
greater in those with a higher amount of lean body mass [93].
In addition to knowing little about the blood glucose response to physical activity
and exercise in women with type 1 diabetes in general, less is known about how the
menstrual cycle (or the use of hormonal contraception) may affect blood glucose
outcomes. In women with type 1 diabetes, cyclic changes in blood glucose levels
have been observed throughout the menstrual cycle with higher blood glucose levels
reported in many women during the luteal phase [94–98]. While one case study
indicated that oral contraception decreased luteal hyperglycemia [99], another study
of self-reported blood glucose in 124 women observed that perimenstrual fluctua-
tions in glucose were still present in 67% of the sample that were using a fixed dose
combined oral contraceptive pill [100]. To date, no studies have examined how the
menstrual cycle and the use of hormonal contraception affect blood glucose
responses to exercise and the resulting risk of postexercise hypoglycemia. Overall,
more research is necessary involving studies designed specifically to examine the
impact of age, sex, and physical fitness.
A recently described confounding factor explaining some of the variability in
blood glucose responses during and after exercise is residual beta-cell function [12].
Recent studies have found that a relatively substantial proportion of individuals with
type 1 diabetes still maintain some residual beta-cell function (as measured by
c-peptide levels) long after their diagnosis [7, 8]. While many of these individuals
would be considered “micro-secretors” [8], some individuals will maintain an
amount of endogenous insulin secretion that is clinically relevant [8]. One small
study to date examining the impact of residual beta-cell function on blood glucose
responses to exercise found that individuals with the highest levels of c-peptide
13 Precision Exercise and Physical Activity for Diabetes 261
spent roughly 70% more time in a euglycemic range following exercise than those
with low or undetectable levels of c-peptide [12]. The authors conclude that quanti-
fying c-peptide could be useful in explaining individual responses to exercise and in
personalizing exercise programs to individual patients [12].
A consideration of patient goals is essential to providing the right exercise and
physical activity advice, especially where carbohydrate intake is concerned. Where
a person is training to compete, finding the right combination of insulin adjustments
and carbohydrate intake for optimal athletic performance [45, 101] is necessary.
Where weight maintenance/weight loss is goals, finding ways to reduce the risk of
hypoglycemia through insulin adjustments in order to prevent the need for addi-
tional carbohydrate intake will be essential. For detailed reviews of insulin adjust-
ments for different intensities of exercise, the reader is referred to Riddell et al. [45].
In the initial stages of type 1 diabetes, there are often a significant number of beta
cells that continue to function [102], which tend to decline in number and in their
ability to secrete insulin over time. This time after diagnosis is often referred to as
the “honeymoon” phase; however, as mentioned earlier, some individuals maintain
some residual function for an extended period of time post-diagnosis [7, 8]. Higher
levels of meal-stimulated c-peptide (≥200 pmol/l) have been associated with lower
A1c, less frequent hypoglycemia, and reduced risk of nephropathy and retinopathy
[103]. Consequently, several studies have attempted to maintain beta-cell function
and extend the “honeymoon” phase in recently diagnosed individuals. Studies
involving various pharmaceuticals have not been successful [104], but one case-
control study suggested that those who exercise regularly are able to substantially
extend their honeymoon phase [105]. These data, however, conflict with the results
of a randomized controlled trial of exercise in newly diagnosed individuals with
type 1 diabetes [106]. Narendran et al. found improvements in physical fitness and
insulin sensitivity in the study participants after performing a minimum of
262 N. G. Boulé and J. E. Yardley
150 minutes/week of MVPA for 12 months, but there did not seem to be any impact
on the rate of beta-cell loss [106]. Newly diagnosed individuals with type 1 diabetes
are, nonetheless, encouraged to exercise for all of the other benefits that can be
gained. There may, however, be a requirement for additional support in this particu-
lar subgroup of individuals, as there may be a tendency to avoid physical activity in
those who are recently diagnosed [107], for fear of hypoglycemia.
Pregnancy
Data on the risks and benefits of exercise during pregnancy in women with type 1
diabetes are very sparse. Compared to nondiabetic women, pregnant women with
type 1 diabetes are at a higher risk of preeclampsia, miscarriage, congenital anoma-
lies, preterm birth, and large for gestational age babies [119–121]. Several of these
risks are associated with higher levels of A1c [119]. One nonrandomized interven-
tion with a small sample size (n = 10) found a decrease in average daily glucose
levels, less time spent in hyperglycemia, and less glucose variability (measured by
CGM) on a day where participants performed three 20-min self-paced walks and
13 Precision Exercise and Physical Activity for Diabetes 263
two 50-min sessions of brisk walking compared to their regular routine [122].
Unfortunately, these changes were also associated with an increased risk of symp-
tomatic hypoglycemia, and frequent/prolonged hypoglycemia has been associated
with adverse fetal outcomes [123]. Further research is required in order to deter-
mine appropriate levels of exercise for this population in order to maximize health
benefits while also minimizing risks.
Older Adults
Due to improvements in diabetes care, individuals with type 1 diabetes are living
longer than they have in the past [124]. Older adults with type 1 diabetes are at a
higher risk of frailty than adults with type 1 diabetes due to a faster loss of muscle
mass with aging [125]. There is evidence to indicate that individuals with type 1
diabetes also have an accelerated loss of bone quality [126]. Combined, these fac-
tors produce a higher risk of falls and fall-related injuries, including fractures, in
older adults with type 1 diabetes compared to those without diabetes [127]. While
exercise is known to counteract all of these functional declines, type 1 diabetes-
specific data related to exercise for older adults are currently lacking. Data related
to hypoglycemia frequency in this population indicate that they are at a high risk of
hypoglycemia in general [128] and therefore probably have a higher risk of hypo-
glycemia with exercise than younger individuals. This premise is consistent with the
findings from a large observational study, where rates of hypoglycemia in physi-
cally active adults with type 1 diabetes aged 45 to <80 years were higher than their
counterparts under the age of 45 with similar physical activity frequency [16]. As
the benefits of exercise on functional mobility [129, 130] and quality of life [129,
131] in older adults have been clearly demonstrated, older adults with type 1 diabe-
tes should make an effort to remain active while also remaining vigilant of their
blood glucose levels during and after activity.
While most studies comparing fasted to fed exercise involve small sample sizes,
there seems to be consensus that blood glucose responses to acute exercise, regard-
less of modality, are different when exercise is performed in a fasting state. In gen-
eral, there tends to be little change or even an increase in blood glucose during
fasted morning exercise, compared to the decrease that is generally observed with
postprandial exercise [132–135]. The strength of existing studies is in their cross-
over design, where all participants were asked to perform a standard exercise proto-
col in both a fed (postprandial state) and fasted (postabsorptive) state on separate
days, in a randomized order, with a washout period between the sessions. These
divergent blood glucose responses to an identical exercise protocol performed by
the same participants have been found with aerobic exercise [132, 133], resistance
264 N. G. Boulé and J. E. Yardley
exercise [135], and HIIE [134] of short to moderate (i.e., 30 to 45 minutes) duration.
While the mechanism behind these trends has yet to be elucidated, it is possible that
they are simply the result of lower circulating insulin when participants exercise in
a fasting state. It has also been surmised that variations in cortisol and growth hor-
mone throughout the day could affect insulin sensitivity and fuel selection during
exercise [136–138]. Thus, fasted morning exercise may be more appropriate for
those who struggle with hypoglycemia during their activities, while those who
experience frequent hyperglycemia may wish to exercise postprandially.
It is generally accepted that when individuals with type 1 diabetes perform exercise
later in the day, the risk of nocturnal hypoglycemia is increased [45]. This phenom-
enon is generally attributed to the fact that there will be fewer meals from which
glycogen reserves can be replenished prior to bedtime, when exercise takes place
later in the day. One observational study of adolescents and young adults with type
1 diabetes showed that late-day MVPA (as measured by accelerometry) increased
the risk of overnight hypoglycemia (measured by CGM) independent of sex, fitness,
and concurrent MVPA [114]. These findings are consistent with two crossover stud-
ies comparing morning versus afternoon exercise, where afternoon exercise was
associated with a greater frequency of nocturnal hypoglycemia [135, 139]. One very
tightly controlled study involving 45 minutes of moderate aerobic exercise in indi-
viduals with type 1 diabetes using glucose infusion overnight postexercise to main-
tain euglycemia showed that glucose needs increased in the early morning (between
1 and 3 am) after a late-day (4 pm) exercise session [56]. As such, a low-glycemic
index bedtime snack [140] or a reduction in nocturnal basal insulin [141] is highly
recommended after late-day activities.
Type 2 Diabetes
Type 2 diabetes has long been known to be a heterogeneous disease, and there have
been many approaches to characterize the diverse phenotype. As the change from
previous nomenclature suggested (i.e., the terms adult-onset diabetes or non-insulin-
dependent diabetes are no longer in use), type 2 diabetes can develop at different
ages and different levels of endogenous insulin secretion. More recent efforts to
characterize type 2 diabetes have led to the identification of four subgroups by
Ahlqvist et al. [143]:
• SIDD = severe insulin-deficient diabetes.
• SIRD = severe insulin-resistant diabetes.
• MOD = mild obesity-related diabetes.
• MARD = mild age-related diabetes.
The main commonality among the subgroups is the presence of hyperglycemia.
Many exercise studies in this population have, therefore, focused on decreasing
average blood glucose levels.
General Considerations
Aerobic Training
Aerobic training, such as brisk walking, is the most commonly prescribed exercise
for people with diabetes. This is in part due to low cost, low risk, and ease of acces-
sibility for many. It is also one of the preferred types of physical activity by the
largest proportion of people with type 2 diabetes [149]. However, walking may not
always be appropriate. For example, some people may have lower body limitations
to walking, and other factors such as neighborhood safety or environmental condi-
tions (e.g., extreme heat or icy sidewalks) may render walking unpleasant or unfea-
sible. There is no evidence, to our knowledge, that other forms of aerobic exercise
266 N. G. Boulé and J. E. Yardley
are less effective (e.g., [150]). Cycling, including stationary cycling, or water-based
activities could therefore be used to achieve a wide range of health benefits from
glycemic management to lowering of blood pressure and improving lipid/lipopro-
tein profiles. That said, it is also important to have realistic expectations in regard to
changes in body composition or fitness with most aerobic training programs, in part
due to the moderate volumes and intensities of activity achieved with most interven-
tions in people with type 2 diabetes. In many trials, meaningful improvements in
A1c occur in the absence of major changes in body composition or body weight
[144, 151].
Resistance Training
Resistance training is also firmly established as part of most guidelines and consen-
sus statements for people with type 2 diabetes (e.g., [44, 152]). Improvements in
mean blood glucose levels (as measured by reductions in A1c) are often comparable
between aerobic and resistance training, and the benefits of aerobic and resistance
training are likely additive [151]. However, many of the adaptations that are targeted
by resistance training are different to aerobic training. In the general population,
resistance training is normally performed with the goal of increasing muscle
strength, power, and/or size. Such changes could be particularly desirable in some
people with type 2 diabetes, such as older adults, and those with low muscle mass/
function (i.e., sarcopenia) who may have poorer metabolic health to begin with
[153]. From a behavioral perspective, resistance training may be considered in those
who have access to resistance training equipment or for whom there are more barri-
ers to aerobic training. Other forms of resistance training, which include less expen-
sive and more accessible equipment, do exist. These alternatives, such as using
resistance bands, may be good for beginning resistance training or maintenance, but
a beneficial effect on A1c has not been consistently demonstrated [154, 155].
In recent years, HIIE has received growing attention in people with and without
diabetes. It can result in similar, and perhaps slightly better, reductions in insulin
resistance and A1c compared to more traditional forms of aerobic training [148,
156, 157]. One of the proposed advantages of HIIE training is that with some forms
the benefits can be achieved with less time or exercise volume than continuous exer-
cise of more moderate intensities. On the other hand, higher-intensity activities can
be intimidating to some participants, as self-efficacy for higher-intensity exercise is
lower [158]. However, it is important to keep in mind that in the context of HIIE, the
term “high intensity” is most often a relative term which is set as a proportion of the
participants’ maximal aerobic fitness level and is not a fixed absolute workload that
might be unattainable by those with lower fitness. Nonetheless, higher-intensity
exercise may come with additional barriers, and there may be associated risks for
13 Precision Exercise and Physical Activity for Diabetes 267
We are not aware of any long-term intervention study focusing on the effect of
breaking sedentary time (e.g., breaks in sitting) in people with type 2 diabetes.
There are several short-term studies in people with and without diabetes (as reviewed
by Loh et al. [161]). Meta-analyses show relatively consistent reduction in cardio-
metabolic risk factors such as glucose and triglycerides with breaking of sedentary
time [161]. Some studies emphasize standing to break up period of sitting, whereas
others add brief exercise periods [161]. Interestingly, when the short-term efficacy
of breaks in sedentary time is compared to continuous aerobic exercise, studies have
shown mixed results. For example, Duvivier et al. [162] found that breaking sitting
with a mix of standing and light-intensity walking improved 24-hour glucose con-
centrations to a greater extent than structured exercise. On the other hand, in the
study by Blankenship et al. [163], continuous walking was more effective than short
walking breaks in lowering daily hyperglycemia. Differences among studies may be
due to the total number and duration of breaks.
Although there are no longer-term intervention studies, cohort studies have iden-
tified associations between the amount of sedentary behavior and the prevalence of
type 2 diabetes [164]. Others have noted that more frequent breaks in sedentary time
are associated with better glycemic management or insulin sensitivity in adults with
type 2 diabetes [165].
General Considerations
We are not aware of any studies comparing the effectiveness of different exercise
interventions within the subgroups of type 2 diabetes described by Ahlqvist et al.
[143] and described in section “Type 2 Diabetes”. However, in secondary analyses
of the Look AHEAD trial, 5145 participants with type 2 diabetes were categorized
as “younger onset,” “older onset,” “severe obesity,” and “poor glucose control”
[166]. The Look AHEAD trial compared an intensive lifestyle intervention to stan-
dard education. The lifestyle intervention aimed to increase physical activity to
175 minutes per week and achieve/maintain a weight loss of 10%. A composite
outcome of cardiovascular events/complications was collected over a median
268 N. G. Boulé and J. E. Yardley
follow-up of 9.4 years. There was a significant interaction among the four sub-
groups and the cardiovascular protectiveness of the combined diet and physical
activity intervention. Only the “poor glucose control” group was associated with
increased risk for adverse cardiovascular outcomes [166]. Other analyses suggested
that previous cardiovascular diseases may also have contributed to negative cardio-
vascular outcomes from the lifestyle intervention, but the association did not reach
statistical significance (p = 0.06) [167].
Another approach to studying the heterogeneity of type 2 diabetes is to consider
the pathological role of various organ systems. Defronzo had characterized the
triumvirate (i.e., insulin resistance in muscle, insulin resistance in the liver, and
impaired insulin secretion from beta cells) and later increased this to the ominous
octet which added other defects (i.e., increased fatty acid release in adipose tissue,
increased glucagon secretion from alpha cells, decreased incretin effect from the
gastrointestinal tract, increased glucose reabsorption in kidneys, and neurotrans-
mitter dysfunction in the brain) [168]. It remains to be seen if different exercise
interventions can preferentially target some specific organ systems. Clearly, regu-
lar aerobic or resistance training can target improvements in insulin resistance at
the level of the skeletal muscle (likely in part through different mechanisms); how-
ever, less is known about the impact on other organ systems (e.g., incretins).
Although age is associated with an increased risk of developing type 2 diabetes, this
disease can present at younger ages. The risk and benefits of physical activity would
also be expected to change with aging or duration of diabetes. Both the categoriza-
tion from Ahlqvist et al. [143] and a recent meta-analysis [169] suggest that diagno-
sis of diabetes at an older age can be associated with reduced risk of complications.
Few exercise studies have been large enough to compare the effects of exercise in
people with type 2 diabetes of different age or duration of the condition. Both older
age and longer duration of diabetes are associated with a greater risk of cardiovas-
cular disease, which may affect the choice of exercise (e.g., see previous discussion
on exercise intensity). Greater duration of diabetes is also associated with a progres-
sive decline in pancreatic volume and insulin secretory capacity [170, 171]. This
decline may indirectly, through medications such as insulin, increase the risk of
hypoglycemia during exercise [172].
From a behavioral perspective, it is also likely that aging is associated with dif-
ferent barriers to physical activity. For example, retirement from employment may
be accompanied with more time for recreational activities. This may, in part, explain
why the Diabetes Prevention Program (DPP) found that a lifestyle intervention
composed of an energy-reduced diet and physical activity led to greater increases in
physical activity and greater reductions in the risk of developing type 2 diabetes
compared to placebo or metformin in older adults [173, 174]. More specifically, in
participants between 25 and 44 years of age, the incidence of diabetes was reduced
by a similar extent in the lifestyle and metformin groups compared to the placebo
13 Precision Exercise and Physical Activity for Diabetes 269
group (6.2 vs. 6.7 vs 11.6 cases/100 person-years) [175]. However, in the partici-
pants between 60 and 85 years of age, the lifestyle intervention reduced the inci-
dence of diabetes more than both the metformin and placebo groups (3.1 vs. 9.6 vs.
11.8 cases/100 person-years) [175].
Sex
Although the prevalence of diabetes is similar in men and women [176] or perhaps
slightly greater in men [177], the relative importance of the underlying pathophysi-
ology can be different. For example, men tend to have greater insulin resistance but
also greater insulin secretion [178]. In addition, men tend to meet the criteria for
fasting hyperglycemia more frequently, whereas women meet the criteria for post-
prandial hyperglycemia more often (as previously reviewed [179]). Some of these
discrepancies may be due to differences in body fat distribution (e.g., men tend to
have more visceral and hepatic fat) but also other less appreciated differences such
as more pronounced counterregulatory responses in men and greater reliance on fat
as fuel in women.
Given the small size of most exercise trials involving people with type 2 diabetes,
most have been underpowered to examine if men and women respond differently to
the interventions. Again, turning to the DPP, which had a combined dietary and
physical activity intervention, it was observed that a greater proportion of men met
the objectives of 7% weight loss and 150 minutes/week of physical activity [180].
Despite these gender differences, the progression to diabetes was similar in both
men and women, perhaps due to the fact that men had slightly more elevated cardio-
metabolic risk factors at baseline (e.g., fasting glucose) [180]. Looking at a large
(n = 596), rigorously controlled exercise study in previously sedentary adults with-
out diabetes, insulin sensitivity increased to a greater extent following training in
men compared to women [178].
It has long been known that type 2 diabetes affects people of different shapes and
sizes. Obesity, and in particular abdominal obesity, is a well-established modifiable
risk factor of type 2 diabetes. However, it has also been recognized that not all
people with type 2 diabetes have excess adiposity. Likewise, the prevalence of sar-
copenia is enhanced in type 2 diabetes [181]. Although there is likely a bidirectional
relationship between type 2 diabetes and sarcopenia (reviewed by Scott et al. [182]),
evidence suggests that both impaired insulin sensitivity and secretion can contribute
to sarcopenia [183]. Unfortunately, as for age and sex, there is no strong body of
evidence to recommend one form of exercise over another in people with type 2
diabetes who have more/less adiposity or muscle mass. In the DPP, reductions in the
incidence of type 2 diabetes in the lifestyle intervention group were significant in all
three BMI categories compared to placebo (BMI from 22 to <30 kg/m2 = 65%; BMI
270 N. G. Boulé and J. E. Yardley
from 30 to <35 kg/m2 = 61%; BMI ≥35 kg/m2 = 51% reduction in the incidence of
diabetes). Reductions in the incidence of diabetes were also superior to metformin
except in participants with BMI ≥35 kg/m2 in whom metformin had similar efficacy
compared to those randomized to the lifestyle intervention [175].
From an adiposity perspective, aerobic training of moderate or higher intensity
can result in reductions in fat mass, including visceral fat [184]. The effect of resis-
tance training may not be as large [185]. However, reductions would typically be
considered small and not largely different from one type of exercise intervention to
another. While small amounts of weight loss are typically observed in overweight/
obese individuals without diabetes with regular exercise training, it may not be as
consistently observed in adults with type 2 diabetes [144]. Changes in visceral fat or
health outcomes can, however, occur in the absence of weight loss [186]. As a result,
changes in total body weight or body fat should not be used to judge the success of
an exercise intervention in type 2 diabetes.
It might seem logical to target sarcopenia with resistance training interventions
designed to target increases in muscle size or function [151, 187]. However, there is
no clear evidence that resistance training is more effective at improving glycemic
management in people with type 2 diabetes and sarcopenia versus those without
sarcopenia [153].
Such additive effects are important to highlight because it is not always the case
that doubling the amount of exercise leads to a doubling of the improvements in
select outcomes. For example, Church et al. [188] randomly assigned 464 post-
menopausal women with a BMI above 25 kg/m2 and elevated blood pressure to a
control group or 3 exercise groups with increasing volume (i.e., energy expenditure
of 4 vs. 8 or 12 kcal/kg, per week). There was no difference in weight loss or waist
circumference between exercise groups [188]. In another study by Church et al.
[189], 262 people with type 2 diabetes were randomly assigned to a control group,
resistance training, aerobic training, or combined resistance plus aerobic training.
However, as opposed to the previously described DARE study, the amount of exer-
cise in the combined training group was similar to the other two training groups, and
only the combined training protocol was associated with improvements in A1c [189].
[175]. However, the Indian Diabetes Prevention Program (IDPP) trial used a similar
design as the DPP with the addition of a combined metformin and lifestyle modifi-
cation group [194]. Surprisingly, the combined effect was similar to either metfor-
min or lifestyle modification alone (ranging from 26.4% to 28.5% reductions in the
risk of developing diabetes).
In people with type 2 diabetes, there is also evidence to suggest that combina-
tions of metformin and exercise can at times lead to surprising, if not to say disap-
pointing, results. Recently, a study of 6447 people with type 2 diabetes from the
NHANES survey (1999–2018) found that increasing physical activity was associ-
ated with improved A1c in those who were not treated with metformin but not in
those who were. We are not aware of longer-term randomized trials in which partici-
pants with type 2 diabetes were assigned to exercise and/or metformin, but several
short-term studies have confirmed these potential negative interactions [195, 196].
Most of these studies have focused on aerobic exercise. However, in older adults
without diabetes, metformin interfered with resistance training-induced increases in
muscle mass [197]. These findings do not necessarily mean that exercise should not
be prescribed in those treated with metformin or that metformin should not be pre-
scribed to those who exercise. There may be other benefits of combined treatment,
and further studies are needed. However, people treated with metformin should not
be surprised if some of the effects of exercise are less pronounced than anticipated.
General Considerations
As we highlighted in the previous studies in prediabetes (e.g., the DPP and IDPP),
lifestyle interventions that include exercise can play an important role in delaying
diabetes and improving many cardiometabolic risk factors. The evidence on
13 Precision Exercise and Physical Activity for Diabetes 273
combining exercise and metformin is not definitive, but the potential negative inter-
action between the two lends support to the idea that it may be worthwhile delaying
metformin treatment in those who want to attempt to increase physical activity lev-
els. Delaying metformin may be particularly useful in older participants with low
muscle mass given the greater efficacy of lifestyle interventions in older participants
[175] (and the potential for greater reductions in fat-free mass with metformin
[197]). Perhaps once it is determined that increasing physical is difficult to achieve,
metformin could be added.
At the diagnosis of prediabetes or type 2 diabetes, there is evidence that some,
but not all, people can be very receptive to behavior change [199, 200]. However,
this time is characterized by many potential other changes such as diet and medica-
tions. Some patients may prefer making one behavior change at a time to avoid
being overwhelmed. That said, there is also evidence that the barriers to physical
activity can be very different to the barriers to diet changes [201, 202]. Consequently,
there may be times when people with type 2 diabetes are more receptive to some
lifestyle interventions than others.
The questions of the timing of specific bouts of exercise have not received much
attention in type 2 diabetes. In general, it would seem that when circulating glucose
and insulin are elevated, the rate of decline in glucose during exercise can be more
pronounced. For example, exercise performed ~1 hour after a meal leads to a greater
decline in glucose during the exercise bout itself, whereas exercise in the fasted state
would lead to little change [203, 204]. Of note, glucose may have declined in the
former situation even in the absence of exercise as postprandial glucose eventually
declines due to glucoregulatory processes. In addition, differences in the change in
glucose during exercise may not reflect glucose changes over a 24-hour period [205,
206]. For example, in the study by Munan et al. [206], exercise after an overnight
fast led to a lesser acute reduction in glucose compared to afternoon exercise (−0.4
vs −1.5 mmol/L, p = 0.02), but there was no difference over 24 hours (7.5 vs
7.3 mmol/L, p = 0.57). Interestingly, fasting glucose was lower the day after fasting
exercise only (6.8 vs 7.3 mmol/L, p = 0.003) suggesting that the timing of exercise
is an important consideration as it can affect some glycemic outcomes but not others.
On the other hand, Savikj et al. [207] compared HIIE performed either in the
morning or the afternoon in participants with type 2 diabetes and concluded that
afternoon HIIE was more efficacious than morning HIIE at improving blood glu-
cose. Differences between this study and the one by Munan et al. [206] include the
fact that Munan prescribed morning exercise after an overnight fast, whereas Savikj
prescribed exercise after a light breakfast and provided a postexercise snack in the
morning condition only. Indeed, a complete understanding of the effects of exercise
timing is not available and includes the timing in the day, the timing in relation to
meals or medications, as well as the type of exercise or characteristics of
participants.
274 N. G. Boulé and J. E. Yardley
Several recent studies, commentaries, and reviews have suggested that exer-
cise should be performed shortly after meals to cause greater immediate improve-
ments in mean blood glucose levels [208–215]. In spite of this attention, clear
recommendations for post-meal (i.e., postprandial) exercise are not yet endorsed
by Canadian [216] or American [44] physical activity guidelines. However, as we
and others have argued [215, 217], the emphasis on post-meal exercise may come
at a cost. There is growing evidence supporting more favorable long-term adapta-
tions when exercise is performed after an overnight fast, which results in greater
depletion of endogenous energy reserves. For example, a study by Van Proeyen
et al. showed that regular exercise training increased muscle glycogen and
improved mitochondrial function when performed in the fasted state but not
when exercise was performed with carbohydrate supplementation [218]. This is
noteworthy because impairments in glycogen storage [219–221] and mitochon-
drial mass or function [222–224] are linked to insulin resistance and type 2
diabetes.
We have studied exercise in the fasted state in several contexts [157, 203,
225, 226]. For example, we compared the effects of 4 weeks of the same exer-
cise prescription performed after an overnight fast versus after breakfast in
recreational cyclists. We observed greater improvements in aerobic fitness, as
well as lower glucagon and glucose levels when exercise was performed after
fasting overnight [157]. These findings are in line with another study by Van
Proeyen et al. [227] who studied active young men (mean physical activity of
~3.5 hours per week at baseline) and found improvements in oral glucose tol-
erance after 6 weeks of training in the fasted state but not when similar train-
ing was performed after breakfast [227]. However, to date, only two studies
have compared training adaptations to several weeks of training in the fasted
state (pre breakfast) versus postprandial exercise training in type 2 diabetes
[228, 229]. The studies were relatively small and did not show consistently
superior benefits of fasted training, in comparison to training in postpran-
dial state.
Summary
There are many health outcomes that are improved (on average) with regular
physical activity in both type 1 and type 2 diabetes. While most activities can be
performed safely with gradual progression and appropriate adjustments, a great
deal of variability exists in the physiological responses to exercise and physical
activity. There is also a great deal of variability in exercise and physical activity
preferences among individuals with diabetes. An effort should be made to tailor
recommendations to individual needs (Fig. 13.1) in order to optimize the use of
this “treatment” to improve the health and quality of life of individuals with
diabetes.
13 Precision Exercise and Physical Activity for Diabetes 275
THE RIGHT
EXERCISE
PRESCRIPTION
THE RIGHT PATIENT
THE RIGHT TIMING
- Age, sex, fitness
-Disease progression
-Body composition
-Time of day
-Co-interventions
-Timing meals of medications
Fig. 13.1 Precision medicine considerations for exercise/physical activity in diabetes mellitus
References
27. Rigla M, Sanchez-Quesada JL, Ordonez-Llanos J, Prat T, Caixas A, Jorba O, et al. Effect of
physical exercise on lipoprotein(a) and low-density lipoprotein modifications in type 1 and
type 2 diabetic patients. Metabolism. 2000;49(5):640–7.
28. de Moraes R, Van Bavel D, Gomes MB, Tibirica E. Effects of non-supervised low intensity
aerobic excise training on the microvascular endothelial function of patients with type 1 dia-
betes: a non-pharmacological interventional study. BMC Cardiovasc Disord. 2016;16:23.
29. Boff W, da Silva AM, Farinha JB, Rodrigues-Krause J, Reischak-Oliveira A, Tschiedel B,
et al. Superior effects of high-intensity interval vs. moderate-intensity continuous training on
endothelial function and cardiorespiratory fitness in patients with type 1 diabetes: a random-
ized controlled trial. Front Physiol. 2019;10:450.
30. Wrobel M, Rokicka D, Czuba M, Golas A, Pyka L, Greif M, et al. Aerobic as well as
resistance exercises are good for patients with type 1 diabetes. Diabetes Res Clin Pract.
2018;144:93–101.
31. Wallberg-Henriksson H, Gunnarsson R, Henriksson J, DeFronzo R, Felig P, Ostman
J, et al. Increased peripheral insulin sensitivity and muscle mitochondrial enzymes but
unchanged blood glucose control in type I diabetics after physical training. Diabetes.
1982;31(12):1044–50.
32. Ramalho AC, de Lourdes Lima M, Nunes F, Cambui Z, Barbosa C, Andrade A, et al. The
effect of resistance versus aerobic training on metabolic control in patients with type-1 diabe-
tes mellitus. Diabetes Res Clin Pract. 2006;72(3):271–6.
33. Maggio AB, Rizzoli RR, Marchand LM, Ferrari S, Beghetti M, Farpour-Lambert NJ. Physical
activity increases bone mineral density in children with type 1 diabetes. Med Sci Sports
Exerc. 2012;44(7):1206–11.
34. Farinha JB, Ramis TR, Vieira AF, Macedo RCO, Rodrigues-Krause J, Boeno FP, et al.
Glycemic, inflammatory and oxidative stress responses to different high-intensity train-
ing protocols in type 1 diabetes: a randomized clinical trial. J Diabetes Complicat.
2018;32(12):1124–32.
35. Durak EP, Jovanovic-Peterson L, Peterson CM. Randomized crossover study of effect of
resistance training on glycemic control, muscular strength, and cholesterol in type I diabetic
men. Diabetes Care. 1990;13(10):1039–43.
36. D’Hooge R, Hellinckx T, Van Laethem C, Stegen S, De Schepper J, Van Aken S, et al.
Influence of combined aerobic and resistance training on metabolic control, cardiovascular
fitness and quality of life in adolescents with type 1 diabetes: a randomized controlled trial.
Clin Rehabil. 2011;25(4):349–59.
37. Mosher PE, Nash MS, Perry AC, LaPerriere AR, Goldberg RB. Aerobic circuit exercise train-
ing: effect on adolescents with well-controlled insulin-dependent diabetes mellitus. Arch
Phys Med Rehabil. 1998;79(6):652–7.
38. Scott SN, Cocks M, Andrews RC, Narendran P, Purewal TS, Cuthbertson DJ, et al. High-
intensity interval training improves aerobic capacity without a detrimental decline in blood
glucose in people with type 1 diabetes. J Clin Endocrinol Metab. 2019;104(2):604–12.
39. Alarcon-Gomez J, Calatayud J, Chulvi-Medrano I, Martin-Rivera F. Effects of a HIIT proto-
col on cardiovascular risk factors in a type 1 diabetes mellitus population. Int J Environ Res
Public Health. 2021;18(3):1262.
40. Plotnikoff RC, Taylor LM, Wilson PM, Courneya KS, Sigal RJ, Birkett N, et al. Factors
associated with physical activity in Canadian adults with diabetes. Med Sci Sports Exerc.
2006;38(8):1526–34.
41. Valerio G, Spagnuolo MI, Lombardi F, Spadaro R, Siano M, Franzese A. Physical activity
and sports participation in children and adolescents with type 1 diabetes mellitus. Nutr Metab
Cardiovasc Dis. 2007;17(5):376–82.
42. Brazeau AS, Rabasa-Lhoret R, Strychar I, Mircescu H. Barriers to physical activity among
patients with type 1 diabetes. Diabetes Care. 2008;31(11):2108–9.
43. Yardley JE, Brockman NK, Bracken RM. Could age, sex and physical fitness affect blood
glucose responses to exercise in type 1 diabetes? Front Endocrinol (Lausanne). 2018;9:674.
278 N. G. Boulé and J. E. Yardley
44. Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Physical
activity/exercise and diabetes: a position statement of the American Diabetes Association.
Diabetes Care. 2016;39(11):2065–79.
45. Riddell MC, Gallen IW, Smart CE, Taplin CE, Adolfsson P, Lumb AN, et al. Exercise
management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol.
2017;5(5):377–90.
46. Rodbard HW, Rodbard D. Biosynthetic human insulin and insulin analogs. Am J Ther.
2020;27(1):e42–51.
47. Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, et al. Regulation of
endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration.
Am J Phys. 1993;265(3 Pt 1):E380–91.
48. Jarhult J, Holst J. The role of the adrenergic innervation to the pancreatic islets in the control
of insulin release during exercise in man. Pflugers Arch. 1979;383(1):41–5.
49. Hedeskov CJ. Mechanism of glucose-induced insulin secretion. Physiol Rev.
1980;60(2):442–509.
50. Ferrannini E, Linde B, Faber O. Effect of bicycle exercise on insulin absorption and subcuta-
neous blood flow in the normal subject. Clin Physiol. 1982;2(1):59–70.
51. McAuley SA, Horsburgh JC, Ward GM, La Gerche A, Gooley JL, Jenkins AJ, et al. Insulin
pump basal adjustment for exercise in type 1 diabetes: a randomised crossover study.
Diabetologia. 2016;59(8):1636–44.
52. Ronnemaa T, Koivisto VA. Combined effect of exercise and ambient temperature on insulin
absorption and postprandial glycemia in type I patients. Diabetes Care. 1988;11(10):769–73.
53. Thow JC, Johnson AB, Antsiferov M, Home PD. Exercise augments the absorption of iso-
phane (NPH) insulin. Diabet Med. 1989;6(4):342–5.
54. Yardley JE, Kenny GP, Perkins BA, Riddell MC, Balaa N, Malcolm J, et al. Resistance
versus aerobic exercise: acute effects on glycemia in type 1 diabetes. Diabetes Care.
2013;36(3):537–42.
55. Zaharieva D, Yavelberg L, Jamnik V, Cinar A, Turksoy K, Riddell MC. The effects of basal
insulin suspension at the start of exercise on blood glucose levels during continuous versus
circuit-based exercise in individuals with type 1 diabetes on continuous subcutaneous insulin
infusion. Diabetes Technol Ther. 2017;19(6):370–8.
56. McMahon SK, Ferreira LD, Ratnam N, Davey RJ, Youngs LM, Davis EA, et al. Glucose
requirements to maintain euglycemia after moderate-intensity afternoon exercise in adoles-
cents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab.
2007;92(3):963–8.
57. Mitchell TH, Abraham G, Schiffrin A, Leiter LA, Marliss EB. Hyperglycemia after intense
exercise in IDDM subjects during continuous subcutaneous insulin infusion. Diabetes Care.
1988;11(4):311–7.
58. Purdon C, Brousson M, Nyveen SL, Miles PD, Halter JB, Vranic M, et al. The roles of
insulin and catecholamines in the glucoregulatory response during intense exercise and
early recovery in insulin-dependent diabetic and control subjects. J Clin Endocrinol Metab.
1993;76(3):566–73.
59. Sigal RJ, Purdon C, Fisher SJ, Halter JB, Vranic M, Marliss EB. Hyperinsulinemia prevents
prolonged hyperglycemia after intense exercise in insulin-dependent diabetic subjects. J Clin
Endocrinol Metab. 1994;79(4):1049–57.
60. Turner D, Gray BJ, Luzio S, Dunseath G, Bain SC, Hanley S, et al. Similar magnitude of
post-exercise hyperglycemia despite manipulating resistance exercise intensity in type 1 dia-
betes individuals. Scand J Med Sci Sports. 2016;26(4):404–12.
61. Campbell MD, West DJ, Bain SC, Kingsley MI, Foley P, Kilduff L, et al. Simulated games
activity vs continuous running exercise: a novel comparison of the glycemic and metabolic
responses in T1DM patients. Scand J Med Sci Sports. 2015;25(2):216–22.
13 Precision Exercise and Physical Activity for Diabetes 279
62. Guelfi KJ, Jones TW, Fournier PA. The decline in blood glucose levels is less with inter-
mittent high-intensity compared with moderate exercise in individuals with type 1 diabetes.
Diabetes Care. 2005;28(6):1289–94.
63. Moser O, Tschakert G, Mueller A, Groeschl W, Pieber TR, Obermayer-Pietsch B, et al.
Effects of high-intensity interval exercise versus moderate continuous exercise on glucose
homeostasis and hormone response in patients with type 1 diabetes mellitus using novel
ultra-Long-acting insulin. PLoS One. 2015;10(8):e0136489.
64. Sigal RJ, Fisher SJ, Halter JB, Vranic M, Marliss EB. Glucoregulation during and after
intense exercise: effects of beta-adrenergic blockade in subjects with type 1 diabetes mel-
litus. J Clin Endocrinol Metab. 1999;84(11):3961–71.
65. Maran A, Pavan P, Bonsembiante B, Brugin E, Ermolao A, Avogaro A, et al. Continuous
glucose monitoring reveals delayed nocturnal hypoglycemia after intermittent high-
intensity exercise in nontrained patients with type 1 diabetes. Diabetes Technol Ther.
2010;12(10):763–8.
66. Rempel M, Yardley JE, MacIntosh A, Hay JL, Bouchard D, Cornish S, et al. Vigorous
intervals and hypoglycemia in type 1 diabetes: a randomized cross over trial. Sci Rep.
2018;8(1):15879.
67. Yardley JE, Kenny GP, Perkins BA, Riddell MC, Malcolm J, Boulay P, et al. Effects of
performing resistance exercise before versus after aerobic exercise on glycemia in type 1
diabetes. Diabetes Care. 2012;35(4):669–75.
68. Bussau VA, Ferreira LD, Jones TW, Fournier PA. The 10-s maximal sprint: a novel approach
to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Diabetes
Care. 2006;29(3):601–6.
69. Kesavadev J, Saboo B, Krishna MB, Krishnan G. Evolution of insulin delivery devices: from
syringes, pens, and pumps to DIY artificial pancreas. Diabetes Ther. 2020;11(6):1251–69.
70. Cengiz E. Automated insulin delivery in children with type 1 diabetes. Endocrinol Metab
Clin N Am. 2020;49(1):157–66.
71. Yardley JE, Iscoe KE, Sigal RJ, Kenny GP, Perkins BA, Riddell MC. Insulin pump ther-
apy is associated with less post-exercise hyperglycemia than multiple daily injections: an
observational study of physically active type 1 diabetes patients. Diabetes Technol Ther.
2013;15(1):84–8.
72. Roy-Fleming A, Taleb N, Messier V, Suppere C, Cameli C, Elbekri S, et al. Timing of insulin
basal rate reduction to reduce hypoglycemia during late post-prandial exercise in adults with
type 1 diabetes using insulin pump therapy: a randomized crossover trial. Diabetes Metab.
2019;45(3):294–300.
73. Aronson R, Li A, Brown RE, McGaugh S, Riddell MC. Flexible insulin therapy with a hybrid
regimen of insulin degludec and continuous subcutaneous insulin infusion with pump sus-
pension before exercise in physically active adults with type 1 diabetes (FIT untethered):
a single-Centre, open-label, proof-of-concept, randomised crossover trial. Lancet Diabetes
Endocrinol. 2020;8(6):511–23.
74. Boughton CK, Hovorka R. Automated insulin delivery in adults. Endocrinol Metab Clin N
Am. 2020;49(1):167–78.
75. Zaharieva DP, Messer LH, Paldus B, O'Neal DN, Maahs DM, Riddell MC. Glucose control
during physical activity and exercise using closed loop technology in adults and adolescents
with type 1 diabetes. Can J Diabetes. 2020;44(8):740–9.
76. Jacobs PG, El Youssef J, Reddy R, Resalat N, Branigan D, Condon J, et al. Randomized
trial of a dual-hormone artificial pancreas with dosing adjustment during exercise com-
pared with no adjustment and sensor-augmented pump therapy. Diabetes Obes Metab.
2016;18(11):1110–9.
77. Taleb N, Emami A, Suppere C, Messier V, Legault L, Ladouceur M, et al. Efficacy of single-
hormone and dual-hormone artificial pancreas during continuous and interval exercise in
adult patients with type 1 diabetes: randomised controlled crossover trial. Diabetologia.
2016;59(12):2561–71.
280 N. G. Boulé and J. E. Yardley
78. Haidar A, Rabasa-Lhoret R, Legault L, Lovblom LE, Rakheja R, Messier V, et al. Single-
and dual-hormone artificial pancreas for overnight glucose control in type 1 diabetes. J Clin
Endocrinol Metab. 2016;101(1):214–23.
79. Castle JR, El Youssef J, Wilson LM, Reddy R, Resalat N, Branigan D, et al. Randomized
outpatient trial of single- and dual-hormone closed-loop systems that adapt to exercise using
wearable sensors. Diabetes Care. 2018;41(7):1471–7.
80. Yardley JE, Rees JL, Funk DR, Toghi-Eshghi SR, Boule NG, Senior PA. Effects of moderate
cycling exercise on blood glucose regulation following successful clinical islet transplanta-
tion. J Clin Endocrinol Metab. 2019;104(2):493–502.
81. Senior P, Lam A, Farnsworth K, Perkins B, Rabasa-Lhoret R. Assessment of risks and ben-
efits of beta cell replacement versus automated insulin delivery systems for type 1 diabetes.
Curr Diab Rep. 2020;20(10):52.
82. Zaharieva DP, Turksoy K, McGaugh SM, Pooni R, Vienneau T, Ly T, et al. Lag time remains
with newer real-time continuous glucose monitoring technology during aerobic exercise in
adults living with type 1 diabetes. Diabetes Technol Ther. 2019;21(6):313–21.
83. Larose S, Rabasa-Lhoret R, Roy-Fleming A, Suppere C, Tagougui S, Messier V, et al.
Changes in accuracy of continuous glucose monitoring using Dexcom G4 platinum over
the course of moderate intensity aerobic exercise in type 1 diabetes. Diabetes Technol Ther.
2019;21(6):364–9.
84. Biagi L, Bertachi A, Quiros C, Gimenez M, Conget I, Bondia J, et al. Accuracy of continuous
glucose monitoring before, during, and after aerobic and anaerobic exercise in patients with
type 1 diabetes mellitus. Biosensors (Basel). 2018;8(1).
85. Taleb N, Emami A, Suppere C, Messier V, Legault L, Chiasson JL, et al. Comparison of two
continuous glucose monitoring systems, Dexcom G4 platinum and Medtronic paradigm Veo
Enlite system, at rest and during exercise. Diabetes Technol Ther. 2016;18(9):561–7.
86. Moser O, Eckstein ML, McCarthy O, Deere R, Pitt J, Williams DM, et al. Performance of
the freestyle libre flash glucose monitoring (flash GM) system in individuals with type 1 dia-
betes: a secondary outcome analysis of a randomized crossover trial. Diabetes Obes Metab.
2019;21(11):2505–12.
87. Fokkert M, van Dijk PR, Edens MA, Diez Hernandez A, Slingerland R, Gans R, et al.
Performance of the Eversense versus the free style libre flash glucose monitor during exercise
and normal daily activities in subjects with type 1 diabetes mellitus. BMJ Open Diabetes Res
Care. 2020;8(1):e001193.
88. Guillot FH, Jacobs PG, Wilson LM, Youssef JE, Gabo VB, Branigan DL, et al. Accuracy of
the Dexcom G6 glucose sensor during aerobic, resistance, and interval exercise in adults with
type 1 diabetes. Biosensors (Basel). 2020;10(10):138.
89. Moser O, Yardley JE, Bracken RM. Interstitial glucose and physical exercise in type 1 diabe-
tes: integrative physiology, technology, and the gap in-between. Nutrients. 2018;10(1):93.
90. Moser O, Riddell MC, Eckstein ML, Adolfsson P, Rabasa-Lhoret R, van den Boom L, et al.
Glucose management for exercise using continuous glucose monitoring (CGM) and intermit-
tently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European
Association for the Study of Diabetes (EASD) and of the International Society for Pediatric
and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American
Diabetes Association (ADA). Pediatr Diabetes. 2020;63:2501–20.
91. Brockman NK, Sigal RJ, Kenny GP, Riddell MC, Perkins BA, Yardley JE. Sex-related dif-
ferences in blood glucose responses to resistance exercise in adults with type 1 diabetes: a
secondary data analysis. Can J Diabetes. 2020;44(3):267–73 e1.
92. Al Khalifah RA, Suppere C, Haidar A, Rabasa-Lhoret R, Ladouceur M, Legault L. Association
of aerobic fitness level with exercise-induced hypoglycaemia in type 1 diabetes. Diabet Med.
2016;33(12):1686–90.
93. Tagougui S, Goulet-Gelinas L, Taleb N, Messier V, Suppere C, Rabasa-Lhoret R. Association
between body composition and blood glucose during exercise and recovery in adolescent and
adult patients with type 1 diabetes. Can J Diabetes. 2020;44(2):192–5.
13 Precision Exercise and Physical Activity for Diabetes 281
94. Barata DS, Adan LF, Netto EM, Ramalho AC. The effect of the menstrual cycle on glucose
control in women with type 1 diabetes evaluated using a continuous glucose monitoring sys-
tem. Diabetes Care. 2013;36(5):e70.
95. Widom B, Diamond MP, Simonson DC. Alterations in glucose metabolism during menstrual
cycle in women with IDDM. Diabetes Care. 1992;15(2):213–20.
96. Trout KK, Rickels MR, Schutta MH, Petrova M, Freeman EW, Tkacs NC, et al. Menstrual
cycle effects on insulin sensitivity in women with type 1 diabetes: a pilot study. Diabetes
Technol Ther. 2007;9(2):176–82.
97. Goldner WS, Kraus VL, Sivitz WI, Hunter SK, Dillon JS. Cyclic changes in glycemia
assessed by continuous glucose monitoring system during multiple complete menstrual
cycles in women with type 1 diabetes. Diabetes Technol Ther. 2004;6(4):473–80.
98. Brown SA, Jiang B, McElwee-Malloy M, Wakeman C, Breton MD. Fluctuations of
Hyperglycemia and insulin sensitivity are linked to menstrual cycle phases in women with
T1D. J Diabetes Sci Technol. 2015;9(6):1192–9.
99. Sacerdote A, Bleicher SJ. Oral contraceptives abolish luteal phase exacerbation of hypergly-
cemia in type I diabetes. Diabetes Care. 1982;5(6):651–2.
100. Lunt H, Brown LJ. Self-reported changes in capillary glucose and insulin requirements dur-
ing the menstrual cycle. Diabetic Med. 1996;13(6):525–30.
101. Riddell MC, Scott SN, Fournier PA, Colberg SR, Gallen IW, Moser O, et al. The competitive
athlete with type 1 diabetes. Diabetologia. 2020;63(8):1475–90.
102. Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, et al. Insulitis
and beta-cell mass in the natural history of type 1 diabetes. Diabetes. 2016;65(3):719–31.
103. Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of
diabetes-related complications in the diabetes control and complications trial. Diabetes Care.
2003;26(3):832–6.
104. Skyler JS. Prevention and reversal of type 1 diabetes–past challenges and future opportuni-
ties. Diabetes Care. 2015;38(6):997–1007.
105. Chetan MR, Charlton MH, Thompson C, Dias RP, Andrews RC, Narendran P. The type 1
diabetes ‘honeymoon’ period is five times longer in men who exercise: a case-control study.
Diabet Med. 2019;36(1):127–8.
106. Narendran P, Jackson N, Daley A, Thompson D, Stokes K, Greenfield S, et al. Exercise to
preserve beta-cell function in recent-onset type 1 diabetes mellitus (EXTOD) – a randomized
controlled pilot trial. Diabet Med. 2017;34(11):1521–31.
107. Matson RIB, Leary SD, Cooper AR, Thompson C, Narendran P, Andrews RC. Objective
measurement of physical activity in adults with newly diagnosed type 1 diabetes and healthy
individuals. Front Public Health. 2018;6:360.
108. American Academic of Pediatrics, American Public Health Association, Education
NRCfHaSiCCaE. Caring for our children: national health and safety performance stan-
dards; Guidelines for early care and education programs. 3rd ed. Washington, DC: American
Academy of Pediatrics; 2011.
109. Quirk H, Blake H, Tennyson R, Randell TL, Glazebrook C. Physical activity interventions
in children and young people with type 1 diabetes mellitus: a systematic review with meta-
analysis. Diabet Med. 2014;31(10):1163–73.
110. MacMillan F, Kirk A, Mutrie N, Matthews L, Robertson K, Saunders DH. A systematic review
of physical activity and sedentary behavior intervention studies in youth with type 1 diabetes:
study characteristics, intervention design, and efficacy. Pediatr Diabetes. 2014;15(3):175–89.
111. Ahn S, Fedewa AL. A meta-analysis of the relationship between children’s physical activity
and mental health. J Pediatr Psychol. 2011;36(4):385–97.
112. Larun L, Nordheim LV, Ekeland E, Hagen KB, Heian F. Exercise in prevention and treatment
of anxiety and depression among children and young people. Cochrane Database Syst Rev.
2006;3:CD004691.
282 N. G. Boulé and J. E. Yardley
132. Ruegemer JJ, Squires RW, Marsh HM, Haymond MW, Cryer PE, Rizza RA, et al. Differences
between prebreakfast and late afternoon glycemic responses to exercise in IDDM patients.
Diabetes Care. 1990;13(2):104–10.
133. Yamanouchi K, Abe R, Takeda A, Atsumi Y, Shichiri M, Sato Y. The effect of walking before
and after breakfast on blood glucose levels in patients with type 1 diabetes treated with inten-
sive insulin therapy. Diabetes Res Clin Pract. 2002;58(1):11–8.
134. Yardley JE. Fasting may alter blood glucose responses to high intensity interval exer-
cise in adults with type 1 diabetes: a randomized acute crossover study. Can J Diabetes.
2020;44(8):727–33.
135. Toghi-Eshghi SR, Yardley JE. Morning (fasting) vs afternoon resistance exercise in indi-
viduals with type 1 diabetes: a randomized crossover study. J Clin Endocrinol Metab.
2019;104(11):5217–24.
136. Yardley JE, Sigal RJ, Riddell MC, Perkins BA, Kenny GP. Performing resistance exercise
before versus after aerobic exercise influences growth hormone secretion in type 1 diabetes.
Appl Physiol Nutr Metab. 2014;39(2):262–5.
137. Vendelbo MH, Christensen B, Gronbaek SB, Hogild M, Madsen M, Pedersen SB, et al. GH
signaling in human adipose and muscle tissue during ‘feast and famine’: amplification of
exercise stimulation following fasting compared to glucose administration. Eur J Endocrinol.
2015;173(3):283–90.
138. Vieira AF, Costa RR, Macedo RC, Coconcelli L, Kruel LF. Effects of aerobic exercise per-
formed in fasted v. fed state on fat and carbohydrate metabolism in adults: a systematic
review and meta-analysis. Br J Nutr. 2016;116(7):1153–64.
139. Gomez AM, Gomez C, Aschner P, Veloza A, Munoz O, Rubio C, et al. Effects of perform-
ing morning versus afternoon exercise on glycemic control and hypoglycemia frequency in
type 1 diabetes patients on sensor-augmented insulin pump therapy. J Diabetes Sci Technol.
2015;9(3):619–24.
140. Campbell MD, Walker M, Trenell MI, Stevenson EJ, Turner D, Bracken RM, et al. A low-
glycemic index meal and bedtime snack prevents postprandial hyperglycemia and associated
rises in inflammatory markers, providing protection from early but not late nocturnal hypo-
glycemia following evening exercise in type 1 diabetes. Diabetes Care. 2014;37(7):1845–53.
141. Campbell MD, Walker M, Bracken RM, Turner D, Stevenson EJ, Gonzalez JT, et al. Insulin
therapy and dietary adjustments to normalize glycemia and prevent nocturnal hypoglycemia
after evening exercise in type 1 diabetes: a randomized controlled trial. BMJ Open Diabetes
Res Care. 2015;3(1):e000085.
142. West DJ, Stephens JW, Bain SC, Kilduff LP, Luzio S, Still R, et al. A combined insulin reduc-
tion and carbohydrate feeding strategy 30 min before running best preserves blood glucose
concentration after exercise through improved fuel oxidation in type 1 diabetes mellitus. J
Sports Sci. 2011;29(3):279–89.
143. Ahlqvist E, Storm P, Karajamaki A, Martinell M, Dorkhan M, Carlsson A, et al. Novel sub-
groups of adult-onset diabetes and their association with outcomes: a data-driven cluster
analysis of six variables. Lancet Diabetes Endocrinol. 2018;6(5):361–9.
144. Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic con-
trol and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials.
JAMA. 2001;286(10):1218–27.
145. Umpierre D, Ribeiro PA, Kramer CK, Leitao CB, Zucatti AT, Azevedo MJ, et al. Physical
activity advice only or structured exercise training and association with HbA1c levels in type
2 diabetes: a systematic review and meta-analysis. JAMA. 2011;305(17):1790–9.
146. Snowling NJ, Hopkins WG. Effects of different modes of exercise training on glucose control
and risk factors for complications in type 2 diabetic patients: a meta-analysis. Diabetes Care.
2006;29(11):2518–27.
147. Pan B, Ge L, Xun YQ, Chen YJ, Gao CY, Han X, et al. Exercise training modalities in patients
with type 2 diabetes mellitus: a systematic review and network meta-analysis. Int J Behav
Nutr Phys Act. 2018;15(1):72.
284 N. G. Boulé and J. E. Yardley
148. Liubaoerjijin Y, Terada T, Fletcher K, Boule NG. Effect of aerobic exercise intensity on gly-
cemic control in type 2 diabetes: a meta-analysis of head-to-head randomized trials. Acta
Diabetol. 2016;53(5):769–81.
149. Forbes CC, Plotnikoff RC, Courneya KS, Boule NG. Physical activity preferences and type
2 diabetes: exploring demographic, cognitive, and behavioral differences. Diabetes Educ.
2010;36(5):801–15.
150. Rees JL, Johnson ST, Boule NG. Aquatic exercise for adults with type 2 diabetes: a meta-
analysis. Acta Diabetol. 2017;54(10):895–904.
151. Sigal RJ, Kenny GP, Boule NG, Wells GA, Prud’homme D, Fortier M, et al. Effects of aero-
bic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized
trial. Ann Intern Med. 2007;147(6):357–69.
152. Sigal RJ, Armstrong MJ, Bacon SL, Boule NG, Dasgupta K, Kenny GP, et al. Physical activ-
ity and diabetes. Can J Diabetes. 2018;42(Suppl 1):S54–63.
153. Terada T, Boule NG, Forhan M, Prado CM, Kenny GP, Prud’homme D, et al. Cardiometabolic
risk factors in type 2 diabetes with high fat and low muscle mass: at baseline and in response
to exercise. Obesity (Silver Spring). 2017;25(5):881–91.
154. Sigal RJ, Armstrong JA, Fowles JR, Kenny GP, McGinley SK, Dineen T, et al. Resistance
bands training improved strength and glycemic control: the DARE-bands trial. Can J
Diabetes. 2018;42(5 Suppl):S11.
155. McGinley SK, Armstrong MJ, Boule NG, Sigal RJ. Effects of exercise training using resis-
tance bands on glycaemic control and strength in type 2 diabetes mellitus: a meta-analysis of
randomised controlled trials. Acta Diabetol. 2015;52(2):221–30.
156. Jelleyman C, Yates T, O’Donovan G, Gray LJ, King JA, Khunti K, et al. The effects of high-
intensity interval training on glucose regulation and insulin resistance: a meta-analysis. Obes
Rev. 2015;16(11):942–61.
157. Terada T, Toghi Eshghi SR, Liubaoerjijin Y, Kennedy M, Myette-Cote E, Fletcher K,
et al. Overnight fasting compromises exercise intensity and volume during sprint inter-
val training but improves high-intensity aerobic endurance. J Sports Med Phys Fitness.
2019;59(3):357–65.
158. Rodgers WM, Blanchard CM, Sullivan MJ, Bell GJ, Wilson PM, Gesell JG. The motivational
implications of characteristics of exercise bouts. J Health Psychol. 2002;7(1):73–83.
159. Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN. Low cardiorespiratory fitness
and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern
Med. 2000;132(8):605–11.
160. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and
mortality among men referred for exercise testing. N Engl J Med. 2002;346(11):793–801.
161. Loh R, Stamatakis E, Folkerts D, Allgrove JE, Moir HJ. Effects of interrupting prolonged
sitting with physical activity breaks on blood glucose, insulin and triacylglycerol measures: a
systematic review and meta-analysis. Sports Med. 2020;50(2):295–330.
162. Duvivier BM, Schaper NC, Hesselink MK, van Kan L, Stienen N, Winkens B, et al. Breaking
sitting with light activities vs structured exercise: a randomised crossover study demonstrat-
ing benefits for glycaemic control and insulin sensitivity in type 2 diabetes. Diabetologia.
2017;60(3):490–8.
163. Blankenship JM, Chipkin SR, Freedson PS, Staudenmayer J, Lyden K, Braun B. Managing
free-living hyperglycemia with exercise or interrupted sitting in type 2 diabetes. J Appl
Physiol (1985). 2019;126(3):616–25.
164. van der Berg JD, Stehouwer CD, Bosma H, van der Velde JH, Willems PJ, Savelberg HH,
et al. Associations of total amount and patterns of sedentary behaviour with type 2 diabetes
and the metabolic syndrome: the Maastricht study. Diabetologia. 2016;59(4):709–18.
165. Sardinha LB, Magalhaes JP, Santos DA, Judice PB. Sedentary patterns, physical activity, and
cardiorespiratory fitness in association to Glycemic control in type 2 diabetes patients. Front
Physiol. 2017;8:262.
13 Precision Exercise and Physical Activity for Diabetes 285
166. Bancks MP, Chen H, Balasubramanyam A, Bertoni AG, Espeland MA, Kahn SE, et al. Type
2 diabetes subgroups, risk for complications, and differential effects due to an intensive life-
style intervention. Diabetes Care. 2021;44(5):1203–10.
167. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, et al.
Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med.
2013;369(2):145–54.
168. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm
for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–95.
169. Nanayakkara N, Curtis AJ, Heritier S, Gadowski AM, Pavkov ME, Kenealy T, et al. Impact of
age at type 2 diabetes mellitus diagnosis on mortality and vascular complications: systematic
review and meta-analyses. Diabetologia. 2021;64(2):275–87.
170. Lu J, Guo M, Wang H, Pan H, Wang L, Yu X, et al. Association between pancreatic atrophy
and loss of insulin secretory capacity in patients with type 2 diabetes mellitus. J Diabetes Res.
2019;2019:6371231.
171. Zangeneh F, Arora PS, Dyck PJ, Bekris L, Lernmark A, Achenbach SJ, et al. Effects of dura-
tion of type 2 diabetes mellitus on insulin secretion. Endocr Pract. 2006;12(4):388–93.
172. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and
effects of different treatment modalities. Diabetes Care. 2005;28(12):2948–61.
173. Wing RR, Hamman RF, Bray GA, Delahanty L, Edelstein SL, Hill JO, et al. Achieving
weight and activity goals among diabetes prevention program lifestyle participants. Obes
Res. 2004;12(9):1426–34.
174. Diabetes Prevention Program Research Group, Crandall J, Schade D, Ma Y, Fujimoto WY,
Barrett-Connor E, et al. The influence of age on the effects of lifestyle modification and met-
formin in prevention of diabetes. J Gerontol A Biol Sci Med Sci. 2006;61(10):1075–81.
175. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl
J Med. 2002;346(6):393–403.
176. Bullard KM, Cowie CC, Lessem SE, Saydah SH, Menke A, Geiss LS, et al. Prevalence of
diagnosed diabetes in adults by diabetes type – United States, 2016. MMWR Morb Mortal
Wkly Rep. 2018;67(12):359–61.
177. Cowie CC, Casagrande SS, Geiss LS. Prevalence and incidence of type 2 diabetes and pre-
diabetes. In: Cowie CC, Casagrande SS, Menke A, Cissell MA, Eberhardt MS, et al. editors.
Diabetes in america. Bethesda: national institute of diabetes and digestive and kidney diseases
(US). 2018.
178. Boule NG, Weisnagel SJ, Lakka TA, Tremblay A, Bergman RN, Rankinen T, et al. Effects
of exercise training on glucose homeostasis: the HERITAGE Family Study. Diabetes Care.
2005;28(1):108–14.
179. Tramunt B, Smati S, Grandgeorge N, Lenfant F, Arnal JF, Montagner A, et al. Sex differences
in metabolic regulation and diabetes susceptibility. Diabetologia. 2020;63(3):453–61.
180. Perreault L, Ma Y, Dagogo-Jack S, Horton E, Marrero D, Crandall J, et al. Sex differences
in diabetes risk and the effect of intensive lifestyle modification in the Diabetes Prevention
Program. Diabetes Care. 2008;31(7):1416–21.
181. Kim TN, Park MS, Yang SJ, Yoo HJ, Kang HJ, Song W, et al. Prevalence and determinant
factors of sarcopenia in patients with type 2 diabetes: the Korean Sarcopenic Obesity Study
(KSOS). Diabetes Care. 2010;33(7):1497–9.
182. Scott D, de Courten B, Ebeling PR. Sarcopenia: a potential cause and consequence of type 2
diabetes in Australia’s ageing population? Med J Aust. 2016;205(7):329–33.
183. Tanaka K, Kanazawa I, Sugimoto T. Reduction in endogenous insulin secretion is a risk fac-
tor of sarcopenia in men with type 2 diabetes mellitus. Calcif Tissue Int. 2015;97(4):385–90.
184. Vissers D, Hens W, Taeymans J, Baeyens JP, Poortmans J, Van Gaal L. The effect of exercise
on visceral adipose tissue in overweight adults: a systematic review and meta-analysis. PLoS
One. 2013;8(2):e56415.
286 N. G. Boulé and J. E. Yardley
185. Ismail I, Keating SE, Baker MK, Johnson NA. A systematic review and meta-analysis of the
effect of aerobic vs. resistance exercise training on visceral fat. Obes Rev. 2012;13(1):68–91.
186. Kay SJ, Fiatarone Singh MA. The influence of physical activity on abdominal fat: a system-
atic review of the literature. Obes Rev. 2006;7(2):183–200.
187. Davidson LE, Hudson R, Kilpatrick K, Kuk JL, McMillan K, Janiszewski PM, et al. Effects
of exercise modality on insulin resistance and functional limitation in older adults: a random-
ized controlled trial. Arch Intern Med. 2009;169(2):122–31.
188. Church TS, Earnest CP, Skinner JS, Blair SN. Effects of different doses of physical activity
on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women
with elevated blood pressure: a randomized controlled trial. JAMA. 2007;297(19):2081–91.
189. Church TS, Blair SN, Cocreham S, Johannsen N, Johnson W, Kramer K, et al. Effects of
aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a
randomized controlled trial. JAMA. 2010;304(20):2253–62.
190. Nabuco HC, Tomeleri CM, Junior PS, Fernandes RR, Cavalcante EF, Nunes JP, et al. Effects
of higher habitual protein intake on resistance-training-induced changes in body composi-
tion and muscular strength in untrained older women: a clinical trial study. Nutr Health.
2019;25(2):103–12.
191. Memelink RG, Pasman WJ, Bongers A, Tump A, van Ginkel A, Tromp W, et al. Effect of
an enriched protein drink on muscle mass and Glycemic control during combined lifestyle
intervention in older adults with obesity and type 2 diabetes: a double-blind RCT. Nutrients.
2020;13(1):64.
192. Wycherley TP, Noakes M, Clifton PM, Cleanthous X, Keogh JB, Brinkworth GD. A high-
protein diet with resistance exercise training improves weight loss and body composition in
overweight and obese patients with type 2 diabetes. Diabetes Care. 2010;33(5):969–76.
193. Esmarck B, Andersen JL, Olsen S, Richter EA, Mizuno M, Kjaer M. Timing of postexercise
protein intake is important for muscle hypertrophy with resistance training in elderly humans.
J Physiol. 2001;535(Pt 1):301–11.
194. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V, et al. The Indian
Diabetes Prevention programme shows that lifestyle modification and metformin prevent type
2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia.
2006;49(2):289–97.
195. Boule NG, Robert C, Bell GJ, Johnson ST, Bell RC, Lewanczuk RZ, et al. Metformin and
exercise in type 2 diabetes: examining treatment modality interactions. Diabetes Care.
2011;34(7):1469–74.
196. Sharoff CG, Hagobian TA, Malin SK, Chipkin SR, Yu H, Hirshman MF, et al. Combining
short-term metformin treatment and one bout of exercise does not increase insulin action in
insulin-resistant individuals. Am J Physiol Endocrinol Metab. 2010;298(4):E815–23.
197. Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, et al. Metformin blunts
muscle hypertrophy in response to progressive resistance exercise training in older adults: a
randomized, double-blind, placebo-controlled, multicenter trial: the MASTERS trial. Aging
Cell. 2019;18(6):e13039.
198. Goodpaster BH, Delany JP, Otto AD, Kuller L, Vockley J, South-Paul JE, et al. Effects of diet
and physical activity interventions on weight loss and cardiometabolic risk factors in severely
obese adults: a randomized trial. JAMA. 2010;304(16):1795–802.
199. Kuznetsov L, Simmons RK, Sutton S, Kinmonth AL, Griffin SJ, Hardeman W, et al. Predictors
of change in objectively measured and self-reported health behaviours among individuals
with recently diagnosed type 2 diabetes: longitudinal results from the ADDITION-Plus trial
cohort. Int J Behav Nutr Phys Act. 2013;10:118.
200. Youngs W, Gillibrand WP, Phillips S. The impact of pre-diabetes diagnosis on behaviour
change: an integrative literature review. Pract Diabetes. 2016;33(5):171–5.
201. Ali HI, Baynouna LM, Bernsen RM. Barriers and facilitators of weight management:
perspectives of Arab women at risk for type 2 diabetes. Health Soc Care Community.
2010;18(2):219–28.
13 Precision Exercise and Physical Activity for Diabetes 287
202. Sohal T, Sohal P, King-Shier KM, Khan NA. Barriers and facilitators for Type-2 diabetes
management in South Asians: a systematic review. PLoS One. 2015;10(9):e0136202.
203. Terada T, Friesen A, Chahal BS, Bell GJ, McCargar LJ, Boule NG. Exploring the variability
in acute glycemic responses to exercise in type 2 diabetes. J Diabetes Res. 2013;2013:591574.
204. Poirier P, Tremblay A, Catellier C, Tancrede G, Garneau C, Nadeau A. Impact of time interval
from the last meal on glucose response to exercise in subjects with type 2 diabetes. J Clin
Endocrinol Metab. 2000;85(8):2860–4.
205. Terada T, Wilson BJ, Myette-Cote E, Kuzik N, Bell GJ, McCargar LJ, et al. Targeting specific
interstitial glycemic parameters with high-intensity interval exercise and fasted-state exercise
in type 2 diabetes. Metabolism. 2016;65(5):599–608.
206. Munan M, Dyck RA, Houlder S, Yardley JE, Prado CM, Snydmiller G, et al. Does exer-
cise timing affect 24-hour glucose concentrations in adults with type 2 diabetes? A follow
up to the exercise-physical activity and diabetes glucose monitoring study. Can J Diabetes.
2020;44(8):711–8.e1.
207. Savikj M, Gabriel BM, Alm PS, Smith J, Caidahl K, Bjornholm M, et al. Afternoon exercise
is more efficacious than morning exercise at improving blood glucose levels in individuals
with type 2 diabetes: a randomised crossover trial. Diabetologia. 2019;62(2):233–7.
208. Nygaard H, Ronnestad BR, Hammarstrom D, Holmboe-Ottesen G, Hostmark AT. Effects of
exercise in the fasted and postprandial state on interstitial glucose in Hyperglycemic indi-
viduals. J Sports Sci Med. 2017;16(2):254–63.
209. Heden TD, Winn NC, Mari A, Booth FW, Rector RS, Thyfault JP, et al. Postdinner resistance
exercise improves postprandial risk factors more effectively than predinner resistance exer-
cise in patients with type 2 diabetes. J Appl Physiol (1985). 2015;118(5):624–34.
210. Colberg SR, Zarrabi L, Bennington L, Nakave A, Thomas Somma C, Swain DP, et al.
Postprandial walking is better for lowering the glycemic effect of dinner than pre-dinner
exercise in type 2 diabetic individuals. J Am Med Dir Assoc. 2009;10(6):394–7.
211. Chacko E. Timing and intensity of exercise for glucose control. Diabetologia.
2014;57(11):2425–6.
212. Chacko E. Timing, intensity and frequency of exercise for glucose control. Acta Diabetol.
2016;54(1):103–4.
213. Chacko E. A time for exercise: the exercise window. J Appl Physiol (1985). 2017;122(1):206–9.
214. Erickson ML, Jenkins NT, McCully KK. Exercise after you eat: hitting the postprandial glu-
cose target. Front Endocrinol. 2017;8:228.
215. Haxhi J, Scotto di Palumbo A, Sacchetti M. Exercising for metabolic control: is timing
important? Ann Nutr Metab. 2013;62(1):14–25.
216. Diabetes Canada Clinical Practice Guidelines Expert C, Sigal RJ, Armstrong MJ, Bacon SL,
Boule NG, Dasgupta K, et al. Physical activity and diabetes. Can J Diabetes. 2018;42(Suppl
1):S54–63.
217. Boule NG, Terada T, Francois ME, Hawley JA, Cotter JD, Kruse NT, et al. Commentaries on
viewpoint: a time for exercise: the exercise window. J Appl Physiol (1985). 2017;122(1):210–3.
218. Van Proeyen K, Szlufcik K, Nielens H, Ramaekers M, Hespel P. Beneficial metabolic
adaptations due to endurance exercise training in the fasted state. J Appl Physiol (1985).
2011;110(1):236–45.
219. Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of mus-
cle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes
by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990;322(4):223–8.
220. Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, et al. Increased glucose
transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-
resistant subjects. N Engl J Med. 1996;335(18):1357–62.
221. Macauley M, Smith FE, Thelwall PE, Hollingsworth KG, Taylor R. Diurnal variation in skel-
etal muscle and liver glycogen in humans with normal health and type 2 diabetes. Clin Sci.
2015;128(10):707–13.
288 N. G. Boulé and J. E. Yardley
222. Goodpaster BH, Brown NF. Skeletal muscle lipid and its association with insulin resistance:
what is the role for exercise? Exerc Sport Sci Rev. 2005;33(3):150–4.
223. Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Dela F. Patients with type 2 dia-
betes have normal mitochondrial function in skeletal muscle. Diabetologia. 2007;50(4):790–6.
224. Ritov VB, Menshikova EV, Azuma K, Wood R, Toledo FG, Goodpaster BH, et al. Deficiency
of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus
and obesity. Am J Physiol Endocrinol Metab. 2010;298(1):E49–58.
225. Terada T, Wilson BJ, Myette-Cote E, Kuzik N, Bell GJ, McCargar LJ, et al. Targeting specific
interstitial glycemic parameters with high-intensity interval exercise and fasted-state exercise
in type 2 diabetes. Metab Clin Exp. 2016;65(5):599–608.
226. Eshghi SR, Fletcher K, Myette-Cote E, Durrer C, Gabr RQ, Little JP, et al. Glycemic and
metabolic effects of two long bouts of moderate-intensity exercise in men with normal glu-
cose tolerance or type 2 diabetes. Front Endocrinol. 2017;8:154.
227. Van Proeyen K, Szlufcik K, Nielens H, Pelgrim K, Deldicque L, Hesselink M, et al. Training
in the fasted state improves glucose tolerance during fat-rich diet. J Physiol. 2010;588(Pt
21):4289–302.
228. Brinkmann C, Weh-Gray O, Brixius K, Bloch W, Predel HG, Kreutz T. Effects of exercising
before breakfast on the health of T2DM patients-a randomized controlled trial. Scand J Med
Sci Sports. 2019;29(12):1930–6.
229. Verboven K, Wens I, Vandenabeele F, Stevens AN, Celie B, Lapauw B, et al. Impact of
exercise-nutritional state interactions in patients with type 2 diabetes. Med Sci Sports Exerc.
2020;52(3):720–8.
Chapter 14
Diabetes Technology for Precision Therapy
in Children, Adults, and Pregnancy
Roger S. Mazze, Alice Pik Shan Kong, Goran Petrovski, and Rita Basu
Introduction
R. S. Mazze (*)
AGP Clinical Academy, Portsmouth, UK
A. P. S. Kong
Chinese University of Hong Kong, Hong Kong, PRC, China
G. Petrovski
Cornell University/Sidra Medicine, Doha, Qatar
R. Basu
Division of Endocrinology, University of Virginia, Charlottesville, VA, USA
e-mail: [email protected]
precision medicine in type 2 diabetes in the near future. Our study supports the sug-
gestion that the optimal approach to tailor management on the basis of risk of pro-
gression and therapeutic response will be to use phenotypic measures to predict
specific outcomes for individuals using multivariable models… In particular, spe-
cific clinical characteristics have been shown to have robust associations with
response to specific type 2 diabetes drug options [which raises] the possibility that
the relative glucose-lowering benefit of the different drugs might be identifiable by
combining simple clinical measures in a model for treatment selection” [4].
CGM Technology
There are two types of CGM systems: external and implantable [6]. External sys-
tems are further divided into real-time (rtCGM) and intermittently scanned (isCGM).
They consist of a sensor/transmitter and receiver. The transmitter rests on the sur-
face of the skin with the attached sensor component (filament) inserted 5 mm under
the skin resting in the interstitium. There it reacts with interstitial glucose molecules
which liberate electrons. The electrons are then transferred to the electrode where
electric current proportionate to the glucose concentration is generated. The trans-
mitter relays data to a wireless receiver (either a free-standing reader or a smart
phone). The receiver uses an algorithm to convert the interstitial glucose reading
into a blood glucose equivalent value. Data are transmitted and recorded in 1-, 2-,
5-, 10-, and 15-minute intervals, depending upon the manufacturer. Additionally,
the length of time the sensor remains in place is manufacturer-dependent—from 3
to 14 days. There is currently one implantable CGM device. It consists of an under-
the-skin sensor that remains in place for 90 days, an external rechargeable smart
transmitter, and a smart phone application for real-time glucose data. The reader-
stored data for all devices can be uploaded to a computer where proprietary soft-
ware produces a variety of reports.
The fundamental difference between the rtCGM and isCGM is the availability of
glucose readings. The rtCGM system data can be accessed anytime by turning on
the display, while the isCGM requires scanning the sensor with the receiver. Both
systems provide alarms and alerts at preset glucose levels [7]. Most CGM systems
have the option of blinding the data to the user. CGM displays include the current
glucose value, the trend (shown using an arrow), and the previous 8 hours repre-
sented by a curve [8].
External real-time and intermittent CGM glucose sensors use electrochemical-
and enzymatic-based methods (i.e., glucose oxidase and glucose dehydrogenase) to
measure interstitial glucose. There are three generations of glucose sensors [9].
First-generation sensors rely on oxygen (cofactors of glucose oxidase compete with
oxygen), and therefore, conditions leading to tissue hypoxia can result in overesti-
mation of glucose concentration. Second-generation sensors are not affected by
hypoxemia because nonphysiological electron acceptors are used to shuttle elec-
trons. Third-generation sensors adopt oxygen-independent cofactor to accept elec-
trons liberated from glucose in interstitial tissues and are without toxicity. All
sensors use an adhesive to hold the sensor/transmitter to the skin.
Measurement of interstitial glucose (ISG) presents some important challenges
that impact its accuracy and reliability. Glucose is transported into the interstitium
292 R. S. Mazze et al.
via passive diffusion when the volume of glucose in the capillary system is greater
than in the interstitial fluid. From there, glucose passes into insulin-sensitive tissue
with the aid of insulin. However, prior to CGM, clinical decision-making relied on
glucose measurement in blood either by laboratory assay or by SMBG. The intro-
duction of ISG raises an important question: Is ISG an accurate and reliable reflec-
tion of blood glucose? The solution was to convert ISG to blood glucose using
simultaneous SMBG calibrations. However, when glucose rapidly changes, the dif-
ference between blood glucose and ISG can be as large as 20% [10]. In terms of
precision medicine, this is a significant error if real-time glucose levels are guiding
clinical decisions. First-generation receivers had to employ multiple calibrations to
readjust the current CGM reading. For patients dependent upon real-time blood
glucose levels, the time lag is a problem if they rely on alarms when glucose levels
reach low thresholds [11]. Consequently, multiple SMBG calibrations are needed.
In 2015, factory calibration was introduced employing the glucose oxidase mecha-
nism for glucose measurement updated with a wired enzyme sensor incorporating
osmium [12]. Because this sensor technology does not produce as much “drift” as
earlier CGM sensors and has a more stable response over time in glucose measure-
ments, it can be calibrated at the time of manufacturing and does not require recali-
bration by the patient. In a study in which two CGM devices (with and without
factory calibration) were worn by the same subject, the difference in glucose values
was negligible [13].
As with all newer technologies, generalized use helps identify their limitations.
It has been found that exogenous and endogenous substances can potentially inter-
fere with CGM sensors leading to inaccurate readings. These include ascorbic acid
(vitamin C), acetaminophen, albuterol, atenolol, dopamine, maltose, xylose, man-
nitol, red wine, and uric acid [14, 15]. It has been reported that some CGM systems,
which use an abiotic (nonenzyme-based), fluorescent glucose-indicating polymer to
measure interstitial glucose levels, are not affected by ascorbic acid and acetamino-
phen, but the readings may be interfered by tetracycline and mannitol [12].
Therefore, specific drug interference profile of different CGM systems should be
noted, especially when there are discrepancies between CGM readings and capil-
lary blood or plasma glucose levels.
AGP 1
AGP 2
Fig. 14.1 Consecutive AGPs with Analytics. The AGP is comprised of the 10th, 25th 50th 75th
and 90 frequency percentile curves produced by using all CGM values collected between 8 and 14
days and plotted by time without regards to date. Glucose exposure is measured by area under the
median (50th percentile) curve, variability by inter-quartile range (dark gray area) and stability by
change in the median. The report includes specific information related to time in range which is
pre-set by the health care professional and hypoglycemia, in terms of its incidence, duration, mag-
nitude and frequency
294 R. S. Mazze et al.
Application of AGP analytics has already expanded the role of CGM in terms of
precision medicine. As shown, CGM can function to identify metabolic defects
under real-life conditions. Can the same technology be used as a diagnostic tool?
Figure 14.2 contains the AGP and daily profiles of a 34-year-old pregnant individual
(BMI 34) whose diagnosis of gestational diabetes during her 26th gestational week
was inconclusive. Consequently, 12 days of blinded CGM (to minimize bias) was
initiated to identify underlying metabolic defects and determine a course of treat-
ment. Based on the AGP and daily profiles, it was possible to confirm that on at least
three occasions glucose values reached just below 10 mmol/L, which would be
considered diagnostic for diabetes in pregnancy. Since the AGP identified a slightly
elevated fasting glucose and meal-related excursions, 500-mg metformin plus a rou-
tine of multiple small meals to reduce glucose excursions was initiated. The patient
was given an open CGM system allowing her to see in real time the impact of diet
on glucose levels. The results are displayed on the right panel of Fig. 14.3. If the
treatment was efficacious, the overnight and fasting glucose levels should decrease,
and postprandial excursions should be reduced.
As shown in Fig. 14.3, the AGP allows precise identification of the underlying
defect at the time of diagnosis (left panel) and provides a means of pinpointing the
impact of the treatment (right panel). The CGM provides the evidence of a change
in the daytime glucose pattern revealing lower glucose exposure and narrower vari-
ability; consequently, it can be reported that both exposure and variability were
addressed by the combination of metformin and meal planning. In this case, CGM
served multiple purposes: it confirmed the diagnosis and specified the metabolic
abnormalities which allowed for a more precise treatment regiment, resulting in
improved glycemic control.
14 Diabetes Technology for Precision Therapy in Children, Adults, and Pregnancy 295
Blinded AGP
FASTING
Fig. 14.2 CGM in Pregnancy. The top panel is the AGP of an individual diagnosed with GDM by
100g OGTT (fasting 6.3 mmol/L and 2 hours 8.5 mmol/L). The subsequent 12 days showed fasting
glucose (08:30-09:30) ranging between 5 and 7.5 mmol/L; and three postprandial incidents (solid
oval) of glucose reaching just below 10 mmol/L
The paradigm shift for CGM allowed for expanded diagnostic and treatment func-
tionality in terms of precision medicine: Is there a parallel in terms of the insulin
pump? With the advent of CGM came the possibility of connecting the two tech-
nologies and expanding their purpose. For the most part, the pump is reserved for
individuals with type 1 diabetes whose glucose control using more conservative
multiple daily injections (MDI) is not adequate in terms of achieving three overall
goals: an improved diurnal glucose profile, lessening hypoglycemia, and enhanced
quality of life [23]. Recently, pumps have been employed in individuals with type 2
diabetes and women with GDM or pre-GDM requiring intensive insulin therapy.
How has the automated insulin delivery by advanced algorithms guided by CGM
contributed to precision medicine?
296 R. S. Mazze et al.
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Fig. 14.3 CGM in Pregnancy. Comparing the blinded CGM with the open GDM the average
glucose exposure has decreased by 0.6 mmol/L. The bottom panels show for the period mid-night
to 09:30 hrs glucose exposure declined from 54.6 mmol/L/9.5 hours to 45.6 mmol/L/9.5 hours).
Daytime exposure (top panels) reduced from 79.8 mmol/L/14.5 hours to 64.8 mmol/L/14.5 hours
The insulin pump is a portable device attached to the skin surface that continu-
ously delivers short-acting insulin via a catheter placed under the skin. There are
two types of devices. A traditional pump which employs a fine tube to connect the
pump to the cannula inserted under the skin. A second type is the patch pump which
is directly linked to a cannula inserted under the skin. Both devices are guided by
algorithms which direct the insulin infusion rate. Insulin pumps provide basal and
bolus infusions. Basal insulin is continuous insulin delivery based on preprogramed
basal rates (open loop system) or insulin dose adjusted based on real-time CGM
sensor glucose levels (hybrid closed-loop system). The basal insulin attempts to
mimic physiologic insulin delivery. Bolus insulin is episodically delivered using
either a bolus advisor (or wizard) or an onboard algorithm. The meal-related bolus
dose is dependent upon carbohydrate data entered by the user. The correction bolus
is based on a pre-programed glucose targets.
Fundamentally, there are two ways in which the pump and CGM can be integrated:
open-loop and hybrid closed loop. For open-loop systems, the CGM data is entered
by the user. Hybrid systems (HCL) provide a direct connection between the pump
14 Diabetes Technology for Precision Therapy in Children, Adults, and Pregnancy 297
and the CGM device allowing both devices to directly interact. The most advanced
development in this area are the automated insulin delivery systems that use real-
time glucose readings from a CGM device and a specific algorithm to adjust insulin
delivery via the pump. There are a number of different versions of the HCL. The
more advanced HCL systems contain both automatic basal insulin delivery and cor-
rection boluses when CGM readings are high. Some of these systems utilize a smart
phone which receives data from a CGM sensor and uses a cloud-based adaptive
predictive control algorithm to direct insulin delivery. In this manner, the smart
phone acts as a CGM receiver and includes a basal and bolus calculator. It sends the
calculations to the pump which then adjusts the timing and insulin infusion rates.
Data are transmitted approximately every 5–15 minutes from the sensor. The con-
trol algorithm residing on the smart phone calculates the insulin infusion rate that is
communicated wirelessly to the pump via a Bluetooth communication’s protocol.
The algorithms are initialized using patient-specific data, such as weight, caloric
intake, activity level, and previous insulin regimen. To meet the dual goals of
reduced hypoglycemia and hyperglycemia, a glucose range is set and adjusted over
time. Advanced HCL systems are designed to continually alter the algorithm to
optimize control. The user is vital in this construct. While glucose and insulin data
are accurate and verifiable, the HCL also depends upon dietary and activity infor-
mation which must be entered by the user.
In terms of precision medicine, it has become axiomatic that “[…] insulin delivery
via CSII pump is more consistent and precise in providing patient’s individual insu-
lin requirements with low risk of severe hypoglycaemia than conventional delivery
devices” [24]. How has this need for “precision insulin delivery” been translated
into clinical practice? The following case report details the myriad functions HCL
therapy may perform.
A 13-year-old female with a 4-year history of type 1 diabetes treated with MDI and
8.9% HbA1c was presented for consideration of pump therapy. Both the patient and
parents requested initiation of pump therapy. Under most circumstances, this would be
sufficient to start a process of training on the pump’s use with CGM. However, apply-
ing the principles of precision medicine suggests the need for greater specificity regard-
ing characterizing her current metabolic status and selecting a starting insulin regimen.
This was accomplished by having the patient wear a CGM sensor for 7 days while
maintaining her current insulin regimen (16 units of long-acting insulin at bedtime,
12 units of rapid-acting insulin before breakfast, and 13 units before dinner). As can be
seen in Fig. 14.4 panel a, there is significant hyperglycemia beginning at 13:00 hours
and lasting throughout the remainder of the day. During this same period, there is note-
worthy glucose variability (11.1 mmol/L average interquartile range). Overnight (10
PM–8 AM), glucose values are more variable, ranging from 10 to 16.7 mmol/L. Three
episodes of hypoglycemia and three of hyperglycemia are also present.
298 R. S. Mazze et al.
Fig. 14.4 AGP for MDI Period (a) and Initiation of HCL (b). Time in range uses fixed values:
<3.9, 3.9–10, 10–13.9 >13.9 mmol/L. Hypoglycemic (<3.9 mmol/L) and hyperglycemic (>13.9
mmol/L)“patterns” are indicated by numbers. The center curve is the average, the shaded area
represents the inter-quartile range (25th to 75th percentile curves) and the outer range is bordered
by the 0 and 90th percentile curves. The Statistics reports data sufficiency, glucose exposure by
estimated A1c and average, as well as, self-reported insulin dose (top panel), automated insulin
dose (lower panel), and self-reported estimated total carbohydrates
Three issues were identifiable: (1) near hypoglycemic levels upon awakening,
(2) significant variability throughout the day, and (3) overnight persistent hypergly-
cemia. It was determined that based on the overall glycemic profile, the patient was
a candidate for pump initiation. The baseline period had multiple purpose: (1) to
obtain a diurnal glucose profile to identify the magnitude, duration, distribution and
frequency of excess glucose exposure reported by the HbA1c, (2) to identify any
underlying hypoglycemia to avoid exacerbation during initiation of the pump, (3) to
determine the starting dose and timing of insulin infusion, and (4) to enable the
patient to experience CGM technology, which is vital to HCL functioning.
Fundamental to initiation of combined pump and CGM technologies is to clearly
state the purpose of these technologies so that their efficacy can be assessed. At its
initiation, the patient was informed that “success” would be measured by glycemic
improvements and patient satisfaction. The baseline AGP serves as an unbiased
assessment of the clinical efficacy of MDI therapy; consequently, the use of the
pump must be evaluated against the MDI AGP, essentially answering the question:
To what degree did the new technology improve glucose exposure, variability, sta-
bility, and the incidence of hypoglycemic and hyperglycemic episodes? Patient sat-
isfaction is less quantitative and can be assessed by the following questions: Was the
patient able to use the technology? Did the technology measurably improve the
quality of life?
Prepump and carbohydrate counting assessment was performed at a clinic visit;
once successfully completed, the patient was scheduled for regular pump training.
The patient attended practical sessions for pump connection and sensor insertion;
pump operations; auto mode feature; auto basal/safe basal; alarms/alerts; trouble-
shooting and pump failure; temporary disconnection and converting back to MDI;
management of hypoglycemia, hyperglycemia, and sick days; DKA; exit to manual
mode and temporary basal; diet; and exercise.
14 Diabetes Technology for Precision Therapy in Children, Adults, and Pregnancy 299
Initiation of HCL system was performed in manual mode (requiring patient input)
based on evaluation of the AGP produced while using MDI (Fig. 14.4 panel a). It was
noted that there was a risk of hypoglycemia; consequently, the total daily insulin was
reduced by 10%. Due to the wide variability overnight and during the daytime, five
basal rates were set. Based on the previous report during MDI, the insulin to carbo-
hydrate ratio was established as 10 g, and the correction factor of 3 mmol/L was set.
Active insulin time was set at 4 hours and the glucose target range was established as
5–7.5 mmol/L to avoid both hypoglycemia and hyperglycemia.
Displayed in Fig. 14.4 panel b is the AGP during the initial pump use when the
manual mode with suspend before low feature (3.5 mmol/L) allows the algorithm to
establish personalized auto mode initiation parameters. Time in range increased to
58%. Auto mode uses the CGM and insulin infusion data as well as the target set-
tings to determine the optimum infusion rate and timing for both basal and bolus
periods. The next period was fully controlled by the auto mode (see Fig. 14.5 panel
c). Time in range continued to increase reaching 69% in the first week of auto mode
initiation, where postmeal hyperglycemia was noted.
By the third week, the patient reached a steady state. Comparing the baseline
AGP (Fig. 14.4 panel a) to the final AGP (Fig. 14.5 panel d), time in range reached
86%, with no hypoglycemic episodes, reduction in hyperglycemia episodes to one,
and overall glucose exposure reduced from 11.7 to 7.7 mmol/L with a concomitant
decrease in eA1C. Glucose variability (as shown by the shaded area) decreased to
2 mmol/L. There was no significant difference in sensor wear, calibrations, set/res-
ervoir change, meals, and carbohydrates per day during this period.
Fig. 14.5 AGP for Pump Adjustments (c) and Stabilization (d). Comparing the adjustment (c)
with the stabilization phase, the magnitude, duration, frequency and distribution of glucose expo-
sure improved. It appears as if the entire AGP narrowed and lowered. This is consistent with a
structured approach in which narrowing the variability and stabilizing the average glucose through-
out the day precede lowering the glucose f = values. Note that this was accomplished without an
increase in total daily insulin. The algorithm maintains glycemic control by using the CGM data to
“teach” the algorithm. As with all technology human behavior can counter the algorithm as shown
by the wide inter-quartile range and outlier range at noon. This is indicative of alterations in diet
each day, interfering with the ability of the algorithm to detect a predictable pattern
300 R. S. Mazze et al.
The use of the HCL system following principles of precision medicine resulted
in a logical process of clinical decision-making relying on accurate and verifiable
data. The onboard algorithm followed a rational series of steps that targeted reduced
variability and increased stability ahead of glucose exposure. This approach less-
ened the risk of hypoglycemia and suggests a model that can be applied to MDI
therapies as well. In this case, CGM corroborated the need for pump therapy and
served to identify the underlying dysglycemia with sufficient specificity to allow a
more rapid initiation of pump therapy.
This chapter began with the proposition that the current paradigm for precision
medicine needs to be altered. The role of glucose sensing and pump technologies in
the diagnosis and treatment of diabetes can be expanded and become central to the
notion of precision medicine. Close examination of the heterogeneity within diabe-
tes classifications suggests new roles for insulin delivery technologies. At diagnosis,
individuals with type 1 diabetes present with varying degrees of β-cell function.
This leads to a variety of glucose patterns that suggest the need for highly individu-
alized treatment. Two specific benefits of initiation of pump therapy combined with
CGM at diagnosis are prolonging β-cell function and characterizing insulin require-
ments. Both benefits require restoration of near euglycemia. It is argued that for
newly diagnosed children with type 1 diabetes, “Sensor-augmented pump therapy
starting from the diagnosis of type 1 diabetes can be associated with less decline in
fasting C-peptide…” [25]. In a study in adolescents, pumps were initiated between
one day and one month after diagnosis. The 28 subjects experienced a decline in
HbA1c from 10.5 +/− 2.4% to between 6.5% and 7.4% over the next 18 months [26].
Endogenous insulin secretion, measured by C-peptide values, remained stable dur-
ing the first 12 months after diagnosis. The researchers concluded that “The study
provided a positive experience with CSII as the initial insulin replacement therapy
in newly diagnosed patients with T1DM with excellent clinical outcomes and appar-
ent prolongations of the honeymoon period” [26].
Compared to type 1 diabetes, type 2 diabetes is highly heterogeneous. The under-
lying defects that characterize type 2 diabetes range from impaired β-cell function
to reduced incretin production. They can be mechanistic, chemical, behavioral, or a
combination. The contributions of insulin resistance and β-cell dysfunction differ to
such an extent that it has been hypothesized that there are a number of subgroups
within the classification. It has been noted that at diagnosis even with comparable
HbA1c, diurnal glucose profiles differ extensively. While measurement of insulin
level and insulin resistance may provide evidence of reduced or impaired β-cell
function, they are limited. What is missing at diagnosis is an understanding of how
much supplemental insulin, if any, is needed. Consequently, the selection of treat-
ment is often “hit or miss,” primarily because the diagnostic criteria and initial
14 Diabetes Technology for Precision Therapy in Children, Adults, and Pregnancy 301
For example, overnight glucose utilization is lower and glucose production higher
in individuals with type 2 diabetes than their nondiabetic counterparts [30]. Reflected
in CGM overnight hyperglycemic patterns, this is due to the central role the liver
plays in regulating carbohydrate tolerance. Furthermore, it is likely that the diabetic
state per se determines the severity of extrahepatic and hepatic insulin resistance
[31]. CGM patterns that show fasting hyperglycemia may be the direct result of
defects in beta cell function which lead to reduced insulin secretion overnight. In a
similar manner, CGM postprandial hyperglycemic patterns may also be the result of
defects in beta cell function [32]. Overnight CGM patterns that show significant
variability, with glucose levels ranging from normal to hyperglycemia, may be
indicative of early type 2 diabetes due to disturbances in nocturnal regulation of
glycemia which are affected by varying degrees of overnight hepatic insulin resis-
tance. This leads to increase in glucose production in type 2 diabetes during the
night [33]. Thus, the underlying cause for abnormal nocturnal glucose production as
revealed in CGM patterns appears to be mild physiological hyperglucagonemia
rather than increase in cortisol [34].
Detecting underlying pathophysiology by employing CGM-based glucose pat-
terns is equally effective in type 1 diabetes by characterizing dysglycemic patterns
that aid in the decision to initiate pump therapy, select the starting basal and bolus
regimen, and guide adjustments. Similarly, CGM may be used to detect dysglyce-
mic patterns in pregnancy caused by human placental lactogen-induced insulin
resistance. Even subtle rises in overnight and postprandial glucose during the first
and second trimesters may be indicators of impending gestational diabetes.
Pump therapy plays a different role in precision medicine, as its purpose is to
mimic the normal physiology of insulin secretion. While CGM aids this by corrobo-
rating normal insulin action, it is pump technology that achieves this by integrating
glycemic patterns reflected in CGM analytics with infusion algorithms. Precision
medicine demands that the goal of pump therapy no longer be defined by HbA1c,
rather by specific characteristics of diurnal glucose exposure, variability, stability,
and hypoglycemia derived from CGM. These characteristics of normal glucose
metabolism under conditions of daily living, in turn, are associated with normal
physiology, which in turn is correlated with prevention of diabetes-related
complications.
The integration of new technologies is a vital element of precision medicine. It is
an essential step if these technologies are to be optimized and if precision medicine
is to meet the goal of individualizing care by identifying the nature of the underlying
defects related to diabetes specific to the individual and designing interventions that
target the defect. CGM does this by characterizing the glucose patterns of a single
individual, not a classification of diabetes; the pump does this by developing an
infusion regimen particular to the individual based on both physiology and behavior.
References
1. Mering J, Florez J. Precision medicine in diabetes: an opportunity for clinical translation. Ann
N Y Acad Sci. 2018;1411(1):140–52.
14 Diabetes Technology for Precision Therapy in Children, Adults, and Pregnancy 303
23. DiMeglio LA, Acerini CL, Codner E, et al. ISPAD clinical practice consensus guidelines 2018:
glycemic control targets and glucose monitoring for children, adolescents, and young adults
with diabetes. Pediatr Diabetes. 2018;19(S27):105–14.
24. Kesavadev J, Jaim SM, Muruganathan A, Das AK. Consensus evidence-based guidelines for
use of insulin pump therapy in the management of diabetes as per indian clinical practice
supplement. J Assoc Physicians India. 2014;62.
25. Kordonouri O, Pankowska E, Rami B, et al. Sensor-augmented pump therapy from the diag-
nosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12
months of treatment Diabetologia. 2010;53(12):2487–95.
26. Ramchandani N, Ten S, Anhalt H, et al. Insulin pump therapy from the time of diagnosis of
type 1 diabetes. Diabetes Technol Ther. 2006;8(6):663–70.
27. Li F-F, Liu B-L, Zhu H-H, et al. Continuous glucose monitoring in newly diagnosed type
2 diabetes patients reveals a potential risk of hypoglycemia in older men. J Diabetes Res.
2017:2740372.
28. Faerch K, Hulman A, Solomon T. Heterogeneity of pre-diabetes and type 2 diabetes:
implications for prediction, prevention and treatment responsiveness. Curr Diabetes Rev.
2015;12(1):30–41.
29. American Diabetes Association. Standards of medical care in diabetes-2022. Diab Care.
2022;45(Suppl. 1):S85–7.
30. Basu A, Basu R, Shah P, Vella A, Johnson CM, Nair KS, Jensen MD, Schwenk WF, Rizza
RA. Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and
muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity. Diabetes.
2000;49(2):272–83.
31. Basu R, Schwenk WF, Rizza RA. Both fasting glucose production and disappearance are
abnormal in people with “mild” and “severe” type 2 diabetes. Am J Physiol Endocrinol Metab.
2004;287(1):E55–62.
32. Basu A, Dalla Man C, Basu R, Toffolo G, Cobelli C, Rizza RA. Effects of type 2 diabetes on
insulin secretion, insulin action, glucose effectiveness, and postprandial glucose metabolism.
Diab Care. 2009;32(5):866–72. PMCID: PMC2671126
33. Basu A, Joshi N, Miles J, Carter RE, Rizza RA, Basu R. Paradigm Shifts in Nocturnal
Glucose Control in Type 2 Diabetes. J Clin Endocrinol Metab. 2018;103(10):3801–9. PMCID:
PMC6179178
34. Basu A, Yadav Y, Carter RE, Basu R. Novel insights into effects of cortisol and glucagon
on nocturnal glucose production in Type 2 diabetes. J Clin Endocrinol Metab. 2020;105(7)
PMCID: PMC7274493
Chapter 15
Adaptive and Individualized Artificial
Pancreas for Precision Management
of Type 1 Diabetes
Introduction
Automated devices for glycaemic control, the so-called artificial pancreas (AP), are
revolutioning diabetes management by reducing patient burden and allowing more
effective control. This has been made possible by incredible progresses in subcuta-
neous (sc) glucose sensing (continuous glucose monitoring (CGM)), by improved
technology of sc insulin pumps and by important development in control algo-
rithms, the core of AP technology. A large spectrum of control techniques has been
explored including proportional integral derivative (PID) equipped in [1] with insu-
lin feedback to mitigate insulin absorption delays, medical doctor reasoning [2] and
model predictive control (MPC) [3–5]. MPC appears to be particularly suited for
glucose control in view of its capability to handle constraints (insulin delivery is
bounded to be positive) and to mitigate insulin absorption delays employing predic-
tive; it has also been employed in dual-hormone AP, infusing glucagon in addition
to insulin [6], and for handling ancillary physical activity measurements [7]. The sc
insulin delivery has important limitations, and recently an AP employing the intra-
peritoneal (ip) insulin delivery has been investigated showing that, at variance with
the sc, the ip does not require meal announcements, thanks to much faster insulin
kinetics [8, 9].
C. Toffanin
Department of Electrical, Computer and Biomedical Engineering, University of Pavia,
Pavia, Italy
C. Cobelli (*)
Department of Woman and Child’s Health, University of Padova, Padova, Italy
e-mail: [email protected]
L. Magni
Department of Civil and Architecture Engineering, University of Pavia, Pavia, Italy
In the last 10 years, an intense clinical research effort has been performed to test
AP prototypes, resulting in numerous trials conducted on kid, adolescent, and adult
subjects affected by T1D. The first clinical experiments were conducted on hospi-
talized subjects (inpatient) to test safety and efficacy of this technology, then experi-
ments in semi-controlled outpatient setting were conducted to safely emulate the AP
unsupervised use by the patient in real life, and finally various AP prototypes entered
the last validation phase, i.e. the sustained independent use of the device in real life
(see, for example, [10–24]). Today, there are three commercial devices on the mar-
ket [25].
In this chapter, we focus on two problems related to the control algorithm which
still deserve novel research, i.e. individualization and adaptivity. Individuals are dif-
ferent; thus, strategies to tune the control algorithm to a specific person are needed.
In addition, individuals change in time; thus, strategies to adapt the controller con-
figuration to a changing metabolic status of a person are key to improve AP long-
term glucose control.
Individualization
The individualization topic has been faced in the last years by several research
groups (for a comprehensive literature review, refer to [26, 27]). For example, a
well-established approach [28, 29] involved simple black box models with fixed
time constants and the possibility to adapt the system gain on the base of well-
known clinical parameters such as TDI.
In this section, the techniques studied by the authors will be summarized:
CR-based [30], impulse response (IR) [31], constrained optimization (CO) [32],
nonparametric (NP) [32] and neural network (NN) approaches. In particular, the
main goal of the works was the improvement in terms of performance of the MPC
algorithm synthesized by the authors on a population model [5] and to design
patient-tailored alarm systems able to prevent hypoglycaemia [33].
CR-Based Models
The first and simpler way to individualize a population model is to divide the popu-
lation in clusters of patients (classes) with similar characteristics and then to use the
average model of the specific cluster the patient belongs to.
The model customization approach [30] is based on subdividing the entire vir-
tual population in subgroups depending on the insulin-to-carbohydrate ratio (CR)
parameter. The CR represents the nominal quantity of carbohydrate compen-
sated by 1 U of insulin. Note that the CR is a parameter defined by the physician
and customized for each patient, so this grouping considers the individual
15 Adaptive and Individualized Artificial Pancreas for Precision Management of Type… 307
characteristics of each patient to react to insulin and meals. The subdivision applied
in silico [30] involves four classes of the adult population of the UVA/Padova
Simulator (UPS), each of which is composed of patients having low, medium-low,
medium-high and high insulin sensitivity on the base of the integer approximations
of the 25th, 50th, and 75th percentiles associated with the CR distribution of the
adult virtual population. For each class, an average model is computed and then
linearized around the basal equilibrium.
The second technique is based on impulse signals, the most exciting inputs, so it is
called impulse response (IR). It has been developed in silico [31] and extended on
in vivo data in [33, 34].
The subsystems from insulin to glucose and from meal carbohydrates to glucose
can be described by two continuous-time transfer functions (TFs). Their structure
and complexity are determined by impulse response experiments on the 100 in
silico subjects of UPS. The use of the UPS is motivated by the impossibility of
performing extensive and possibly unsafe experiments on real subjects: insulin
boluses without meal intake and uncontrolled meals (meals without insulin boluses).
The identification technique is divided into two steps: the first one is entirely devel-
oped on the “average” in silico patient (Av) of the UPS to obtain the TFs, and then
a patient-tailored model is identified using patient real-life data collected in
closed loop.
Seen the good results obtained in silico, this technique was applied to in vivo
data [33] coming from 1-month trial in free-living condition [35]. The technique
was adapted to deal with the characteristics of the trial: the system was discretized,
and a residual error e(k) was added to consider the effect of unmeasured factors like
physical exercise, stress, illness, etc. and other unmodelled dynamics.
The third technique that consists in the identification of a linear model having a
fixed parametric structure is a grey-box identification approach based on a con-
strained optimization (CO) [32]. In particular, the linearization of the metabolic
model included in the UPS around the basal equilibrium is considered, and its
matrices are identified through the solution of a CO problem. Several elements have
been fixed equal to zero according to the structure of the in silico model; in this
way, a priori information are included, and the computational burden of the optimi-
zation is reduced. The identification is performed by relying on historical input-
output data associated with the patient. The CGM subcutaneous glucose
308 C. Toffanin et al.
The nonparametric (NP) approach described in [32] belongs to the class of black
box identification techniques and can be used to identify patient-specific glucose-
insulin models by relying on historical insulin administrations and meal intakes and
CGM measurements. Given a set of historical input-output data associated with a
specific patient, the NP approach identifies a one-step ahead predictor that is subse-
quently converted in a state-space model obtained through a minimal realization of
a given dimension. The identification process is performed through a kernel-based
regression in which the stable spline kernel introduced in [37] is considered. The
final result is a linear time-invariant model involving a white Gaussian noise signal
to represent the uncertainties affecting the model. The impulse responses and the
Gaussian noise are identified through kernel-based regression processes described
in [32].
In the last decade, machine learning approaches have been applied to glucose con-
trol problem with promising results. These approaches have been investigated to
perform glucose forecasting [38] for in silico adult subjects. In particular, a deep
learning approach based on a novel, two-headed long short-term memory imple-
mentation is proposed which takes in input the previous values obtained through
continue glucose monitoring, the carbohydrate intake, the suggested insulin therapy
and that forecasts the interstitial glucose level of the patient. With a large dataset
available, these techniques could be directly applied on the in vivo data. In [38], the
population model obtained in silico was adapted to a real patient with promising
results. These approaches are currently under study for both control and hypo-
avoidance purposes.
15 Adaptive and Individualized Artificial Pancreas for Precision Management of Type… 309
Adaptivity
One of the main problems related to the glucose control together with the inter-
patient variability is the intra-patient variability that calls for time-variant models or
adaptation techniques. The significant level of subject-specific glycaemic variability
requires continuously adapting the control policy to successfully face daily changes
in patient’s metabolism and lifestyle. In the last year, several research groups tried
to face this problem exploring different techniques. For example, in [39], the authors
designed a dual-layer control scheme: the lower layer is composed of multiple con-
trollers that deal with short-term disturbances, while the upper one is responsible for
long-term (e.g. weeks) parameter adaptation of lower layer control algorithms. The
purpose of this layer is to handle chronic changes in the patient’s glucose metabolic
process and lifestyle through a long-term data-driven multivariate parameter learn-
ing framework based on historical performance. In [40], an online selective rein-
forcement learning algorithm for a real-time adaptation based on ongoing
interactions with the patient is used to tailor the artificial pancreas. Adaptation
includes two online procedures: online sparsification and parameter updating of the
Gaussian process used to approximate the control policy by detecting novel infor-
mation from the arriving data stream. The adaptation can also be applied indirectly
to advanced techniques such as the MPC [41] through the update of the nominal
basal insulin around which the MPC instantaneously varies the basal insulin. In this
approach also, the meal bolus is adapted on the base of the correction made by the
MPC the previous day. The MPC can be also made adaptive through change of the
control penalty in the cost function of the controller as in [42]. This adaptive con-
troller resulted able to actively perform insulin infusion when blood glucose is rap-
idly increasing but cautiously reduces/suspends insulin infusion when glucose rate
of change is positively small or negative. In [43], a run-to-run (R2R) approach
adapts the parameters of the model used in the MPC for the prediction, adjusting the
insulin sensitivity and postprandial insulin.
The adaptation techniques explored by the authors involve mainly R2R
approaches used to daily adapt the aggressiveness of the controller and/or the con-
ventional basal-bolus therapy on the base of the performances achieved the previous
day. A very promising approach has been also tested in vivo with interesting results
[44]. In particular, in [45], the aggressiveness of the MPC controller proposed by the
author was updated considering the patient position on the CVGA [31]: this grid
considers the maximum and the minimum BG level reached by the patient in the
observation period, and the R2R algorithm tries to lead it to the optimal bottom left
corner where no hypoglycaemia/hyperglycaemia events occurred.
An innovative R2R approach to improve the glucose control was presented in
[46, 47]. This approach exploits a switching updating law in order to adapt the
basal-bolus therapy to avoid at first the hypoglycaemia events and then to improve
the time in target, avoiding hyperglycaemia and leading the average glucose to the
310 C. Toffanin et al.
target. Previous R2R approaches were based on a few blood glucose measurements,
while the authors used a subcutaneous continuous glucose monitoring in order to
obtain more relevant clinical performance indices, such as the percentage of time
spent below 70 mg/dl, above 180 mg/dl, and the average glucose. The convergence
of the proposed R2R approach is proved by resorting to the Lyapunov theory for
piecewise affine systems [46]. While in [46] only the basal amount along all day is
updated, in [47] both, the nocturnal basal and the diurnal CR are changed in order
to improve the control obtained via an adaptive MPC approach [5]. The adaptation
of the MPC is obtained through the update of the aggressiveness of the controller,
thanks to the updating of the CR which the aggressiveness is based on. In silico
simulations were performed by using the UPS enriched by incorporating three novel
features: intraday and interday variability of insulin sensitivity; different distribu-
tions of CR at breakfast, lunch, and dinner; and dawn phenomenon. After about
2 months, using the R2R approach with a scenario characterized by a random ±30%
variation of the nominal insulin sensitivity, the time in range and the time in tight
range are increased by 11.39% and 44.87%, respectively, and the time spent above
180 mg/dl is reduced by 48.74%. Making an AP adaptive is key for long-term real-
life outpatient studies and seen the good in silico results; an in vivo testing was
performed on 18 subjects involved in a 1-month trial [44] under free-living condi-
tions. Time in target with adaptive MPC (R2R-AP) was higher than with the non-
adaptive one (NA-AP), although the increase was not significant: mean 66.90%
(standard deviation: 13.34) versus 61.82% (11.12), P = 0.10. The increase was sig-
nificant during the night, 74.01% (14.61) versus 64.31% (15.71), P = 0.03, and at
wake-up time, median 92.43% (25th; 75th percentiles: 78.22; 99.53) versus 84.54%
(57.14; 88.52), P = 0.02. Time above target (>10 mmol/L) during the whole day was
30.98% (13.22) versus 36.17% (11.53), P = 0.10. The decrease was significant dur-
ing the night, 24.23% (15.03) versus 34.49% (16.25), P = 0.03, and at wake-up
time, 7.57% (0.00; 14.29) versus 14.29% (8.25; 42.86), P = 0.05. Time spent below
target (<3.9 mmol/L) was low and similar to the two treatments. The R2R-AP
improves glucose control over NA-AP during the night, and it maintains equivalent
control performance during the day.
New approaches explored by the authors in terms of adaptivity involve the use of
a multiple model predictor (MMP) [48] in order to improve the glucose prediction
taking into account the intraday variability of the patients. A correlation between
postprandial glucose profiles and different day periods (DPs) was found analysing
experimental data [35]. The data-driven MMP based on real-data analysis uses three
basic models specific of each DP identified through the IR technique. Its prediction
capabilities compared to the ones of a daily model predictor, built using a single
model identified on a daily subset, showed an improvement in terms of prediction
capabilities during breakfast.
15 Adaptive and Individualized Artificial Pancreas for Precision Management of Type… 311
Conclusions
References
1. Steil GM, Palerm CC, Kurtz N, Voskanyan G, Roy A, Paz S, Kandeel FR. The effect of insulin
feedback on closed loop glucose control. J Clin Endocrinol Metabol. 2011;96(5):1402–8.
2. Atlas E, Nimri R, Miller S, Grunberg EA, Phillip M. MD-logic artificial pancreas system: a
pilot study in adults with type 1 diabetes. Diabetes Care. 2010;33(5):1072–6.
3. Hovorka R, Canonico V, Chassin LJ, Haueter U, Massi-Benedetti M, Federici MO, Pieber TR,
Schaller HC, Schaupp L, Vering TAO. Nonlinear model predictive control of glucose concen-
tration in subjects with type 1 diabetes. Physiolog Measurement. 2004;25(4):905.
4. Grosman B, Dassau E, Zisser HC, Jovanovi L, Doyle FJ III. Zone model predictive con-
trol: a strategy to minimize hyper-and hypoglycemic events. J Diabetes Sci Technol.
2010;4(4):961–75.
5. Toffanin C, Messori M, Di Palma F, De Nicolao G, Cobelli C, Magni L. Artificial pan-
creas: model predictive control design from clinical experience. J Diabetes Sci Technol.
2013;7(6):1470–83.
6. Russell SJ, El-Khatib FH, Nathan DM, Magyar KL, Jiang J, Damiano ER. Blood glucose
control in type 1 diabetes with a bihormonal bionic endocrine pancreas. Diabetes Care.
2012;35(11):2148–55.
7. Turksoy K, Bayrak ES, Quinn L, Littlejohn E, Cinar A. Multivariable adaptive closed-loop
control of an artificial pancreas without meal and activity announcement. Diabetes Technol
Ther. 2013;15(5):386–400.
8. Renard E. Insulin delivery route for the artificial pancreas: subcutaneous, intraperitoneal, or
intravenous? Pros and cons. J Diabetes Sci Technol. 2008;2(4):735–8.
9. Dassau E, Renard E, Place J, Farret A, Pelletier M-J, Lee J, Huyett LM, Chakrabarty A,
Doyle FJ III, Zisser HC. Intraperitoneal insulin delivery provides superior glycaemic regu-
lation to subcutaneous insulin delivery in model predictive control-based fully-automated
artificial pancreas in patients with type 1 diabetes: a pilot study. Diabetes Obes Metab.
2017;19(12):1698–705.
10. Leelarathna L, Dellweg S, Mader JK, Allen JM, Benesch C, Doll W, Ellmerer M, Hartnell S,
Heinemann L, Kojzar HAO. Day and night home closed-loop insulin delivery in adults with
type 1 diabetes: three-center randomized crossover study. Diabetes Care. 2014;37(7):1931–7.
11. Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, Balliro C, Hillard
MA, Nathan DM, Damiano ER. Outpatient glycemic control with a bionic pancreas in type 1
diabetes. N Engl J Med. 2014;371(4):313–25.
12. Nimri R, Muller I, Atlas E, Miller S, Kordonouri O, Bratina N, Tsioli C, Stefanija MA, Danne
T, Battelino TAO. Night glucose control with MD-logic artificial pancreas in home setting: a
single blind, randomized crossover trial—interim analysis. Pediatr Diabetes. 2014;15(2):91–9.
312 C. Toffanin et al.
13. Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, Balliro C, Hillard
MA, Nathan DM, Damiano ER. Outpatient glycemic control with a bionic pancreas in type 1
diabetes. N Engl J Med. 2014;371(4):313–25.
14. Del Favero S, Place J, Kropff J, Messori M, Keith-Hynes P, Visentin R, Monaro M, Galasso S,
Boscari F, Toffanin CAO. Multicenter outpatient dinner/overnight reduction of hypoglycemia
and increased time of glucose in target with a wearable artificial pancreas using modular model
predictive control in adults with type 1 diabetes. Diabetes Obes Metab. 2015;17(5):468–76.
15. Kropff J, Del Favero S, Place J, Toffanin C, Visentin R, Monaro M, Messori M, Di Palma F,
Lanzola G, Farret AAO. 2 month evening and night closed-loop glucose control in patients
with type 1 diabetes under free-living conditions: a randomised crossover trial. The lancet
Diabetes & endocrinology. 2015;3(12):939–47.
16. Thabit H, Tauschmann M, Allen JM, Leelarathna L, Hartnell S, Wilinska ME, Acerini CL,
Dellweg S, Benesch C, Heinemann LAO. Home use of an artificial beta cell in type 1 diabetes.
N Engl J Med. 2015;373(22):2129–40.
17. Del Favero S, Boscari F, Messori M, Rabbone I, Bonfanti R, Sabbion A, Iafusco D, Schiaffini R,
Visentin R, Calore RAO. Randomized summer camp crossover trial in 5-to 9-year-old children:
outpatient wearable artificial pancreas is feasible and safe. Diabetes Care. 2016;39(7):1180–5.
18. Bergenstal RM, Garg S, Weinzimer SA, Buckingham BA, Bode BW, Tamborlane WV,
Kaufman FR. Safety of a hybrid closed-loop insulin delivery system in patients with type 1
diabetes. JAMA. 2016;316(13):1407–8.
19. Russell SJ, Hillard MA, Balliro C, Magyar KL, Selagamsetty R, Sinha M, Grennan K,
Mondesir D, Ekhlaspour L, Zheng HAO. Day and night glycaemic control with a bionic pan-
creas versus conventional insulin pump therapy in preadolescent children with type 1 diabetes:
a randomised crossover trial. The lancet Diabetes & endocrinology. 2016;4(3):233–43.
20. Garg SK, Weinzimer SA, Tamborlane WV, Buckingham BA, Bode BW, Bailey TS, Brazg RL,
Ilany J, Slover RH, Erson SMAO. Glucose outcomes with the in-home use of a hybrid closed-
loop insulin delivery system in adolescents and adults with type 1 diabetes. Diabetes Technol
Ther. 2017;19(3):155–63.
21. Tauschmann M, Thabit H, Bally L, Allen JM, Hartnell S, Wilinska ME, Ruan Y, Sibayan J,
Kollman C, Cheng PAO. Closed-loop insulin delivery in suboptimally controlled type 1 diabe-
tes: a multicentre, 12-week randomised trial. Lancet. 2018;392(10155):1321–9.
22. Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, Laffel LM,
Levy CJ, Pinsker JE, Wadwa RPAO. Six-month randomized, multicenter trial of closed-loop
control in type 1 diabetes. N Engl J Med. 2019;381(18):1707–17.
23. Sherr JL, Buckingham BA, Forlenza GP, Galderisi A, Ekhlaspour L, Wadwa RP, Carria L, Hsu
L, Berget C, Peyser TAAO. Safety and performance of the omnipod hybrid closed-loop system
in adults, adolescents, and children with type 1 diabetes over 5 days under free-living condi-
tions. Diabetes Technol Ther. 2020;22(3):174–84.
24. Collyns OJ, Meier RA, Betts ZL, Chan DS, Frampton C, Frewen CM, Hewapathirana NM,
Jones SD, Roy A, Grosman BAO. Improved glycemic outcomes with medtronic minimed
advanced hybrid closed-loop delivery: results from a randomized crossover trial comparing
automated insulin delivery with predictive low glucose suspend in people with type 1 diabetes.
Diabetes Care. 2021;44(4):969–75.
25. Boughton CK, Hovorka R. New closed-loop insulin systems. Diabetologia. 2021:1–9.
26. Zarkogianni K, Litsa E, Mitsis K, Wu P-Y, Kaddi CD, Cheng C-W, Wang MD, Nikita KS. A
review of emerging technologies for the management of diabetes mellitus. IEEE Trans Biomed
Eng. 2015;62(12):2735–49.
27. Oviedo S, Vehì J, Calm R, Armengol J. A review of personalized blood glucose prediction
strategies for T1DM patients. Inter J Numer Meth Biomed Eng. 2017;33(6)
28. van Heusden K, Dassau E, Zisser HC, Seborg DE, Doyle FJ III. Control-relevant mod-
els for glucose control using a priori patient characteristics. IEEE Trans Biomed Eng.
2011;59(7):1839–49.
29. Lee JB, Dassau E, Seborg DE, Doyle FJ. Model-based personalization scheme of an arti-
ficial pancreas for type 1 diabetes applications. In: 2013 American Control Conference.
Washington; 2013.
15 Adaptive and Individualized Artificial Pancreas for Precision Management of Type… 313
30. Messori M, Ellis M, Cobelli C, Christofides PD, Magni L. Improved postprandial glucose
control with a customized model predictive controller. In: 2015 American Control Conference
(ACC). Chicago; 2015.
31. Soru P, De Nicolao G, Toffanin C, Dalla Man C, Cobelli C, Magni L, A. H. C. A. Others. MPC
based artificial pancreas: strategies for individualization and meal compensation. Annu Rev
Control. 2012;36(1):118–28.
32. Messori M, Toffanin C, Del Favero S, De Nicolao G, Cobelli C, Magni L. Model individualiza-
tion for artificial pancreas. Comput Methods Prog Biomed. 2019;171:133–40.
33. Toffanin C, Del Favero S, Aiello EM, Messori M, Cobelli C, Magni L. Glucose-insulin
model identified in free-living conditions for hypoglycaemia prevention. J Process Control.
2018;64:27–36.
34. Toffanin C, Aiello EM, Cobelli C, Magni L. Hypoglycemia prevention via personal-
ized glucose-insulin models identified in free-living conditions. J Diabetes Sci Technol.
2019;13(6):1008–16.
35. Renard E, Farret A, Kropff J, Bruttomesso D, Messori M, Place J, Visentin R, Calore R,
Toffanin C, Di Palma FAO. Day-and-night closed-loop glucose control in patients with type
1 diabetes under free-living conditions: results of a single-arm 1-month experience compared
with a previously reported feasibility study of evening and night at home. Diabetes Care.
2016;39(7):1151–60.
36. Del Favero S, Facchinetti R, Sparacino G, Cobelli C. Improving accuracy and precision of glu-
cose sensor profiles: retrospective fitting by constrained deconvolution. IEEE Trans Biomed
Eng. 2013;61(4):1044–53.
37. Pillonetto G, De Nicolao G. A new kernel-based approach for linear system identification.
Automatica. 2010;46(1):81–93.
38. Aiello EM, Lisanti G, Magni L, Musci M, Toffanin C. Therapy-driven deep glucose forecast-
ing. Eng Appl Artif Intell. 2020;87:103255.
39. Shi D, Dassau E, Doyle FJ III. Multivariate learning framework for long-term adaptation in the
artificial pancreas. Bioengineering Translat Med. 4(1):61–74; 019.
40. De Paula M, Acosta GG, Martìnez EC. On-line policy learning and adaptation for real-time
personalization of an artificial pancreas. Expert Sys Applicat. 42(4):2234–55, 201.
41. El-Khatib FH, Russell SJ, Magyar KL, Sinha M, McKeon K, Nathan DM, Damiano
ER. Autonomous and continuous adaptation of a bihormonal bionic pancreas in adults and
adolescents with type 1 diabetes. J Clin Endocrinol Metabol. 2014;99(5):1701–11.
42. Shi D, Dassau E, Doyle FJ. Adaptive zone model predictive control of artificial pancreas
based on glucose-and velocity-dependent control penalties. IEEE Trans Biomed Eng.
2018;66(4):1045–54.
43. Resalat N, Hilts W, Youssef JE, Tyler N, Castle JR, Jacobs PG. Adaptive control of an artificial
pancreas using model identification, adaptive postprandial insulin delivery, and heart rate and
accelerometry as control inputs. J Diabetes Sci Technol. 2019;13(6):1044–53.
44. Messori M, Kropff JADFS, Place J, Visentin R, Calore R, Toffanin C, Di Palma F, Lanzola
G, Farret AAO. Individually adaptive artificial pancreas in subjects with type 1 diabe-
tes: a one-month proof-of-concept trial in free-living conditions. Diabetes Technol Ther.
2017;19(10):560–71.
45. Magni L, Forgione M, Toffanin C, Dalla Man C, Kovatchev B, De Nicolao G, Cobelli C. Run-
to-run tuning of model predictive control for type 1 diabetes subjects: in silico trial. J Diabetes
Sci Technol. 2009;3(5):1091–8.
46. Toffanin C, Messori M, Cobelli C, Magni L. Automatic adaptation of basal therapy for
type 1 diabetic patients: a run-to-run approach. Biomedical Signal Processing and Control.
2017;31:539–49.
47. Toffanin C, Visentin R, Messori M, Di Palma F, Magni L, Cobelli C. Toward a run-to-run adap-
tive artificial pancreas: in silico results. IEEE Trans Biomed Eng. 2017;65(3):479–88.
48. Toffanin C, Aiello E, Del Favero S, Cobelli C, Magni L. Multiple models for artificial pan-
creas predictions identified from free-living condition data: a proof of concept study. J Process
Control. 2019;77:29–37.
Chapter 16
Evolving Approaches to Type 1 Diabetes
Management
Jay S. Skyler
Ideal therapeutic goals for type 1 diabetes (T1D) include automated insulin delivery
(AID); prevention of immune destruction, to preserve beta cell mass or function;
and replacement or regeneration of insulin-secreting beta cells. This chapter will
discuss progress in each of these approaches.
J. S. Skyler (*)
Diabetes Research Institute, University of Miami Miller School of Medicine,
Miami, FL, USA
e-mail: [email protected]
algorithms evolve to the needs of each individual patient [14–15]. Newer systems
may well have algorithms that control delivery of additional hormones besides insu-
lin, such as glucagon and/or an amylin analogue [16–18]. Other chapters in this
book discuss the detailed development of control algorithms and the use of AID
systems as precision medicine tools for adults and children and during pregnancy.
Automated insulin delivery systems have evolved from “low-glucose suspend”
in which insulin delivery was interrupted if the CGM value crossed a low threshold
[19] to “predictive low-glucose suspend” in which insulin delivery was interrupted
when the CGM value was falling and predicted that it would cross a low threshold
[20] to “hybrid closed loop” which provided control of basal glucose (principally
overnight) but required mealtime initiation of bolus insulin delivery by the patient
[21] to full “automated closed loop” which controls both basal insulin delivery and,
to some extent, mealtime bolus insulin delivery [9–13]. Currently available com-
mercial systems have achieved 70–75% time in range (TIR) of 70–180 mg/dl
[3.9–10 mmol/l] for adults and 67–73% TIR for children or adolescents. As impor-
tant, these systems have reduced time spent <54 mg/dl [3.0 mmol/l] to less than
0.5%. The systems still need improvement to achieve ideal glycemic control.
Besides improving the control algorithms with such things as deep learning and big
data analytics, one limitation that currently exists is the slowness of insulin absorp-
tion in response to modulation by the control algorithm. There is hope that the
development of ultrarapid insulins, or intra-peritoneal insulin delivery, will speed
up directed insulin delivery. Unfortunately, the first evaluation of an ultrarapid insu-
lin in an AID system did not result in improved outcome [22]. Meaningful trials of
AID with peritoneal insulin delivery have not yet been reported.
Algorithms for AID are evolving so that the patient may merely have to press a
button to indicate initiation of a meal, so that the system will respond differently
than it would to mere changes in prevailing glucose level [23]. Future systems
potentially may also detect physical activity such as by the use of an accelerometer,
sleep pattern, and other variables. However, one must remain cautious, since the
more systems and devices that are integrated, the greater the complexity, and the
increased potential for technical risks. Nonetheless, technology is advancing to the
point that we can anticipate that AID systems will provide near normal glucose
levels without risk of hypoglycemia.
is a progressive decline in beta-cell function, spanning years [24]. This gives one
the opportunity to intervene in an attempt to modify the course of the disease.
Such intervention may precede the clinical stage of the disease, in an attempt to
halt the progression of the disease, or may occur after the clinical onset of the
disease, in an attempt to preserve – or ideally to improve – residual beta-cell func-
tion [25, 26].
Beginning in the 1980s, randomized controlled clinical trials have been con-
ducted in an effort either to delay or prevent clinical onset of the disease or to pre-
serve beta-cell function. Prevention studies have begun in stage 1 of the disease, i.e.,
individuals with two or more diabetes-related autoantibodies, or in stage 2 of the
disease, i.e., those with both autoantibodies and dysglycemia as evidence of decline
of beta-cell function. In general, the goal of such prevention studies is to delay pro-
gression to stage 3, i.e., clinical T1D. To date, none of the multiple trials initiated in
stage 1 have had convincing evidence demonstrating a delay in development of
clinical T1D [27]. In contrast, in one trial, the anti-CD3 monoclonal antibody tepli-
zumab, initiated in stage 2 T1D, was shown to delay progression to clinical T1D
[28, 29].
There have been a number of interventions tested after clinical onset of T1D
that have been shown to preserve residual beta-cell function, at least transiently
[30–42]. In some cases, the beneficial effect, compared to that of placebo, was
sustained for more than 1 year. Unfortunately, often the intervention was discon-
tinued, on the misguided assumption that the intervention would permanently alter
the course of the disease, only to see a decline in beta-cell function toward that of
the placebo group [40, 41]. Yet, in a few cases, a short course of therapy – as short
as 2 days or 6 or 14 days – has resulted in sustained beneficial effect for 2 years or
more [33, 34, 39].
It is possible that intervening after the appearance of antibodies, or certainly after
the clinical onset of T1D, may be too late to alter the disease course. In an attempt
to intervene prior to the immune process taking hold, efforts are underway to con-
duct population screening for genetic susceptibility at birth or shortly thereafter and
attempt primary prevention before appearance of antibodies [43]. Any such inter-
vention initiated for a primary prevention trial would require that the studies be
subject-centric and relatively nonintrusive.
An alternative strategy to potentially improve outcomes in preserving beta-cell
function in recent onset T1D is to use a combination of agents. These might include
agents that arrest background innate immunity and inflammation (e.g., anti-TNFα),
stop adaptive immunity (e.g., anti-CD3 or antithymocyte globulin (ATG)), and/or
stimulate protective or regulatory immunity (e.g., low-dose interleukin-2 or infu-
sion of regulatory T cells). In addition to immune intervention, one might consider
agents that improve beta-cell health or function (e.g., GLP-1 receptor agonists). It
remains to be shown whether a combination strategy might improve outcomes of
clinical trials [44, 45].
318 J. S. Skyler
Beta-cell replacement has been accomplished for many years by either whole pan-
creas transplantation or isolated islet transplantation [46]. Whole pancreas trans-
plantation has usually accompanied simultaneous kidney transplantation in patients
with diabetes with end-stage renal disease, since they will require immune suppres-
sion to prevent allograft organ rejection. Occasionally, pancreas transplants have
been done following kidney transplantation or have been done alone, in the absence
of kidney transplantation [47]. Organs are almost invariably obtained from cadaver
donors. Isolated islet transplantation has generally been done in individuals with
recurrent severe hypoglycemia resulting in seizures, loss of consciousness, emer-
gency room visits, or hospitalization [48]. Again, islets are obtained from cadaver
donor pancreases, with the islets isolated and purified [49] before being trans-
planted, usually via portal vein infusion, but more recently in other locations such
as the omentum [50].
There are three issues which have limited both pancreas and islet transplantation.
These are (1) the availability and source of cells (there has been an average of only
1200 pancreas donors per year in the United States) [51], (2) the alloimmune
response leading to organ rejection, and (3) the recurrence of the autoimmune
response which led to T1D in the first place [52, 53].
To provide availability of cells, there are three strategies that have been pro-
posed: (1) xenotransplantation using pig islets [54], particularly using specially
bred pigs that are devoid of porcine viruses [55], (2) use of human embryonic stem
cells (hESCs) [56, 57], and (3) use of induced pluripotent stem cells (iPSCs) [58–
60]. Each of these strategies has the potential of providing an essentially unlimited
source of cells.
There are two general strategies for stem cell transplantation: (1) a patient-
specific approach using reprogramming or transdifferentiation of cells to create
islets, such as by converting liver cells (obtained by biopsy) to insulin-secreting
cells in the laboratory [61], and (2) a generic approach using allogeneic cells, e.g.,
a bank of human embryonic stem cells (hESCs) or induced pluripotent stem cells
(iPSCs). The latter approach creates cells that may be used for multiple patients,
using cells that are centrally produced and more easily commercialized. Indeed,
randomized clinical trials are currently underway with both hESCs [62] and
iPSCs [63].
For both hESCs and iPSCs, there needs to be immune protection both against
alloimmune rejection and potentially against autoimmune recurrence. This might be
accomplished by the use of immunosuppressive or immunomodulatory drugs.
Alternatively, one could create a physical barrier protecting the infused cells from
the immune system using encapsulation [64, 65]. Ultimately, one might use gene
editing for either immune evasion or immune protection [66].
16 Evolving Approaches to Type 1 Diabetes Management 319
Conclusions
References
1. Clemens AH, Chang PH, Myers RW. The development of Biostator, a glucose controlled insu-
lin infusion system (GCIIS). Horm Metab Res Suppl. 1977;7:23–33.
2. Pickup JC, Keen H, Parsons JA, Alberti KGMM. Continuous subcutaneous insulin infusion:
an approach to achieving normoglycemia. Br Med J. 1978;1:204–7.
3. Tamborlane WV, Sherwin RS, Genel M, Felig P. Reduction to normal of plasma glucose in
juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump. N
Engl J Med. 1979;300:573–8.
4. Skyler JS, Seigler DE, Reeves ML. Optimizing pumped insulin delivery. Diabetes Care.
1982;5:135–9.
5. Farkas-Hirsch R, Hirsch I. Continuous subcutaneous insulin infusion: a review of the past and
its implementation for the future. Diabetes Spectrum. 1994;7(80-84):136–8.
6. Renard E. Implantable closed-loop glucose-sensing and insulin delivery: the future for insulin
pump therapy. Curr Opin Pharmacol. 2002;2:708–16.
7. Hovorka R. Closed-loop insulin delivery: from bench to clinical practice. Nat Rev Endocrinol.
2011;7:385–95.
8. Weinzimer SA, Steil GM, Swan KL, Dziura J, Kurtz N, Tamborlane WV. Fully automated
closed-loop insulin delivery versus semiautomated hybrid control in pediatric patients with
type 1 diabetes using an artificial pancreas. Diabetes Care. 2008;31:934–9.
9. Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, et al. Six-
month randomized, multicenter trial of closed-loop control in type 1 diabetes. N Engl J Med.
2019;381:1707–17.
10. Breton MD, Kanapka LG, Beck RW, Ekhlaspour L, Forlenza GP, Cengiz E, et al. A randomized
trial of closed-loop control inchildren with type 1 diabetes. N Engl J Med. 2020;383:836–45.
320 J. S. Skyler
11. Brown SA, Forlenza GP, Bode BW, Pinsker JE, Levy CJ, Criego AB, at al. Multicenter trial of
a tubeless, on-body automated insulin delivery system with customizable glycemic targets in
pediatric and adult participants with type 1 diabetes. Diabetes Care. 2021;44:1630–40.
12. Collyns OJ, Meier RA, Betts ZL, Chan DSH, Frampton C, Frewen CM, et al. Improved glyce-
mic outcomes with medtronic minimed advanced hybrid closed-loop delivery: results from a
randomized crossover trial comparing automated insulin delivery with predictive low glucose
suspend in people with type 1 diabetes. Diabetes Care. 2021;44:969–75.
13. Fuchs J, Allen JM, Boughton CK, Wilinska ME, Thankamony A, de Beaufort C, et al.
Assessing the efficacy, safety and utility of closed-loop insulin delivery compared with sensor-
augmented pump therapy in very young children with type 1 diabetes (KidsAP02 study): an
open-label, multicentre, multinational, randomised cross-over study protocol. BMJ Open.
2021;11(2):e042790.
14. Kovatchev B. A century of diabetes technology: signals, models, and artificial pancreas con-
trol. Trends Endocrinol Metab. 2019;30:432–44.
15. El-Khatib FH, Russell SJ, Magyar KL, Sinha M, McKeon K, Nathan DM, et al. Autonomous
and continuous adaptation of a bihormonal bionic pancreas in adults and adolescents with type
1 diabetes. J Clin Endocrinol Metab. 2014;99:1701–11.
16. Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, et al. Outpatient
glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med. 2014;371:313–25.
17. El-Khatib FH, Balliro C, Hillard MA, Magyar KL, Ekhlaspour L, Sinha M, et al. Home use
of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a
multicentre randomised crossover trial. Lancet. 2017;389:369–80.
18. Haidar A, Tsoukas MA, Bernier-Twardy S, Yale JF, Rutkowski J, et al. A Novel Dual-Hormone
Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled
Crossover Trial. Diabetes Care. 2020;43:597–606.
19. Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, et al. Threshold-based
insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369:224–32.
20. Battelino T, Nimri R, Dovc K, Phillip M, Bratina N. Prevention of hypoglycemia with predic-
tive low glucose insulin suspension in children with type 1 diabetes: a randomized controlled
trial. Diabetes Care. 2017;40:764–70.
21. Bergenstal R, Garg S, Weinzimer SA, Buckingham BA, Bode BW, Tamborlane WV, et al.
Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes.
JAMA. 2016;316:1407–8.
22. Boughton CK, Hartnell S, Thabit H, Poettler T, Herzig D, Wilinska ME, et al. Hybrid closed-
loop glucose control with faster insulin aspart compared with standard insulin aspart in adults
with type 1 diabetes: a double-blind, multicentre, multinational, randomized, crossover study.
Diabetes Obes Metab. 2021;23:1389–96.
23. Garcia-Tirado J, Diaz JL, Esquivel-Zuniga R, Koravi CLK, Corbett JP, Dawson M, et al.
Advanced closed-loop control system improves postprandial glycemic control compared with
a hybrid closed-loop system following unannounced meal. Diabetes Care. 2021:dc210932.
https://doi.org/10.2337/dc21-0932. Online ahead of print.
24. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69–82.
25. Atkinson MA, Roep BO, Posgai A, Wheeler DCS, Peakman M. The challenge of modulating
β-cell autoimmunity in type 1 diabetes. Lancet Diabetes Endocrinol. 2019;7:52–64.
26. Roep BO, Wheeler DCS, Peakman M. Antigen-based immune modulation therapy for type 1
diabetes: the era of precision medicine. Lancet Diabetes Endocrinol. 2019;7:65–74.
27. Jacobsen LM, Schatz DA. Insulin immunotherapy for pretype 1 diabetes. Curr Opin Endocrinol
Diabetes Obes. 2021;28:390–6.
28. Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, et al. An anti-CD3
antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med. 2019;381:603–13.
29. Sims EK, Bundy BN, Stier K, Serti E, Lim N, Long SA, et al. Teplizumab improves and
stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med.
2021;13(583):eabc8980.
16 Evolving Approaches to Type 1 Diabetes Management 321
30. Feutren G, Assan R, Karsenty G, Du Rostu H, Sirmai J, Papoz L, et al. Cyclosporin increases
the rate and length of remissions in insulin dependent diabetes of recent onset. Results of a
multicentre double-blind trial. Lancet. 1986;2:119–24.
31. The Canadian-European Randomized Control Trial Group. Cyclosporin-induced remission of
IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced
insulin secretion. Diabetes. 1988;37:1574–82.
32. Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S. Immunosuppression
with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl
J Med. 1988;319:599–604.
33. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3
monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692–8.
34. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, et al.
Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med.
2005;352:2598–608.
35. Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W, et al.
Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-
onset type 1 diabetes in a randomized controlled trial: Metabolic and immunologic features at
baseline identify a subgroup of responders. Diabetes. 2013;62:3766–74.
36. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al.
Rituximab, B-lymphocyte depletion and preservation of beta-cell function. N Engl J Med.
2009;361:2143–52.
37. Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Co-stimulation
modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised double-
blind. Placebo-Controlled Trial Lancet. 2011;378:412–9.
38. Rigby MR, DiMeglio LA, Rendell MS, Felner EI, Dostou JM, Gitelman SE, et al. Targeting of
memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results
of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol.
2013;1:284–94.
39. Haller MJ, Long SA, Blanchfield JL, Schatz DA, Skyler JS, Krischer JP, et al. Low-dose anti-
thymocyte globulin preserves C-peptide and reduces A1c in new onset type 1 diabetes: two
year clinical trial data. Diabetes. 2019;68:1267–76.
40. von Herrath M, Bain SC, Bode B, Clausen JO, Coppieters K, Gaysina L, et al. Anti-
interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with
recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial.
Lancet Diabetes Endocrinol. 2021;9:212–24.
41. Quattrin T, Haller MJ, Steck AK, Felner EI, Li Y, Xia Y, et al. Golimumab and beta-cell func-
tion in youth with new-onset type 1 diabetes. N Engl J Med. 2020;383:2007–17.
42. Gitelman SE, Bundy BN, Ferrannini E, Lim N, Blanchfield JL, DiMeglio LA, et al. Imatinib
therapy for patients with recent-onset type 1 diabetes: a randomised, double blind, multicentre,
placebo controlled phase 2 trial. Lancet Diabetes Endocrinol. 2021;9:502–14.
43. Ziegler AG, Danne T, Dunger DB, Berner R, Puff R, Kiess W, et al. Primary prevention
of beta-cell autoimmunity and type 1 diabetes - The Global Platform for the Prevention of
Autoimmune Diabetes (GPPAD) perspectives. Mol Metab. 2016;5:255–62.
44. Smilek DE, Ehlers ME, Nepom GT. Restoring the balance: immunotherapeutic combinations
for autoimmune disease. Dis Model Mech. 2014;7:503–13.
45. Skyler JS. The prevention & reversal of type 1 diabetes – past challenges & future opportuni-
ties. Diabetes Care. 2015;38:997–1007.
46. Gruessner AC, Gruessner RW. Long-term outcome after pancreas transplantation: a registry
analysis. Curr Opin Organ Transplant. 2016;21:377–85.
47. Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, et al. Phase 3
trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia.
Diabetes Care. 2016;39:1230–40.
322 J. S. Skyler
48. Vantyghem MC, Chetboun M, Gmyr V, Jannin A, Espiard S, Le Mapihan K, et al. Ten-year
outcome of islet alone or islet after kidney transplantation in type 1 diabetes: a prospective
parallel-arm cohort study. Diabetes Care. 2019;42:2042–9.
49. Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, et al. Assessment of the severity
of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplanta-
tion. Diabetes. 2004;53:955–62.
50. Ricordi C, Lacy PE, Finke EH, Olack BJ, Sharp DW. Automated method for isolation of
human pancreatic islets. Diabetes. 1988;37:413–20.
51. Baidal DA, Ricordi C, Berman DM, Alvarez A, Padilla N, Ciancio G, et al. Bioengineering of
an intraabdominal endocrine pancreas. N Engl J Med. 2017;376:1887–9.
52. Kandaswamy R, Stock PG, Miller J, Skeans MA, White J, Wainright J, et al. OPTN/SRTR
2019 annual data report: pancreas. Am J Transplant. 2021;21(Suppl 2):138–207.
53. Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, et al. Recurrence
of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosup-
pression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes.
2010;59:947–57.
54. Burke GW 3rd, Vendrame F, Pileggi A, Ciancio G, Reijonen H, Pugliese A. Recurrence of
autoimmunity following pancreas transplantation. Curr Diab Rep. 2011;11:413–9.
55. Ludwig B, Ludwig S, Steffen A, Knauf Y, Zimerman B, Heinke S, et al. Favorable outcome
of experimental islet xenotransplantation without immunosuppression in a nonhuman primate
model of diabetes. Proc Natl Acad Sci U S A. 2017;114:11745–50.
56. Niu D, Wei HJ, Lin L, George H, Wang T, Lee IH, et al. Inactivation of porcine endogenous
retrovirus in pigs using CRISPR-Cas9. Science. 2017;357:1303–7.
57. D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, et al. Production
of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat
Biotechnol. 2006;24:1392–401.
58. Schulz TC, Young HY, Agulnick AD, Babin MJ, Baetge EE, Bang AG, et al. A scalable system
for production of functional pancreatic progenitors from human embryonic stem cells. PLoS
One. 2012;7(5):e37004.
59. Pagliuca FW, Millam JR, Gürtler M, Segel M, Van Devort A, Ryu JH, et al. Generation of
functional human pancreatic beta cells in vitro. Cell. 2014;159:428–39.
60. Sneddon JB, Qizhi T, Stock P, Bluestone JA, Roy D, Desai T, et al. Stem cell therapies for
treating diabetes: progress and remaining challenges. Cell Stem Cell. 2018;6:810–23.
61. Meivar-Levy I, Ferber S. Liver to pancreas transdifferentiation. Curr Diab Rep. 2019;19:76.
62. Pepper AR, Bruni A, Pawlick R, O’Gorman D, Kin T, Thiesen A, et al. Posttransplant char-
acterization of long term functional hESC-derived pancreatic endoderm grafts. Diabetes.
2019;68:953–62.
63. ClinicalTrials.Gov NCT04786262. A safety, tolerability, & efficacy study of VX-880 in par-
ticipants with type 1 diabetes. Accessed 1 Sept, 2021.
64. Desai TA, Tang Q. Islet encapsulation therapy - racing towards the finish line? Nat Rev
Endocrinol. 2018;14:630–2.
65. Stock AA, Manzoli V, De Toni T, Abreu MM, Poh YC, Ye L, et al. Conformal coating of
stem cell-derived islets for beta cell replacement in type 1 diabetes. Stem Cell Reports.
2020;14:91–104.
66. Parent AV, Faleo G, Chavez J, Saxton M, Berrios DI, Kerper NR, et al. Selective deletion of
human leukocyte antigens protects stem cell-derived islets from immune rejection. Cell Rep.
2021;36:109538.
67. Zhou Q, Melton DA. Pancreas Regeneration. Nature. 2018;557:351–8.
68. Wang P, Karakose E, Choleva L, Kumar K, DeVita RJ, Garcia-Ocaña A, et al. Human beta
cell regenerative drug therapy for diabetes: past achievements and future challenges. Front
Endocrinol. 2021;12:671946.
69. Skyler JS. Hope versus hype: where are we in type 1 diabetes? Diabetologia. 2018;61:509–16.
Index
Z
U Zaharia, O.P., 89–104
Umpierrez, G., 199–207 Zeevi, D., 237, 241, 242
United Kingdom Prospective Diabetes Study Zhao, L., 238
(UKPDS), 20
US Food and Drug Administration
(FDA), 180