2022 - Book - PrecisionMedicineInDiabetes Precision Medicine in DiabeteS

Precision
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
ISBN 978-3-030-98926-2 ISBN 978-3-030-98927-9 (eBook)

https://doi.org/10.1007/978-3-030-98927-9
© Springer Nature Switzerland AG 2022

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Foreword
Precision medicine is gaining a lot of attention in clinical practice, particularly with

the development of drugs in some disease states such as cancer, where compared to
previous toxic chemotherapy, the use of targeted treatments based on genetic muta-
tions in the tumors has led to considerable success with fewer side effects. However,
such an approach has so far been elusive in the management of diabetes. Nevertheless,
the availability of new drugs and the wealth of data in clinical trials as well as new
developments in technology have led to the development of approaches to be more
precise in our treatment of people with type 2 diabetes, in particular, so that good
control of glucose and prevention of complications may be achieved. This book,
Precision Medicine in Diabetes, is therefore a useful summary of the current state
of knowledge in this field.
The book begins with a discussion of current therapeutics and a call for tailoring
the metabolic derangement, pointing out that one size does not fit all. This is fol-
lowed by discussions about diabetes and the heart, with considerable new data in
this aspect of diabetes management derived from large cardiovascular outcome tri-
als. This focuses not only on glucose-lowering but also on lipid management and
leads to an approach for implementation of precision medicine in both type 1 and
type 2 diabetes.
The most classic area where precision medicine can be applied in diabetes is the
recognition that a small but significant proportion of people with what appears to be
type 2 diabetes actually have the monogenic form previously called variants of
maturity-onset diabetes in the young [MODY]. Recent advances have pointed out
the huge therapeutic advantages of recognition of monogenic diabetes leading to
better treatments from what appears miraculous in patients with mutations of the
potassium channel, who respond to sulfonylurea drugs rather than insulin, which
can be stopped in many cases, as well as successful treatment of other forms of
monogenic diabetes with either sulfonylureas or, importantly, no treatment at all in
the case of mutations of the glucokinase gene.
Novel approaches in the management of diabetes due to precise therapy have led
to better management of patients in the hospital, better diets have led to remission
of diabetes in some cases, and surgical approaches have also led to remission along
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
Lastly, I wish to dedicate this book to my father, a dedicated physician himself

whom I lost during the lockdown in 2020; my mother, who encouraged me to be
independent and freethinking; and to my loving family, my husband and two
daughters, who have always inspired me to do better.
Charlottesville, VA, USA Rita Basu

Contents
1 Precision Medicine Approaches for Management

of Type 2 Diabetes�� 1
David Chen, Jordan Fulcher, Emma S. Scott, and Alicia J. Jenkins
2 Precision Medicine for Diabetes and Cardiovascular Disease�� 53
Siu-Hin Wan and Horng H. Chen
3 Precision Medicine for Diabetes and Dyslipidemia�� 65
Ethan Alexander, Elizabeth Cristiano, and John M. Miles
4 Imaging in Precision Medicine for Diabetes�� 89
Oana Patricia Zaharia, Vera B. Schrauwen-Hinderling, and
Michael Roden
5 Implementation of Precision Genetic Approaches for
Type 1 and 2 Diabetes�� 111
Ronald C. W. Ma and Juliana C. N. Chan
6 Precision Genetics for Monogenic Diabetes�� 131
Andrea O. Y. Luk and Lee-Ling Lim
7 Diabetic Kidney Disease: Identification, Prevention,
and Treatment�� 149
M. Luiza Caramori and Peter Rossing
8 Precision Medicine for Diabetic Neuropathy�� 171
Long Davalos, Amro M. Stino, Dinesh Selvarajah, Stacey
A. Sakowski, Solomon Tesfaye, and Eva L. Feldman
9 Inpatient Precision Medicine for Diabetes�� 199
Georgia Davis, Guillermo E. Umpierrez, and Francisco J. Pasquel
10 Precision Medical Management Strategies for
Diabetes Remission�� 211
Sangeetha R. Kashyap and Saif M. Borgan
ix
x Contents
11 Surgical Management for Diabetes Remission�� 217

A. Maria Daniela Hurtado and Maria Collazo-Clavell
12 Precision Nutrition for Type 2 Diabetes�� 233
Orly Ben-Yacov and Michal Rein
13 Precision Exercise and Physical Activity for Diabetes�� 251
Normand G. Boulé and Jane E. Yardley
14 Diabetes Technology for Precision Therapy in Children,
Adults, and Pregnancy�� 289
Roger S. Mazze, Alice Pik Shan Kong, Goran Petrovski,
and Rita Basu
15 Adaptive and Individualized Artificial Pancreas for Precision
Management of Type 1 Diabetes�� 305
Chiara Toffanin, Claudio Cobelli, and Lalo Magni
16 Evolving Approaches to Type 1 Diabetes Management�� 315
Jay S. Skyler
Index�� 323
Contributors
Ethan Alexander Divisions of Endocrinology, Metabolism and Genetics,

University of Kansas School of Medicine, Kansas City, KS, USA
Rita Basu Division of Endocrinology, University of Virginia,
Charlottesville, VA, USA
Orly Ben-Yacov Department of Computer Science and Applied Mathematics and
Department of Molecular Cell Biology, Weizmann Institute of Science,
Rehovot, Israel
Saif M. Borgan Endocrinology and Metabolism Institute, Cleveland Clinic
Foundation, Cleveland, OH, USA
Normand G. Boulé Faculty of Kinesiology, Sport, and Recreation, University of
Alberta, Edmonton, AB, Canada
Alberta Diabetes Institute, Edmonton, AB, Canada
M. Luiza Caramori Division of Diabetes, Endocrinology and Metabolism,
Department of Medicine, Division of Pediatric Nephrology, Department of
Pediatrics, University of Minnesota, Minneapolis, MN, USA
Juliana 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
David Chen Monash School of Medicine, Monash University, Melbourne, VIC,
Australia
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
Horng H. Chen Department of Cardiovascular Diseases, Mayo Clinic,
Rochester, MN, USA
xi
xii Contributors
Claudio Cobelli Department of Woman and Child’s Health, University of Padova,

Padova, Italy
Maria Collazo-Clavell Division of Endocrinology, Diabetes, Metabolism, and
Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA
Elizabeth Cristiano Divisions of Endocrinology, Metabolism and Genetics,
University of Kansas School of Medicine, Kansas City, KS, USA
Long Davalos Department of Neurology, University of Michigan, Ann
Arbor, MI, USA
Georgia Davis Division of Endocrinology, Department of Medicine, Emory
University School of Medicine, Atlanta, GA, USA
Eva L. Feldman Department of Neurology, University of Michigan, Ann
Arbor, MI, USA
Jordan Fulcher NHMRC Clinical Trials Centre, University of Sydney, Sydney,
NSW, Australia
Austin and Repatriation General Hospital, Melbourne, VIC, Australia
A. Maria Daniela Hurtado Division of Endocrinology, Diabetes, Metabolism,
and Nutrition, Department of Medicine, Mayo Clinic Health System, La
Crosse, WI, USA
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of
Medicine, Mayo Clinic, Rochester, MN, USA
Alicia 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
Sangeetha R. Kashyap Cleveland Clinic Lerner College of Medicine,
Cleveland, OH, USA
Alice Pik Shan Kong Chinese University of Hong Kong, Hong Kong, PRC, China
Lee-Ling 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
Andrea O. Y. Luk Department of Medicine and Therapeutics, The Chinese
University of Hong Kong, Hong Kong, SAR, China
Kong, Hong Kong, SAR, China
Ronald C. W. Ma Department of Medicine and Therapeutics, The Chinese
University of Hong Kong, Hong Kong, China
Contributors xiii
Kong, Hong Kong, China
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
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
Emma S. Scott NHMRC Clinical Trials Centre, University of Sydney, Sydney,

NSW, Australia
Royal North Shore Hospital, Sydney, NSW, Australia
Dinesh Selvarajah Department of Oncology and Metabolism, Medical School,
University of Sheffield, Sheffield, UK
Jay S. Skyler Diabetes Research Institute, University of Miami Miller School of
Medicine, Miami, FL, USA
Amro M. Stino Department of Neurology, University of Michigan, Ann
Arbor, MI, USA
Solomon Tesfaye Diabetes Research Unit, Sheffield Teaching Hospital,
Sheffield, UK
Chiara Toffanin Department of Electrical, Computer and Biomedical Engineering,
University of Pavia, Pavia, Italy
Guillermo E. Umpierrez Division of Endocrinology, Department of Medicine,
Emory University School of Medicine, Atlanta, GA, USA
Siu-Hin Wan Minneapolis Heart Institute, United Hospital, Saint Paul, MN, USA
Jane E. Yardley Faculty of Kinesiology, Sport, and Recreation, University of
Alberta, Edmonton, AB, Canada
Augustana Faculty, University of Alberta, Edmonton, AB, Canada
Women’s and Children’s Health Research Institute, Edmonton, AB, Canada
Oana Patricia Zaharia 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
Neuherberg, Germany
Introduction
Precision Medicine in Diabetes describes solid approaches to diagnosing and treat-

ing diabetes in various divisions of medicine.
Alicia Jenkins, David Chen, Jordan Fulcher, and Emma S. Scott write the first
chapter, “Precision Medicine Approaches for Management of type 2 Diabetes.” It
summarizes the relevant evidence base from the literature and major guidelines for
type 2 diabetes care, including the prevention and treatment of diabetes and its asso-
ciated complications. Dr. Jenkins uses mnemonics, flowcharts, and summary tables
to guide the busy clinician in type 2 diabetes care. She reviews some ongoing
research that will likely enhance the application of precision medicine in diabetes,
and notes that “efforts must be made to ensure equitable access for all people with
diabetes as per locally available resources.”
Horng H. Chen and Siu-Hin Wan author the second chapter, “Precision Medicine
for Diabetes and Cardiovascular Disease.” They describe how diabetes is a definite
risk factor for the development and progression of coronary heart disease and heart
failure. Evidence shows that patients with both cardiovascular risk and diabetes are
at increased risk of myocardial infarctions, strokes, heart failure, and death com-
pared to the general population. To manage the conditions of diabetes and heart
failure, patients must incorporate both lifestyle modifications as well as glycemic
control. Some additional cardiovascular benefits may come from newer pharmaco-
logic agents such as SGLT2 inhibitors and GLP1 agonists.
In “Precision Medicine for Diabetes and Dyslipidemia,” Chap. 3, John Miles,
Ethan Alexander, and Elizabeth Cristiano discuss several classes of medications that
primarily target LDL cholesterol and have been shown to reduce cardiovascular
events. Medication classes include the statins, ezetimibe, PCSK9 inhibitors, and
bempedoic acid. However, other agents that do not target LDL cholesterol show
promise, but need additional study, such as fibrates and omega-3 fatty acids. The
chapter concludes with what they thinks is a neglected area of diabetic dyslipidemia
management, which is the role of diabetes-specific pharmacotherapy. Several drug
classes, including metformin, GLP-1 receptor agonists, and thiazolidinediones, tar-
get lipoprotein abnormalities and have shown to reduce cardiovascular risk. Thus,
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
proportion of individuals starting kidney replacement therapy due to diabetes varies

significantly, ranging from 13% in China to 66% in Singapore. Chronic kidney dis-
ease (CKD) risk is about 50% for patients with T1D and 30% for those with T2D,
and those with T2D and CKD are at higher risk for cardiovascular morbidity and
mortality than those without CKD.
Chapter 8, entitled “Precision Medicine for Diabetic Neuropathy,” is the work of
Eva Feldman, Long Davalos, Amro M. Stino, Dinesh Selvarajah, Stacey
A. Sakowski, and Solomon Tesfaye. They note that the most prevalent diabetic and
prediabetic complication is diabetic peripheral neuropathy (DPN), which leads to
substantial morbidity. Distal symmetric polyneuropathy is the most common mani-
festation, which can present with tingling, pain, and loss of sensory function. A
multi-faceted understanding of evolving concepts in the underlying pathophysiol-
ogy of DPN is required because DPN due to type 1 (T1D) and type 2 (T2D) diabetes
represents largely different disease processes. Particularly in T2D, there is growing
evidence suggesting that metabolic syndrome, obesity, and dyslipidemia contribute
to the development of DPN. In addition, functional MRI, quantitative sensory test-
ing, and even genomic data assist to more precisely phenotype and classify DPN
neuropathic pain. Ultimately, the goal is for treatments to be individualized based
on better understanding of underlying pathogenesis and pain processes.
Guillermo E. Umpierrez, Georgia Davis, and Francisco J. Pasquel are the authors
of Chap. 9, “Inpatient or Hospital Precision Medicine for Diabetes.” In the past few
decades, the tools for monitoring and treating patients living with diabetes have
expanded exponentially, with opportunities to manage the disease through targeted
approaches according to needs and clinical characteristics of individuals. Current
advances in genetics and systems biology can identify diabetes phenotypes through
data from multiple sources to better determine an individual’s needs. However, in
the hospital setting, there is still limited application of these concepts. To develop
inpatient precision diabetes medicine, they review advances and opportunities in
precision diagnostics (characterization of unique individual-level data for more
accurate disease-state classification and inpatient risk stratification), precision mon-
itoring (real-time continuous glucose data with remote monitoring capabilities and
patient-specific glycemic control targets), and precision therapeutics (addition of
non-insulin agents with associated benefits beyond glycemic control, computer-
based decision algorithms, and automated insulin delivery).
In Chap. 10, “Precision Medical Management Strategies for Diabetes Remission,”
Sangeeta R. Kashyap and Saif Borgan write about remission of type 2 diabetes mel-
litus. Remission is a period of at least 6–12 months to normalization of blood glu-
cose levels to levels below the threshold at which diabetes is diagnosed, in the
absence of active pharmacological agents. An area of controversy has been the dura-
tion of normalization, which has caused some degree of heterogeneity across stud-
ies. Because the genetic and environmental factors that led to the development of
this chronic disease still exist in many patients who achieve this state, “remission”
is usually the term used, not “cure.”
Maria Collazo-Clavell and Maria Daniela Hurtado write Chap. 11, “Precision
Surgical Management Strategies for Diabetes Remission.” The term “diabesity” is
xviii Introduction
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
functionality of continuous glucose monitoring (CGM) and continuous insulin infu-

sion (pump) technologies. It addresses their current usage in clinical practice and
shows how they contribute to precision medicine, discussing their future applica-
tions in the diagnosis and treatment of diabetes. The terms type 1 and type 2 diabe-
tes as well as diabetes in pregnancy are major classifications of a condition and
suggest “one term fits all.” However, genomics has identified numerous subtypes,
suggesting that not all conditions within the same classification are the same. Little
emphasis has been on glucose sensing, insulin delivery technologies, and their roles
in metabolic profiling to identify the distinguishing features within these subgroups
that contribute to greater diagnostic specificity and improved treatment. As a result,
the precision medicine paradigm needs to shift to allow for the technologies of con-
tinuous glucose monitoring (CGM) and continuous insulin infusion (pump) towards
improving metabolic profiling and consequently glycemic control.
Chapter 15, “Adaptive and Individualized Artificial Pancreas for Precision
Management of Type 1 Diabetes,” is written by Claudio Cobelli, Chiara Toffanin,
and Lalo Magni. They describe how automated insulin delivery systems (artificial
pancreas, AP) are revolutionizing type 1 diabetes management. Incredible progress
in subcutaneous (sc) glucose sensing, sc insulin pumps, and control algorithms
make these systems possible. Several control strategies are being explored, for
example, proportional derivative integral control and model predictive control, by
using the sc insulin delivery route. Also under investigation is AP employing intra-
peritoneal (ip) insulin delivery. Important issues are control algorithm individual-
ization and adaptivity, that is, capability to adapt to the changing in-time metabolic
status of a person. These issues are both very relevant for precision medicine
because they would allow the fine-tuning of glucose control to a specific person or
a subgroup of people.
Jay S. Skyler authors Chap. 16, “Evolving Precision Medicine Approaches to
Type 1 Diabetes Management.” There is much progress in therapeutic approaches
for type 1 diabetes (T1D). These include automated insulin delivery (AID); preven-
tion of immune destruction, to preserve beta cell mass or function; and replacement
or regeneration of insulin-secreting beta cells.
Chapter 1
Precision Medicine Approaches
for Management of Type 2 Diabetes
David Chen, Jordan Fulcher, Emma S. Scott, and Alicia J. Jenkins
Introduction
Personalized medicine, sometimes referred to as precision medicine, is defined as

“the capacity to predict disease development and influence decisions about lifestyle
choices or to tailor medical practice to an individual,” and it underpins best practice
medicine [1]. Oncologists do this well, often treating patients not just on tumor
location(s) but also on their tumor markers and underlying molecular abnormalities,
any comorbidities, and patient preferences [2]. Advances in basic and clinical sci-
ence, molecular medicine, “omics” (e.g., genomics), “big data,” electronic health
records, and decision support tools increase feasibility of increasingly individual-
ized care for many medical conditions, including diabetes.
D. Chen
Monash School of Medicine, Monash University, Melbourne, VIC, Australia
J. Fulcher
Austin and Repatriation General Hospital, Melbourne, VIC, Australia
E. S. Scott
Royal North Shore Hospital, Sydney, NSW, Australia
A. J. Jenkins (*)
Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
Department of Endocrinology, St. Vincent’s Hospital, Melbourne, VIC, Australia
e-mail: [email protected]
© Springer Nature Switzerland AG 2022 1

R. Basu (ed.), Precision Medicine in Diabetes,
https://doi.org/10.1007/978-3-030-98927-9_1
2 D. Chen et al.
Diabetes is pandemic, currently affecting 9.3% of the global population aged

20–79 years [3]. Of people with diabetes, an estimated 85–95% have Type 2 diabe-
tes, and about 79% of people with diabetes globally live in disadvantaged regions
where access to optimal diabetes care may be limited [3]. Even people with diabetes
in advantaged regions may not be able to access or afford all recommended evi-
dence-based therapies. Associated with serious acute and chronic complications,
diabetes places significant personal and socioeconomic burdens on the individual,
their family and friends, community, healthcare system, and country. Compared to
the background population, people with diabetes are more than twofold likely to
develop cardiovascular disease (CVD) [4], 15 times more likely to have a non-
traumatic lower limb amputation [5], and 25 times more likely to become blind [6].
In addition, diabetes is the leading cause of end-stage renal disease (ESRD) [7], and
pregnant women with diabetes have a two- to fourfold greater risk of pre-eclampsia
[8], which is also associated with increased risk of Type 2 diabetes, hypertension,
CVD, and heart failure [9], both for the mother and her offspring [10–12].
The Metabolic Milieu of Diabetes
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.
Precision Medicine: Now and Later
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
T2D with progressive

deterioration of insulin secretion
T2D with micro- and/or

macrovascular complications
Fig. 1.1 The metabolic milieu of Type 2 diabetes
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
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
- Lifestyle modifications including the use of technology-assisted tools[82]

- Refer to self-management education and support programs[216, 249]
- Consider metformin 500mg–2g daily in high-risk individuals[79]
- Consider bariatric surgery in morbidly obese, high-risk patients[250]
- Annual screening for diabetes - fasting blood glucose, OGTT or HbA1c
- Screen for and treat vascular risk factors[251] (GLOBES STRIVED)
Diabetes (no complications)

GLOBES STRIVED – glucose, lipid control, obesity, BP, emotions, smoking, screening, treatment to target,
inflammation/infections, vaccination, education, devices
Glucose - Aim for HbA1c ≤7% in most patients[110]

o Consider less stringent targets (e.g., 7.5–8%) in certain patients e.g., long duration
diabetes, frail, existing CVD, history of severe hypoglycemia
o Consider more aggressive target (e.g.,≤6.5%) at diagnosis/early in the course of disease
- ADA Standards of Medical Care in Diabetes for guidelines on pharmacologic glycemic
treatment[135]
Lipid - Aim for LDL-C < 2.0mmol/L in most patients
control‡[154] o Consider a more aggressive target (e.g., 1.8mmol/L) in those at very high vascular risk
(10y ASCVD risk > 20%)
o Consider a less aggressive target (e.g., <2.6mmol/L) in those without other vascular risk
factors (or 10y ASCVD risk <10%)
- Age 40–75y
o Moderate intensity statin (e.g., atorvastatin 10–20mg nocte, rosuvastatin 5–10mg daily) –
no other CVD risk factors
o High intensity statin (e.g., atorvastatin 40–80mg nocte, rosuvastatin 20–40mg daily) –
with CVD risk factors, especially if 10y ASCVD risk >10%
- Age <40y
o Moderate intensity statin in patients with CVD risk factors or long duration diabetes (≥10
years)
- Age >75y
o Consider initiating statin therapy according to patient discussion weighing vascular risk
and other comorbidities
- Consider adding ezetimibe in patients at very high vascular risk (10y ASCVD risk >20%) who
are not at target LDL-C on maximally tolerated statin therapy
- Do not stop statins because of an increase in blood glucose levels or HbA1c
Obesity - Initial weight loss of 5–10% through lifestyle changes (such as VLCD†) in overweight/obese
patients[252]
- Consider pharmacological therapies such as orlistat[253]
- Consider metabolic/bariatric surgery in morbidly obese (BMI >35) patients with multiple
comorbidities[254]
BP - Aim for BP <140/85mmHg in most patients[255]
o Lower targets (e.g.,<130/80mmHg) in high CVD risk patients if achievable
- RAAS blocker (ACEI or ARB, not both) recommended as part of treatment[196]
- CCB and/or thiazide diuretic – especially in older patients[256, 257]
- Consider twodrugs for initial therapy if BP ≥20/10mm Hg above target goal[258]
- ≥1BP drug at bedtime[199]
- BP self-monitoring at home in hypertensive patients[259]
Emotions - Formal screening tools for diabetes distress[260] (e.g., PAID, DDS-2)
- Ask "How is your diabetes being a pain for you at the moment?"
- Consider input from diabetes educators, psychologists and psychiatrists
Smoking - Counsel for smoking cessation[204]
- Refer to support program[204]
- Pharmacotherapy (e.g., nicotine, varenicline or bupropion)[204]
Fig. 1.2 Evidence-based clinical practice points for adults with pre-diabetes and diabetes
Screening[14] - HbA1c 4 times a year

- Annual lipids, ocular health and foot care
- BP and weight at each clinic visit
- Comprehensive eye examination by an ophthalmologist or optometrist at diagnosis and every 2
years thereafter[261]
- Annual renal function including a spot urine albumin creatinine ratio or 24h urinary albumin
excretion rate and eGFR and serum creatinine levels[78]
- Annual screening for neuropathy using simple clinical tests[78, 262]
Treatment to - Aim to treat to recommended risk factor targets (Table 1)
target - Electronic decision support tools can assist with identifying patients not at target
Inflammation - People with diabetes are at increased risk of infection (e.g., UTI, fungal infections, periodontal
/ Infections disease)
Vaccination - Recommend all age-appropriate vaccinations
Education - Refer for structured diabetes patient education[216, 249]
- Refer to dietician for assessment and education[263]
- ≥150 minutes of moderate-vigorous exercise over ≥3 days/week & 2–3 sessions of resistance
training on non-consecutive days[264]
Devices - Consider devices such as physical activity trackers, smart phone apps, home BP monitor
- Consider glucometers/CGM, particularly for patients requiring insulin therapy
Aspirin - Not empirically recommended for all patients
- Consider on an individual basis in high vascular risk patients (10y ASCVD risk >10%) only
after consideration of bleeding risks
Diabetes with CVD Diabetes with heart failure Diabetes with microvascular
complications complications
See Table 1.7
See Table 1.6 See Table 1.8
†Prescribe with caution, especially in patients on insulin or sulfonylureas

‡Recommended to use a contemporary risk calculator that is applicable to the population being treated
Lifestyle modifications are first-line therapy for the control of glucose, lipids, obesity, BP and CVD risk
OGTT: oral glucose tolerance test, BP: blood pressure, CVD: cardiovascular disease, VLCD: very low-calorie
diet, ACEI: ACE inhibitor, ARB: angiotensin receptor blocker, CCB: calcium channel blocker, PAID: problem
areas in diabetes questionnaire, DDS-2: diabetes distress screening scale, p.a.: per annum
Fig. 1.2 (continued)
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.
argeted Screening for Type 2 Diabetes

T
and Diabetes Prevention
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].
Mnemonic to Guide Diabetes Care
In pre-diabetes or Type 2 diabetes, it is important to address more than just glucose

(Table 1.1). We previously published a mnemonic checklist for healthcare profes-
sional trainees and for clinicians regarding diabetes care: GLOBE2S2, which stands
for Glucose, Lipids and lipid drugs, Obesity, Blood pressure and blood pressure
drugs, Education and Emotion, and Smoking and Screening [87]. We now extend
this mnemonic to GLOBES STRIVED, which stands for Glucose, Lipids and lipid
drugs, Obesity, Blood pressure and blood pressure drugs, Emotion, and Smoking
(GLOBES) and Screening, TReating to target, Infection, Vaccination, Education,
and Devices (STRIVED). This is summarized in Table 1.2 and discussed further in
this chapter, with various elements being expanded upon in other chapters. There
are additional treatments to be considered in people with diabetes complications,
and we discuss this later in this chapter, including some mnemonics.
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
Benefits of Multiple Risk Factor Control
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.
Table 1.3 Cardiac and renal effects of novel glucose-lowering drugs

SGLT2 inhibitors
Cardiac effects
Meta-analysis of three RCTs (n = 34,322):
Modest secondary prevention of atherosclerotic events
Significant reductions in CV mortality or hospitalizations for heart failure (hHF),
regardless of prior history of CVD or heart failure [129]
Empagliflozin reduced MACE (composite of CV mortality, myocardial infarction, and
stroke) by 14%, hHF by 35%, CV mortality by 38%, and all-cause mortality by 32% [268]
Canagliflozin reduced MACE by 14% and hHF by 33%, with borderline non-significant
all-cause mortality reduction by 13%, but increased amputations by nearly twofold and
fractures [269]
Dapagliflozin was non-inferior compared to placebo for MACE, with a significant
reduction in the composite endpoint (hHF or CV death) [270]
Renal effects
Meta-analysis of four RCTs of empagliflozin, canagliflozin, and dapagliflozin [127]:
Reduced composite primary endpoint (dialysis, transplantation, CKD death) by 33%
Protected from acute kidney injury and end-stage renal disease (ESRD)
Consistent benefits across all baseline eGFR subgroups, and irrespective of albuminuria
or use of RAS blockade
Canagliflozin significantly reduced the composite endpoint (ESRD, doubling of creatinine
level and renal death) by 34%, with no increased risk of amputations or fractures [271]
SGLT2 inhibitors were renoprotective irrespective of heart failure status, age, and baseline
kidney function [272–277]
A combination of an SGLT2 inhibitor with exenatide twice a day may have a synergistic
benefit on kidney function in obese Type 2 diabetes patients [278]
Incretin drugs: glucagon-like peptide 1 receptor (GLP-1) agonists
Cardiac effects
Meta-analysis of seven trials (n = 56,004) showed significant reductions in MACE by 12%,
cardiovascular mortality by 12%, stroke by 16%, myocardial infarction by 9%, all-cause
mortality by 12%, and hHF by 9% [279]
Daily liraglutide significantly reduced MACE by 13% and reduced CVD and all-cause
mortality by 22% and 15%, respectively [280]
Once-weekly semaglutide, albiglutide, and dulagutide all significantly reduced MACE, but
semaglutide increased retinopathy complications by 76% [281–283]
Renal effects
GLP-1 agonists reduce albuminuria in Type 2 diabetes [284]
Meta-analysis showed reduced composite outcome of new-onset microalbuminuria, eGFR
loss, progression to ESRD, or renal death by 17%, mainly due to macroalbuminuria benefit
[279]
Incretin drugs: — dipetdiyl-peptidase 4 (DPP-4) inhibitors
Cardiac effects
RCTs showed neutral effects in high-risk T2D patients [285–288]
Meta-analysis showed DPP-4 inhibitors may increase risk of heart failure in patients with
existing CVD or multiple vascular risk factors [289]
Renal effects
Meta-analysis of 23 RCTs showed reduced albuminuria development or progression in
Type 2 diabetes
The CARMELINA study, first well-powered RCT of DPP-4 inhibitors for kidney
outcomes, showed linagliptin did not reduce the composite kidney outcome (death due to
kidney failure, ESRD, or sustained eGFR decrease ≥40%) in high CVD or CKD risk Type 2
diabetes subjects over a median of 2.2 years [286]
1
Table 1.4 Prevention of CVD complications in patients with Type 2 diabetes

Primary prevention Secondary prevention
Reduces CV
Risk factor Main agents Reduces CV events mortality Reduces CV events Reduces CV mortality
Thrombosis Aspirin, clopidogrel (only Yesa [237] (I) No [237] (I) Yes [237] (I) Yes [237] (I)
in patients who cannot
tolerate aspirin)
Lipids Statins Yes [150] (I) Yes [150] (I) Yes [150] (I) Yes [150] (I)
Ezetimibe Insufficient evidenceb No [290] (I) Yes [290] (I) No [290] (I)
[290]
Fibrates Yesc (I) No [291, 292] (II) Yes [293]d (I) No [293] (I)
PCKS9 inhibitors (e.g., Insufficient evidence Insufficient Yes [294] (II) No [295] (II)
evolocumab) evidence
Hypertension ACEi/ARBs, diuretics, Yes [193, 256] (I) Yes [193, 256] (I) Yes [193, 256] (I) Yes [193, 256] (I)
calcium channel blockers,
beta-blockers,
spironolactone
Hyperglycemia Biguanides, sulphonylureas, Yes, although intense glycemic control has been shown to have greater CV benefits in patients with
DPP-4 inhibitorse, short-duration diabetes and no known CVD [296] (I)
thiazolidinedionese, insulin
SGLT2-inhibitors No [129] (I) Yes [129] (I) Yes [129] (I) Yes [129] (I)
GLP-1 receptor agonists Insufficient evidence Insufficient Yes [280] (I) Yes [280] (I)
Precision Medicine Approaches for Management of Type 2 Diabetes
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
Primary prevention Secondary prevention

Reduces CV
Risk factor Main agents Reduces CV events mortality Reduces CV events Reduces CV mortality
Obesity Orlistat Insufficient evidence Insufficient Insufficient evidence Insufficient evidence
evidence
Bariatric surgery (morbidly Yes [189] (II) Yes [189] (II) Yes, but less effect than in Yes, but less effect than in
obese) primary prevention [189] primary prevention [189] (II)
(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
Only consider in high vascular risk patients (10y ASCVD risk >10%) after consideration of bleeding risks
b
While a Cochrane review showed limited evidence regarding ezetimibe in the primary prevention of CVD, several major societies recommend ezetimibe in
patients at very high vascular risk (10y ASCVD risk >20%) due to the cholesterol hypothesis that vascular risk decreases as LDL-C is reduced
c
A Cochrane review showed a modest benefit with fibrates in the primary prevention of CVD (absolute risk reductions <1%), while the FIELD and ACCORD
trials showed CV benefits with fenofibrate only in diabetes subjects with dyslipidemia
d
A Cochrane review showed fibrates reduced the primary composite outcome (non-fatal stroke, non-fatal MI, and vascular death) only when including clofi-
brate data (clofibrate was discontinued in 2012 due to safety concerns), though reduced MI even without clofibrate data
e
Can cause adverse CVD outcomes in certain settings
D. Chen et al.
1
Table 1.5 Prevention of microvascular complications in patients with Type 2 diabetes

Risk factors Main agents Reduces retinopathy Reduces nephropathy Reduces neuropathy
Primary Secondary Primary prevention Secondary Primary Secondary
prevention prevention prevention prevention prevention
Lipids Statins Yes, in a Yes, in a Reduces Reduces Insufficient Insufficient
meta-analysis meta-analysis albuminuria but not albuminuria but not evidence evidence
of cohort of cohort eGFR/BUNa [300] eGFR/BUNa [300]
studies [299] studies [299] (I) (I)
(III) (III)
Fibrates Yes, in a Yes [180, 181] Protective for eGFR Protective for eGFR Yes, in FIELD Yes, in FIELD
cohort study (II) and albuminuria. and albuminuria. trial (abstract trial (abstract
[301] (III) However, rise in However, rise in only) [302] only) [302]
serum Cra [182, serum Cra [182,
183] (II) 183] (II)
Hypertension ACEi/ARBs Yes [303] (I) Yesb [303, Yes [305] (II) Yes [306] (II) No [307] (II) Insufficient
304] evidence
Diuretics, calcium channel Yes [303] (I) No [303] Yes [308] (II) Yes [308] (II) No [307] (II) Insufficient
blockers, beta-blockers evidence
Hyperglycemia Biguanides, sulphonylureas, Yes [99] (I) Yes, in Yes [99] (II) Yes [309] (II) Yes [132, Yes [311] (II)
SGLT-2 inhibitors, DPP-4 recently 310] (I)
inhibitors, GLP-1 agonist, diagnosed
thiazolidinediones, insulin diabetes
Precision Medicine Approaches for Management of Type 2 Diabetes
[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].
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
Calorie restriction diets In motivated patients with short-duration Type 2 diabetes,

a medically supervised very-low-calorie diet (VLCD) can have significant benefits,
as shown in the DiRECT trial where nearly half (46%) of the intervention group
(825–853 kcal/day for 3–5 months and withdrawal of antihypertensive and antidia-
betic medications) achieved diabetes remission at 12 months versus only 6% in the
control group [91, 92].
16 D. Chen et al.
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

Diabetic neuropathy
Screening
Large nerve: loss of vibration, ankle reflexes, and 10 g monofilament sensation
Small nerve: loss of sensation to pinprick and temperature
Consider investigations to exclude other causes of neuropathy
Treatment
Optimizing glycemia reduces onset and progression [311]
Minimize alcohol consumption
Vitamin B12 supplements if levels are low
In the FIELD trial, long-term fenofibrate reduced new neuropathy and increased reversal
of known neuropathy (abstract only) [302]
For painful neuropathy, pregabalin and duloxetine are usually effective [344–346]
Tricyclic depressants alpha lipoic acid and topical treatments (e.g., capsaicin creams,
lignocaine sprays/patches) may be tried in individual patients, but have a less robust evidence
base [347–350]
Referral
Refer to neurologist (or relevant specialist) if:
Doubt about cause of neuropathy
Issues with clinical management (e.g., difficulty controlling neuropathic pain)
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.
prospective evidence linking CGM-related glucose metrics to future complications

is available.
Personalizing Glucose Targets
Meta-analyses have shown substantially reduced risk of microvascular complica-

tions with better glycemia, usually measured by HbA1c, and some CVD benefit,
albeit less than for microvascular complications [99, 100].
A HbA1c <7% (53 mmol/mol) is recommended for most people with diabetes
(Table 1.1), although recently, the American College of Physicians suggested a gen-
eral HbA1c target of 7–8% (53–64 mmol/mol) [101]. Glucose targets can be per-
sonalized to optimize clinical outcomes. While lowering glycemia usually reduces
the risk of complications, overtreatment may increase the risk of hypoglycemia,
subsequent CVD events, and mortality [13–15], which subsequently increase care
costs for the patient and for the healthcare system. Hypoglycemia is associated with
increased CVD and mortality risk [102–104]. Potential mechanisms by which
hypoglycemia may increase adverse vascular events include prolongation of the
cardiac QT interval, which combined with hypoglycemia-related catecholamine
surges and the relative excess of insulin-induced hypokalemia may induce a cardiac
arrhythmia and sudden death. This is sometimes referred to as the “dead-in-bed”
syndrome, which was first recognized in young people with Type 1 diabetes [105,
106]. Severe hypoglycemia may also lead to a seizure. Other adverse effects of
hypoglycemia include vascular endothelial dysfunction (with vasoconstriction),
increased inflammation, oxidative stress, and a prothrombotic tendency, which can
last for several days after the hypoglycemic event [107]. Another indirect associa-
tion between hypoglycemia and cardiovascular events may be that frailty and
reduced ability for self-care may increase risk of both cardiovascular events, death,
and of hypoglycemia [108].
Subset analyses of major trials suggest that more intensive glucose control may
have cardiovascular benefits in patients with short-duration Type 2 diabetes; hence,
a more stringent target (e.g., HbA1c ≤6 or 6.5%, 42 or 48 mmol/mol) should be
considered in patients with (a) Type 2 diabetes for less than 5 years, (b) Type 2 dia-
betes treated with lifestyle and oral hypoglycemic agents (OHAs) with minimal side
effects, and (c) women with Type 2 diabetes who are pregnant or anticipating preg-
nancy (HbA1c target ≤6%) [109, 110]. To mitigate risk of hypoglycemia, a less
stringent HbA1c target (e.g., ≤8%, 64 mmol/mol) is reasonable in patients with (a)
a history of severe hypoglycemia or impaired hypoglycemia awareness or (b) mul-
tiple comorbidities with limited life expectancy (6). Diabetes care guidelines now
often recommend personalization of HbA1c targets, taking into consideration such
factors as patient age, diabetes duration, pregnancy, comorbidities including CVD
and kidney disease, risk of and problems from hypoglycemia, level of
independence, and types of medications. Less stringent HbA1c targets should be

considered in frail people living alone or in care facilities [109].
Particular care must be taken to the prescription of medications for people with
impaired kidney function, which is common in diabetes and may be secondary to
aging, diabetic kidney disease, hypertension, or other comorbidities. Kidney
dysfunction-related pharmacokinetic changes may increase the risk of hypoglyce-
mia and other side effects, which are likely to be higher for people with chronic
kidney disease (CKD) stages 4 and 5 (estimated glomerular filtration rates (eGFR)
<30 and <15 ml/min/1.73 m2, respectively) [109]. Several large studies have dem-
onstrated that even for metformin, which is often the first-line drug for pre-diabetes
and for Type 2 diabetes, errors in its prescription, usually to people with more severe
CKD than recommended, are common [111–113]. Over the past three decades,
there has been progressive relaxation of the lower limit of renal function deemed
safe for metformin use and also a shift from using serum creatinine levels to eGFR,
with metformin usually being regarded as safe to commence in those with an eGFR
over 45 ml/min/1.73 m2 [114, 115] and can be continued in those with eGFR over
30 ml ml/min/1.73 m2 [116]. A major concern related to metformin use in moderate-
to-severe CKD, liver disease, or heart failure is that of metformin-associated lactic
acidosis (MALA). While MALA is of low incidence (<10 cases per 100,000 patient-
years), it has a mortality rate of approximately 50% [117]. Further research into this
widely used, low-cost, and generally well-tolerated OHA may provide more detail
regarding its safety and efficacy in people with more severe CKD. Another glucose-
related complication of OHA drugs, in particular with sodium glucose transporter 2
(SGLT2) inhibitors, is that of diabetic ketoacidosis, which may be associated with
normal or relatively mildly elevated glucose levels, so-called euglycemic DKA
[118–120]. As many drugs used in diabetes care may require dosage adjustment or
cessation with kidney or liver disease, regular monitoring of kidney and liver func-
tion and review of medications are required.
Higher glucose variability (GV), usually assessed by CGM or blood glucose
levels in the short term (over days to 2 weeks) and by HbA1c standard deviation
(SD) or coefficient of variation (CV) in the long term (months–years), has been
independently associated with higher risk of micro- and macrovascular complica-
tions and mortality [121–123]. In a post hoc analysis of the Fenofibrate Intervention
and Event Lowering in Diabetes (FIELD) study, GV was calculated as the SD and
CV of HbA1c and of fasting plasma glucose in 9795 adults with Type 2 diabetes.
Baseline factors associated with higher on-study GV included younger age, longer-
known diabetes duration, male sex, and higher use of drug therapies. HbA1c and/or
fasting glucose CV in the first 2 years were significantly associated with increased
risk of on-trial complications for the remaining trial time (a total of a median of
5 years) including microvascular complications, CVD, stroke, and increased total,
coronary, and non-coronary mortality [97]. Impaired vasodilation, increased oxida-
tive stress and inflammation, prothrombotic effects, and epigenetic changes may be
mediators [124]. Means to lower GV include diet, exercise, some glucose control
20 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.
Rationale for Glucose Targets
Personalization of the intensity of glucose control is supported by some clinical tri-

als. Some glucose drugs have pleiotropic effects that may reduce complication risk
above and beyond their glucose benefits. The favorable effects of SGLT2 inhibitors
on cardiovascular, heart failure, and diabetic kidney disease are key examples
[127–129].
Macrovascular disease benefit Type 2 diabetes trials contrast in their findings.
Supportive trials of benefit include The United Kingdom Prospective Diabetes
Study (UKPDS) and the Veterans Affairs Diabetes Trial (VADT). Their 10-year
observational follow-up studies showed long-term reductions in CVD events with
intensive glucose control (median achieved HbA1c ≈7% in both trials) [130, 131].
In contrast, the Action to Control Cardiovascular Risk in Diabetes (ACCORD)
and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR
Controlled Evaluation (ADVANCE) trials, which studied high cardiovascular risk
adults with Type 2 diabetes and achieved lower median HbA1c levels of ≈6.4% in
their intensively treated group, were not favorable. ADVANCE demonstrated no
differences in macrovascular events or cardiovascular mortality between the
intensive and standard treatment groups [104], while ACCORD was stopped early
due to a 22% increased mortality with intensive glucose treatment [102]. The
ACCORD trial participants had long-duration diabetes with greater prevalence of
complications. More antidiabetic drugs (including insulin and thiazolidinediones)
were required to achieve tight glycemic control, and there were issues relating to
weight gain and increased severe hypoglycemia in the intensively treated group
[110]. This is in contrast to the UKPDS study, which evaluated newly diagnosed
T2D patients where tight glucose control was easier to achieve. It is now man-
dated that before glucose control agents are approved by regulatory bodies such as
the USA’s Therapeutic Goods Association (TGA) for clinical use, trials must dem-
onstrate their cardiovascular safety. Very large and moderately long-duration clin-
ical trials are required.
Microvascular disease benefit Multiple trials have demonstrated benefits of better

glycemia. In the UKPDS, intensive glucose treatment reduced cumulative micro-
vascular endpoints by 25% [131], while a recent meta-analysis found significant
reductions in kidney and eye events (20% and 13% respectively), but not in nerve
events [99]. Retinal benefits may be greater in younger patients with shorter-
duration diabetes. The ACCORD and ADVANCE trials in older subjects showed no
or marginal retinal benefits with intensive glucose control [102, 132], while the
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.
Novel Glucose Control Agents
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].
Individualizing Glucose-Lowering Medications
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.
Lipids and Lipid Drugs
ssociations Between Lipids, Diabetes, and Chronic

A
Diabetes Complications
Adverse traditional lipid profiles, including elevated triglycerides, LDL-cholesterol

(LDL-C), and low HDL-cholesterol (HDL-C) levels, have been both associated with
and predictive of Type 2 diabetes per se and of its chronic complications [143–146].
This dyslipidemia may be exacerbated by poor glycemic control, obesity, kidney or
liver dysfunction, suboptimal lifestyle, genetics, and some drugs (e.g., thiazides)
[147]. Links between abnormal lipids and CVD are stronger and more consistent than
for microvascular complications. Associations between lipids and complications may
be direct and/or indirect such as via obesity and lifestyle-related factors [148].
22 D. Chen et al.
Statins and Diabetes Complications
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.
Microvascular disease Statins’ effects on microvascular complications are less

well studied, with there being a lack of robust randomized controlled trials with a
microvascular complication primary endpoint. Most results are from databases or
meta-analyses, briefly summarized below.
Early statin studies did not report any diabetic microvascular benefit. More
recent evidence, predominantly from very large databases and meta-analyses of
statin trials, suggest some retinopathy benefit, including for sight-threatening reti-
nopathy [156–161]. The literature is mixed regarding renoprotection. In a meta-
analysis (11 statin RCTs, 543 CKD diabetes subjects), statins reduced albuminuria
but not proteinuria nor eGFR [162]. In a 28 trial meta-analysis (n = 183,419) of
cardioprotection by eGFR categories, statins significantly reduced the risk of a first
major vascular event by 21% per mmol/L reduction in LDL-C, with less benefit as
eGFR declined [163]. Diabetic neuropathy studies are lacking. Statin studies mainly
in the general population [164] and a meta-analysis did not find any links between
statins and neuropathy [165].
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].
Other LDL-Lowering Drugs
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
Most predominantly LDL-C-lowering drugs also have some triglyceride-lowering

effects [172].
Fibrates The major triglyceride-lowering drug, fenofibrate, did not reduce CVD in
the (T2D) FIELD or ACCORD trials, except in those with dyslipidemia (elevated
triglycerides and low HDL-C) [179, 180], which is common in Type 2 diabetes. In
both studies, fenofibrate significantly reduced retinopathy [180, 181] independent
of lipid levels and was renoprotective [182, 183]. In the FIELD trial, fenofibrate also
reduced microvascular-related amputations [184]. Trials of fenofibrate with diabetic
retinopathy as the primary endpoint are in progress. The active form of fenofibrate,
fenofibric acid, is now available for clinical use; however, its efficacy in reducing
diabetic retinopathy progression has not been evaluated in clinical trials.
Unlike the fibrate gemfibrozil, where there is an increased risk of statin intoler-
ance and rhabdomyolysis, fenofibrate can be taken with a statin [185].
Fish oils can also lower triglycerides, but there is no evidence of protection
against the microvascular or macrovascular complications of Type 2 diabetes. In a
RCT of 15,480 diabetes patients without CVD, there was no difference in the risk
of serious vascular events for n − 3 fatty acid supplements vs. placebo [186].
Suggested Lipid Drug Use in People with Type 2 Diabetes
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
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
Hypertension is common in many non-diabetic populations, and its incidence is

usually increased in people with Type 2 diabetes. Due to BP lability and “white-coat
hypertension,” 24-hour BP monitoring and at-home measurements are more reliable
than in-clinic measures [192]. In addition to individual trials (including UKPDS), a
meta-analysis of 40 trials found that that among Type 2 diabetes patients, each
26 D. Chen et al.
10 mmHg reduction in systolic BP lowered all-cause mortality by 13%, CVD events

by 11%, albuminuria by 17%, and diabetic retinopathy by 13% [193].
Individualizing BP Targets
Recommended BP targets vary depending on the Type 2 diabetic patient’s cardio-

vascular and renal risk. While a BP target of <140/90 mmHg is reasonable in
patients at lower CVD risk (ASCVD risk <15%), a lower BP target of 130/80 mmHg
is advised in those at higher CVD risk (ASCVD risk >15%) if achievable [78].
Targeting lower systolic BPs (e.g., <120 mmHg) has not been shown to reduce
major CVD in diabetic patients but increases serious adverse events of hypotension
and renal dysfunction [194]. A combination of lifestyle (low salt, minimum alcohol,
DASH diet, weight loss, exercise, non-smoking) and pharmacological treatments is
recommended to optimize BP.
Selecting BP-Lowering Drugs
In patients with existing CVD or renal or retinal disease, angiotensin-converting

enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) are recom-
mended as first-line therapy [78]. In Black patients, a calcium channel blocker
(CCB) or a thiazide diuretic is preferred as the first-line agent [195] as hypertension
is more often salt responsive in Black populations than in Caucasian groups.
Thiazide diuretics are recommended first line in the elderly population [196] but can
be associated with worsening of glucose, lipid, and uric acid levels. This is not a
feature of the once-daily indapamide (Natrilix) member of the thiazide class, which
is also available as a slow-release preparation. Otherwise, ACEis, ARBs, CCBs, and
thiazide diuretics are all reasonable therapies for primary prevention. A meta-
analysis including both primary and secondary prevention trials, but excluding
patients with heart failure, revealed that RAAS drugs were not superior to other
classes of BP agents (e.g., CCBs, thiazides, beta-blockers) at reducing hard CVD
and renal endpoints in diabetic patients [197]. In patients with a systolic BP
20 mmHg above goal, dual antihypertensive therapy is advised [198], but a combi-
nation of ACEis and ARBs should not be used due to adverse effects on renal func-
tion [199]. In addition, taking antihypertensive medications at bedtime is
recommended. In a Type 2 diabetes RCT, taking antihypertensive treatment at bed-
time compared to upon wakening improved ambulatory control BP and significantly
reduced cardiovascular risk by 67% [200]. Often multiple BP-lowering drugs may
be needed to meet recommended BP targets and to avoid side effects associated
with high drug dosages. Combination tablets can help with patient adherence. In
general, drug doses can be titrated after 4 weeks of a regimen.
A suggested flow-chart covering hypertension therapy is shown in Fig. 1.3. Other
excellent guidelines are available such as from the ADA [13].
Confirm diagnosis of HTN

Multiple BP readings required
Consider home BP self-monitoring & 24-h ambulatory
BP monitoring
Consider & exclude secondary causes of HTN (5−10%)

Renal artery stenosis, Cushing syndrome,
hyperaldosteronism, pheochromocytoma, obstructive sleep
apnea, thyroid disease, aortic
coarctation, drugs (i.e. steroids, illicit drugs, antidepressants)
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
Consider specialist referral if not meeting BP target
Fig. 1.3 Management of hypertension in adults with Type 2 diabetes
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.
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
In an American Association of Diabetes Educators systematic review, diabetes self-

management education was associated with a 0.74% HbA1c reduction [217]. People
should be educated at diabetes diagnosis with further education over their lifetime.
Diabetes is a complex condition, and personalized treatment goals and available medi-
cations will change over time. Ideally, patients should be referred for structured diabe-
tes education and to a dietician, and care team members should avoid providing
conflicting advice. Clinicians may assist patient education by referral to reliable web-
sites, such as those by the ADA (www.diabetes.org) and Diabetes Australia (www.dia-
betesaustralia.com.au). Accurate information may still be misunderstood by the patient,
and some social media sites or lay people may provide unreliable information, includ-
ing the use of unproven therapies. Clinicians should be open to discussing such topics.
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.
helpful. Clinician-prescribed 24-hour BP monitoring can help diagnose hyperten-

sion and monitor therapy. Loss of nocturnal BP dipping is often the first sign of
hypertension and has been associated with increased risk of chronic diabetes com-
plications [218, 219].
Glucose Monitoring
Devices Glucose levels can be assessed by self-monitoring of capillary blood,

which is usually reserved for people requiring insulin therapy. Some blood glucose
meters have in-built bolus calculators which can guide insulin dosing for meals or
high glucose corrections [220]. In a study of Type 1 and insulin-using Type 2 diabe-
tes subjects, the use of a blood glucose meter to estimate insulin doses was associated
with significantly less insulin dosing errors than manual calculations and was pre-
ferred by patients [221].
More recently, CGM or flash glucose monitoring (FGM) can provide interstitial
fluid glucose measures at 5–15-minute intervals over 6–14 days, depending on
which system is used. Current systems are based on glucose oxidase chemistry, as
are blood glucose test strips. Both masked and real-time systems are available, some
of which are factory calibrated and do not require blood glucose calibration by the
user. Data from masked systems are uploaded for review by a clinician, and unlike
real-time CGM or FGM systems, the glucose data are not immediately available to
the wearer. Real-time systems provide glucose data to the wearer via a glucose
meter device or a smartphone app. Most have alarms to alert the wearer (and some-
times a remote carer) to low, high, and rapidly changing glucose levels. Data down-
loads (via the Cloud) enable more detailed data analyses and sharing [222–226].
CGM and FGM data can be particularly helpful in revealing otherwise unrecog-
nized nocturnal hypoglycemia and rebound hyperglycemia, preventing the potential
harmful increase in basal insulin doses and in drawing attention to the need for the
addition of bolus insulin to basal insulin. For example, in the primacy-care based
INITATION trial of adults with suboptimal glucose control of their Type 2 diabetes,
episodic masked CGM use (3 monthly for 12 months) did not improve HbA1c lev-
els differentially between the intervention and standard care group, but three times
more of the CGM group were commenced on bolus insulin than in the control
group [227].
Advantages and disadvantages of interstitial fluid glucose monitoring Advantages
of interstitial fluid glucose monitoring include reduced finger-prick burden, an
abundance of glucose data, alarms for glucose levels which may require interven-
tion, and the ability to measure GV. Unlike HbA1c, interstitial fluid glucose moni-
tors are not adversely impacted by anemia or hemoglobinopathies, but can be
impacted by substances such as paracetamol (aminocetaphen), salicyclic acid, and
high-dose vitamin C [228, 229]. While simultaneous interstitial fluid and blood glu-
cose levels may be well aligned, particularly when the person is not in the post-
prandial state or has exercised, the mean average difference between interstitial
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.
Future directions Interstitial fluid glucose-monitoring devices are continuing to

evolve and will likely have improved accuracy, factory calibration, duration of use,
capacity for long-term implantation, and ability to measure analytes other than glu-
cose such as ketones, lactate, and physical movement [235, 236].
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.
Management of Type 2 Diabetes Patients with Known CVD
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
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).
Management of Arterial Disease and Heart Failure
A cardiologist, neurologist, or vascular surgeon and vascular imaging can guide

decisions regarding medical therapy alone or surgery. Current evidence suggests
that diabetic patients have a better prognosis with bypass grafts (preferably arterial
vs. venous [240]) compared to angioplasty or stent procedures [241]. Drug-eluting
stents are more effective than non-drug-eluting stents [242], with both requiring
temporary antiplatelet cover.
We and others have reviewed heart failure in diabetes [243–247], and it is cov-
ered in detail in another chapter. Heart failure, which may be due to ischemia,
hypertension, or diabetic cardiomyopathy, or a combination thereof, is more com-
mon and has a poorer prognosis in people with Type 2 diabetes than in non-diabetic
subjects. Heart failure can be divided into that with reduced or preserved ejection
fraction (heart failure with reduced ejection fraction (HFrEF) or HFpEF), with the
latter accounting for about 50% of heart failure. Table 1.7 provides key points for
HFrEF care. A long subclinical phase is recognized, but no routine cardiac imaging
for its diagnosis, such as echocardiography or cardiac MRI, is recommended.
Treatment of HFpEF is particularly difficult as there are no specific treatments yet
and no therapies shown to reduce mortality.
An evidence-based mnemonic for treatment of HFrEF [248], devised by co-
authors (JF) and colleagues, is BANDAID2 (beta-blocker, ACEi/ARB/angiotensin
receptor-neprilysin inhibitor (ARNI), nitrate-hydralazine, diuretics, aldosterone
antagonist, ivabradine, devices, and digoxin). Further detail is provided in Table 1.7
and in the original paper [248]. In addition, SGLT-2 inhibitors or GLP-1 analogues
should be considered in Type 2 diabetic patients with heart failure [78]. In class II
or III HFrEF patients without prior angioedema, current guidelines recommend
switching ACEi/ARB therapy to an ARNI (e.g., Entresto). In a large RCT, ARNI
reduced the composite outcome of cardiovascular mortality or HF by 20% [249].
anagement of Microvascular Complications in Type 2

M
Diabetes
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.
Acknowledgments DC was supported by a University of Sydney and Australian National Health

and Medical Research Council (NHMRC) Clinical Trials Centre (CTC) Summer Research
Scholarship. AJJ is supported by an NHMRC Practitioner Fellowship. This work is dedicated to
DC’s parents, Mary Liu and Phillip Chen, who have been DC’s greatest supports throughout his
medical training.
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Chapter 2
Precision Medicine for Diabetes
and Cardiovascular Disease
Siu-Hin Wan and Horng H. Chen
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.
Cardiovascular and Metabolic Cross-talk
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

54 S.-H. Wan and H. H. Chen
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.
Cardiovascular Complications of Diabetes
Diabetes promotes heart disease, including accelerated atherosclerosis, hyperten-

sion, direct damage to the myocardium, and subsequent development of heart fail-
ure (Fig. 2.1).
2 Precision Medicine for Diabetes and Cardiovascular Disease 55
Heart failure
Diabetic Diastolic with reduced
cardiomyopathy dysfunction or preserved
ejection
Endothelial
dysfunction
Microvascular
disease Accelerated Myocardial
atherosclerosis infarction
Macrovascular Hypertension
disease
Hyperlipidemia
Stroke
Fig. 2.1 Mechanisms of heart disease in diabetes
Coronary Artery Disease
Hyperglycemia in diabetes mellitus leads to multiple mechanisms that accelerate

coronary artery disease, including inflammation and damage of coronary arteries,
proliferation of vascular smooth muscle, hyperlipidemia, and endothelial dysfunc-
tion. Microvascular and macrovascular disease is a hallmark of diabetes sequalae.
Angiographic studies in patients with diabetes demonstrate greater disease burden
and greater likelihood of multivessel coronary artery disease [14, 15]. Coronary
artery calcification on CT imaging and myocardial flow reserve by PET imaging
also demonstrate greater coronary disease among those with diabetes [16, 17].
Furthermore, disease burden is directly associated with blood glucose.
Mechanisms of increased cardiovascular risk include endothelial dysfunction
and increased thrombosis risk. Endothelial dysfunction is one of the mechanisms by
which diabetes leads to worse coronary outcomes. Insulin resistance is thought to
contribute to this pathophysiology, and antiglycemic agents appear to reverse endo-
thelial dysfunction [18, 19].
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
Hypertension is strongly correlated with diabetes and leads to cardiac remodeling.

Microvascular and macrovascular damage in diabetes may lead to the development
of hypertension [25]. Accelerated atherosclerosis results in hypertension, which
subsequently worsens cardiac disease. Chronic increases in afterload result in car-
diac remodeling and myocyte hypertrophy. This can subsequently lead to diastolic
dysfunction and symptomatic heart failure with preserved ejection fraction. This
can also lead to disruption in normal coronary flow and further acceleration in
atherosclerosis.
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
hypertrophy, myocardial damage from advanced glycation end products and

increased inflammatory pathways, and abnormal endothelial function. All these
mechanisms including coronary artery disease, hypertension, and diabetic cardio-
myopathy contribute to symptomatic heart failure.
Epidemiology and Burden of Diabetes and Heart Disease
Coronary Artery Disease
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,
Table 2.1 Burden of heart disease and diabetes

Risk with diabetes
Cardiovascular outcomes and burden
Myocardial infarction, 7-year period 20%
Mortality, 12-year period 10%
Relative risk heart failure development 2–10×
[28, 29]
[30, 31]
[4, 33–39]
obesity, renal dysfunction, and additional cardiovascular comorbidities such as cor-

onary artery disease and peripheral artery disease. Studies show that the prevalence
of diabetic cardiomyopathy in the general population is approximately 1.1% [40].
Once patients with diabetes develop heart failure, they become at increased risk
of poor outcomes, including hospitalization and mortality [41, 42]. Those with dia-
betes and heart failure with preserved ejection fraction had an even higher risk of
heart failure hospitalization and mortality compared to those with reduced ejection
fraction. Furthermore, those with pre-diabetes and heart failure are also at increased
risk of worse outcomes.
Hypertension
Metabolic syndrome is a condition where diabetes, obesity, hypertension, and

hyperlipidemia co-exist. Diabetes, in addition to being an independent risk factor
for cardiovascular disease, is associated with many cardiovascular risk factors,
including hypertension. Treatment for hypertension is also more aggressive among
patients with diabetes, given increased cardiovascular risk when these two condi-
tions exist concurrently.
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].
Management of Diabetes and Heart Disease
Glycemic Control
The cardiovascular disease outcomes, including myocardial infarction and death

among those with type 2 diabetes, are directly related to glycemic control in addi-
tion to multifaceted risk factor reduction, and this principle remains the foundation
for management of patients with diabetes [46]. Mechanistically, there is microvas-
cular benefit with glycemic control, although macrovascular benefits have not been
directly demonstrated. Therefore, for macrovascular disease prevention, including
myocardial infarction and stroke, glycemic control should be combined with life-
style modifications such as exercise, diet, lipid management, and tobacco cessation.
Multifactor risk reduction should include exercise, as well as aggressive blood

pressure and dyslipidemia management. Exercise in observational studies has been
shown to decrease cardiovascular mortality among those with diabetes [47].
Studies have shown that for each increase in 1% of HbA1c, there is a 1.2–1.4
relative odds of cardiovascular disease and all-cause mortality [48–50]. The mecha-
nism of benefit is thought to be reduction in microvascular disease.
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
Sodium glucose cotransporter 2 (SGLT2) inhibitors act mainly by preventing reab-

sorption of urinary glucose in the proximal tubule. In addition to lifestyle modifica-
tion and metformin, emerging data have demonstrated improved cardiac and renal
outcomes for those with diabetes and cardiovascular disease. Specifically, trials
have demonstrated benefit in those with diabetes and coronary artery disease and
heart failure [54–56].
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
Glucagon-like peptide-1 receptor (GLP1) agonist is a novel class of antiglycemic

agent that has also demonstrated favorable outcomes in diabetes and heart disease
[59]. GLP1 agonists activate the GLP1 receptor, resulting in greater insulin synthe-
sis and release of insulin. Benefits of GLP1 agonists, in addition to serum glucose
reduction, also include weight loss and blood pressure. Studies have demonstrated
that in those with type 2 diabetes, addition of a GLP1 agonist results in lower car-
diovascular event rates and lower all-cause mortality [60].
Natriuretic Peptides
Natriuretic peptide deficiency is caused in part by insulin resistance and obesity.

Natriuretic peptide deficiency leads to diabetes development, hypertension, and
hypertrophy of the myocardium [61]. Genetic variants may play a role in levels of
circulating natriuretic peptides, and further studies into the genetic variants in natri-
uretic peptide expression may provide insights into development of diabetes and
heart failure [62].
Further studies are needed to determine if natriuretic peptide supplementation
might result in prevention of diabetes and heart failure, given that low levels of cir-
culating natriuretic peptides are associated with higher risk of diabetes development
[63]. Post hoc analysis from the PARADIGM-HF trial showed that neprilysin inhi-
bition, which raises natriuretic peptide levels, results in greater reduction in HbA1c
[64]. Promising are studies showing infusion of BNP resulted in lower plasma glu-
cose after loading [65].
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
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.
Disclosures Dr. Chen has patented designer peptides.
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Chapter 3
Precision Medicine for Diabetes
and Dyslipidemia
Ethan Alexander, Elizabeth Cristiano, and John M. Miles
Introduction
Cardiovascular disease (CVD) accounts for roughly one-quarter of deaths in the

USA annually, and its largest component is coronary heart disease (CHD) [1]. The
presence of diabetes mellitus (predominantly type 2 diabetes, or T2DM) increases
the risk of cardiovascular death by two- to threefold [2–4]. Although conventional
risk factors do not entirely explain this enormous increase in risk in patients with
T2DM, dyslipidemia is a major contributor to this risk [5, 6]. Dyslipidemia is
defined as triglyceride concentrations >200 mg/dl and/or HDL cholesterol levels
<40 mg/dl, combined with an increase in small, dense LDL (sdLDL) particles [7];
using this definition, it is present in half or more of patients with T2DM [8]. In this
chapter, we will review the pathogenesis and treatment of diabetic dyslipidemia.
Pathogenesis
Insulin resistance is central to the pathogenesis of dyslipidemia in nondiabetic indi-

viduals [9, 10] and is present in the majority of people with T2DM [11] as well as
some individuals with type 1 diabetes [12, 13]. The dyslipidemia of diabetes is
driven by hyperlipolysis in adipose tissue, leading to overproduction of VLDL [6];
it often precedes the development of hyperglycemia, and it has been suggested by
McGarry that abnormalities in lipid metabolism play a causal role in the pathogen-
esis of type 2 diabetes [14]. In nondiabetic relatives of individuals with T2DM,
E. Alexander · E. Cristiano · J. M. Miles (*)

Divisions of Endocrinology, Metabolism and Genetics, University of Kansas School of
Medicine, Kansas City, KS, USA

66 E. Alexander et al.
hyperinsulinemia is accompanied by higher triglyceride concentrations and qualita-

tive abnormalities in lipoprotein metabolism that include increased VLDL particle
size and a shift toward smaller, dense HDL particles [15]. Using the euglycemic-
hyperinsulinemic clamp and HOMA-IR techniques to assess insulin sensitivity in
adults and children, several investigators have demonstrated that both the triglycer-
ide/HDL-C ratio [16, 17] and the triglyceride/glucose product [18] correlate with
insulin sensitivity.
While low-density lipoprotein cholesterol (LDL-C) typically lies within the nor-
mal reference range, the structure and size of the LDL particle is altered. The sdLDL
particle is considered to be more atherogenic due to its lower affinity for the LDL-C
receptor, leading to decreased metabolic clearance, as well as its susceptibility to
oxidation and ease of trans-endothelial passage [19–21]. The LDL particle size shift
to sdLDL is mediated by increased cholesterol ester transfer protein (CETP) func-
tion due to increased flux of triglyceride-rich lipoproteins, primarily VLDL; this
leads to increased exchange of triglycerides in very-low-density lipoprotein (VLDL)
for cholesterol in LDL-C and HDL-C [20, 21], perhaps contributing to reduced
HDL-C. The triglycerides in both LDL-C and HDL-C are then hydrolyzed in the
liver, effectively reducing particle size [20, 21]. Hypertriglyceridemia is due primar-
ily to overproduction of VLDL (and apolipoprotein B100) [22], which in turn is
caused by increased delivery of free fatty acids (FFA) to the liver [23]. Visceral
adipose tissue is a major contributor to hepatic FFA supply [24]. In patients with
type 2 diabetes, there is a relationship between increased visceral fat mass and both
larger VLDL particles and smaller LDL and HDL particles [25].
Treatment
In spite of the proliferation of useful medications for the treatment of dyslipidemia,

lifestyle modification remains a building block upon which effective treatment
should be based. However, lifestyle modification alone is rarely sufficient; thus, the
vast majority of patients will require pharmacological treatment. We will first dis-
cuss medications that primarily target LDL cholesterol. These include statins,
PCSK9 inhibitors, ezetimibe, and bempedoic acid.
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
studies, it is important to note that pravastatin 40 mg has been found to be equipo-

tent to less than 10 mg atorvastatin with respect to lowering of LDL-C [41]. The
TNT trial found that atorvastatin 80 mg was more effective in reducing events than
atorvastatin 10 mg in patients with coronary heart disease [42]. Thus, in all three
secondary prevention trials, the highest approved dose of atorvastatin was compared
with the lowest available dose or an equivalent of even lower potency. These obser-
vations confirm that high-intensity statin therapy has greater effectiveness than
moderate-intensity therapy, but they obscure the curvilinearity of the relationship
between dose and risk reduction [6]. This is important because statin side effects
tend to be dose-related [43, 44]; management of statin intolerance can be extremely
difficult [45], requiring resources that are not consistently available to primary care
physicians. If the incremental benefit of doubling a statin dose is small [46], one can
make a case for moderate-dose statin therapy to minimize discontinuation of statin
treatment [47], especially in a primary care setting.
Primary Prevention
Moderate-intensity statin therapy has been shown to provide considerable benefit in

people with diabetes. The CARDS (Collaborative Atorvastatin Diabetes Study) trial
compared the effect of atorvastatin 10 mg versus placebo for primary prevention of
cardiovascular events in ~2800 diabetes subjects with a median follow-up of
3.9 years [48]. Participants had a mean hemoglobin A1c of 7.8% at baseline, normal
LDL-C levels (averaging 117 mg/dl), and normal HDL-C concentrations (average
54 mg/dl). Mean triglyceride levels were 150 mg/dl, indicating the presence of
hypertriglyceridemia in roughly half of the participants. Individuals receiving ator-
vastatin had an impressive 37% reduction in cardiovascular events and a 27%
decrease in all-cause mortality compared with placebo. Atorvastatin produced virtu-
ally no change in HDL-C but significant decreases in LDL-C (−40%), triglycerides
(−19%), and non-HDL cholesterol (−36%). The reduction in events in a population
with relatively mild to absent lipid abnormalities argues in favor of moderate-
intensity statin treatment in most if not all individuals with type 2 diabetes. Other
studies have produced equivocal results. In the primary prevention ASCOT study in
patients with hypertension, there was clear cardiovascular benefit of atorvastatin
10 mg when compared to placebo. However, significant benefit was not demon-
strable in the subset of individuals with diabetes. The investigators acknowledged
that the study was probably underpowered in the diabetes subgroup and that the
drop-in rate in diabetic patients receiving placebo was relatively high [49, 50]. The
ASPEN study also failed to demonstrate significant cardiovascular benefit from
atorvastatin 10 mg in subjects with diabetes without established coronary heart dis-
ease [51]. However, rather high drop-in and dropout rates in that study compromise
its interpretability [52]. A Cochrane review investigated the use of statins for the
primary prevention of cardiovascular disease. The analysis included 18 randomized
control trials, 14 of which had specific enrollment criteria, including trials looking
at primary prevention in diabetes. This review found that there were significant
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].
Do Statins Increase Newly Incident Diabetes?
The JUPITER trial was a randomized, double-blind, placebo-controlled primary

prevention study in over 17,000 nondiabetic individuals comparing high-intensity
rosuvastatin (20 mg) to placebo [54]. A secondary endpoint of the study was the
development of new diabetes. Baseline hemoglobin A1c was 5.7% in both groups.
After a median follow-up of 1.9 years, hemoglobin A1c was higher in the rosuvas-
tatin group (5.9% versus 5.8%, p = 0.001). A diagnosis of new diabetes was more
frequent in the rosuvastatin-treated subjects (3.0% vs 2.4%, p = 0.01), although the
diagnoses were not adjudicated. As a result, the FDA subsequently added a warning
to the label mentioning the risk of diabetes [55]. In the JUPITER trial, a post hoc
analysis indicated that the increase in diabetes risk in rosuvastatin-treated partici-
pants was present in subjects with risk factors for diabetes, but not those in whom
risk factors were absent [56]. Subsequent meta-analyses concluded that the relation-
ship between statin use and new diabetes is equivocal [57] or absent [58]. A recent
retrospective cohort study in ~6000 patients ≥70 years of age without a significant
risk for developing diabetes showed no increase in newly incident diabetes with
initiation of statin therapy [59]. In the same study, diabetes risk was increased in
younger patients, many of whom had diabetes risk factors, with statin exposure
[59]. In our view the effect of statins on diabetes appears to be small and is vastly
outweighed by the cardiovascular benefits, as recently suggested by Bell [60].
PCSK-9 Inhibitors
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important enzyme in

the hepatic clearance of LDL-C. LDL-C binds to the LDL receptor in the liver and
is internalized into the hepatocyte where it is metabolized [61]. Normally, the LDL
receptor is recycled repeatedly to the cell surface in order to continue to clear
LDL-C from the circulation [62]. Circulating PCSK9 binds to the LDL receptor on
the hepatocyte and leads to receptor degradation, effectively limiting LDL-C clear-
ance from the circulation [61–63]. It has been shown that gain of function mutations
in PCSK9 are associated with increased cardiovascular risk, whereas loss of func-
tion mutations produce lower circulating LDL-C levels [62]. In addition to effects
on LDL-C, PCSK9-mediated degradation of LDL receptors can have an impact on
triglyceride-rich lipoprotein metabolism, since both VLDL and chylomicron rem-
nants are cleared at the LDL receptor via binding to apolipoprotein E [64].
The Fourier trial tested evolocumab, the first available PCSK9 inhibitor, in the
treatment of over 27,000 patients with cardiovascular disease taking a minimum of
atorvastatin 20 mg daily or its equipotent equivalent [65]. Evolocumab reduced

LDL-C concentrations to a median of 30 mg/dL compared with ~90 mg/dL in the
placebo group. With relatively brief follow-up (2.2 years), evolocumab produced a
relative risk reduction of 15% for the primary (MACE 5) endpoint and 20% for the
secondary (MACE 3) endpoint versus placebo. There were significant reductions in
key secondary composite endpoints in patients in the highest quartile for LDL-C
concentration (126 mg/dL) and the lowest (73 mg/dL) [65]. Approximately 37% of
participants in the study had diabetes, and the outcomes were similar in this sub-
group [66]. There was no increase in newly diagnosed diabetes nor worsening of
diabetes control associated with evolocumab treatment [66].
The ODYSSEY OUTCOMES Trial evaluated alirocumab in ~19,000 patients
with acute coronary syndrome who were receiving a high-intensity statin [67]. With
a median follow-up of 2.8 years, the primary composite endpoint (MACE 4) in
alirocumab- treated patients was reduced by 14%. The greatest risk reduction
occurred in patients whose baseline LDL levels were >100 mg/dl. A subgroup anal-
ysis showed no difference in endpoints among patients with diabetes, who repre-
sented 29% of participants. There was no difference in worsening diabetes or
new-onset diabetes [67]. A separate study was conducted in subjects with type 1 and
type 2 diabetes treated with insulin and alirocumab versus placebo; participants
included individuals on varying doses of statins, some on no statin at all because of
statin intolerance [68]. The average LDL-C decrease with alirocumab was 49% in
both type 1 and type 2 patients, and there was no apparent adverse interaction
between alirocumab and insulin [68]. A subsequent meta-analysis of 14 trials (1524
patients) in primarily T2DM patients with baseline hemoglobin A1c averaging
6.9% versus nondiabetic individuals found similar decreases in LDL-C and a simi-
lar safety profile in the two groups; the most common side effect was a local reac-
tion at the injection site [68].
Epidemiological studies have shown that a low HDL particle number is associ-
ated with markers of insulin resistance and metabolic syndrome [69]. Using NMR
measurements of HDL particle number and size, Ingueneau et al. recently studied
95 patients from an outpatient lipid clinic and found that PCSK9 inhibitors increased
HDL-C by 7% and also HDL particle number, especially in patients not taking
statins [70]. There was also an overall increase in HDL particle size, due primarily
to an increase in medium-sized HDL particle number with little change in the num-
ber of small HDL and occurring in spite of a decrease in extra-large HDL particle
number; this occurred because the latter were more than an order of magnitude less
numerous than medium-sized particles [70]. Using the same technique, PCSK9
inhibitors were shown to increase overall VLDL particle size, primarily by decreas-
ing the number of small, atherogenic VLDL remnants [71]. This effect can be
explained by an effect of PCSK9 inhibitors on clearance of VLDL remnants at the
LDL receptor, as mentioned above, and the effects on HDL may be secondary.
In summary, inhibitors of PCSK9 can reduce risk in patients with diabetes on
statin therapy when additional LDL-C lowering is desired. Additional studies are
needed to elucidate the mechanisms via which these agents exert their effects on the
metabolism of multiple lipoproteins.
Ezetimibe
Ezetimibe is an oral medication whose mechanism of action is to inhibit cholesterol

absorption into the enterocyte at the brush border in the intestines and can lower
LDL-C by approximately 24% [72–74]. In the secondary prevention IMPROVE-IT
trial, ezetimibe 10 mg once daily vs placebo was added to simvastatin 40 mg daily
alone [72]. This trial enrolled over 18,000 patients and had a MACE 5 endpoint
[72]. After 6 years of follow-up, the risk of myocardial infarction was 13% lower in
the ezetimibe plus simvastatin group. In a subsequent diabetes subgroup (n = 4933)
analysis of IMPROVE-IT, the investigators found that patients were more likely to
present with non-ST segment elevation acute coronary syndrome as compared to
nondiabetic patients (p < 0.001), and there were greater relative risk reductions in
MI (24%) and ischemic stroke (39%) in this group than in nondiabetic subjects [75].
At study baseline, people with diabetes had higher triglyceride and lower HDL-C
levels. Changes in these lipoprotein concentrations were not reported. Overall, anal-
ysis of data in this subgroup showed that adding ezetimibe to simvastatin in patients
with diabetes added cardiovascular risk reduction. Ezetimibe added to atorvastatin
produces greater improvement in LDL-C compared to doubling the atorvastatin
dose [76]. In patients receiving maximally tolerated statin therapy, an ezetimibe/
bempedoic acid combination resulted in greater reductions in LDL-C than bempe-
doic acid alone [77]. In summary, ezetimibe lowers LDL-C concentrations and
reduces risk. The benefits of ezetimibe appear to occur in the absence of a change in
HDL-C or LDL particle size [78]. Thus, a treatment that targets LDL-C and is com-
plementary to statins is capable of reducing risk without improving the major ele-
ments of diabetic dyslipidemia. As a result, both the ACC/AHA and the Endocrine
Society include ezetimibe as an option when LDL-C goal has not been achieved
[26, 79].
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
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.
Non-LDL Directed Medications
In the treatment of diabetic dyslipidemia, there is a potential role for medications

that do not primarily target LDL-cholesterol metabolism. The clinical trials that
have been conducted tend to be smaller than those with agents directed toward
LDL-cholesterol, perhaps because some of them are considered nutraceuticals and
to some extent have less proprietary interest behind them. These medications
include fibrates and omega-3 fatty acids.
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
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
Table 3.1 Lipid values in five fibrate trials

Study (reference) n Total cholesterol Triglycerides HDL-C LDL-C
89 4081 289 175 47 NA
91 3090 213 145 35 148
94 2531 175 160 32 111
92 9795 195 153 42 119
93 5518 175 162 38 101
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.
Omega-3 Fatty Acids
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
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].
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
Because cardiovascular events dominate mortality in T2DM, it is critically impor-

tant to emphasize diabetes medications that have favorable effects on cardiovascular
outcomes and de-emphasize treatments that might have deleterious effects. For
many years, the only available medications for diabetes treatment were in the insu-
lin provision category, including sulfonylureas and insulin itself. Evidence has
accumulated to indicate that insulin provision therapy may raise blood pressure.
This evidence is direct for insulin itself [124, 125] and indirect for sulfonylureas [6].
The likely cause is weight gain [6, 124, 125]. Insulin treatment has also been associ-
ated with an increase in newly incident heart failure and worsening of heart failure
outcomes [126]. In our view, it is appropriate to de-emphasize insulin provision
treatment in most T2DM patients, where insulin resistance due to overweight and
obesity is prominent [127].
Metformin
Metformin is recommended as first-line treatment in international guidelines on

T2DM [128]. The reason for this is the rather dramatic reduction in myocardial
infarction resulting from metformin treatment reported in the UK Prospective
Diabetes Study [129]. The chief strength of this study was a two-decade follow-up –
unheard of in modern clinical trials. Metformin decreases energy intake [130], low-
ers triglycerides [131, 132], raises (in some studies) HDL-C [133], increases LDL
particle size [134], and lowers blood pressure [6]. It also is associated with improved
heart failure outcomes [126, 135]. Metformin and statins have much in common.
Both are treatments for which there is arguably no substitute. Both are safe, inex-
pensive, and effective, and both have side effects that can interfere with treatment.
The gastrointestinal side effects of metformin, in our experience, can usually be
managed without discontinuation of the drug.
GLP-1 Receptor Agonists
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
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
The thiazolidinedione class of diabetes medications was developed in Japan in the

1980s, in large part because of the lipid-lowering properties of some of the agents.
Pioglitazone has robust triglyceride-lowering and HDL-C-raising effects [150]. In
addition, it increases LDL particle size [151] and lowers blood pressure. It has been
shown in clinical trials to reduce stroke [152]. It produced equivocal results in the
PROACTIVE study, which missed a significant effect on the primary composite
cardiovascular endpoint (p = 0.095) but did result in a significant 16% reduction in
the principal secondary endpoint, p = 0.027 [153]. We use pioglitazone as a third-
line treatment in selected diabetic patients with dyslipidemia on condition they are
treated with either metformin or a GLP-1RA or both, in order to mitigate weight gain.
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
Cardiovascular events dominate outcomes in T2DM, and dyslipidemia, which

affects over half of all patients, is a major contributor. A variety of lipid-specific
medications, beginning with statins, are useful in management, and the use of mul-
tiple agents has a place in treatment. In addition, aggressive diabetes pharmaco-
therapy, with an emphasis on medications that have been shown to improve
dyslipidemia in T2DM, is warranted.
Acknowledgments We thank W. S. Harris for helpful comments.
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Chapter 4
Imaging in Precision Medicine for Diabetes
Oana Patricia Zaharia, Vera B. Schrauwen-Hinderling, and Michael Roden
ole of Noninvasive Imaging Techniques

R
in Precision Diabetology
People with diabetes mellitus present heterogeneous metabolic features and – in

contrast to current paradigms – with large variation in both insulin resistance and
beta-cell dysfunction [1]. Indeed, differences in metabolic regulation exist among
individuals even in those with comparable glycemic control [2].Moreover, differ-
ences in tissue-specific metabolism and diabetes-related comorbidities and compli-
cations are present already at diagnosis of diabetes [3, 4]. These features may
represent primordial factors for identifying subtypes (subgroups, clusters) of diabe-
tes mellitus and contribute to diagnostic procedures and therapeutic decisions.
Recent advances in comprehensive phenotyping allowed to propose subgroups of
patients of non-autoimmune diabetes with different susceptibility to
O. P. Zaharia · M. 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
V. 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

90 O. P. Zaharia et al.
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.
I maging Tools for Assessing Body Composition and Adipose

Tissue Compartments
Obesity is associated with an increased risk of developing insulin resistance and

type 2 diabetes [15], and the large majority of people with type 2 diabetes are over-
weight or obese. Differences in adipose tissue compartments might enable an early
identification of people at risk of diabetes-related complications, as not only the
amount but also the distribution of adipose tissue is expected to play an essential
role in the pathogenesis and disease progression of diabetes [16]. A classification of
the different adipose tissue compartments and the ectopic fat depots to be further
addressed in this chapter is presented in Fig. 4.1 [17].
Particularly, visceral adipose tissue (VAT) has been suggested to play an impor-
tant role in the pathogenesis of insulin resistance, abnormal glucose metabolism
(“prediabetes”), and type 2 diabetes. This is based on the observation of a stronger
correlation of insulin resistance with VAT than with total fat mass [18–20]. However,
the quantification of VAT volume is dependent on body height, and therefore, nor-
malization to body size or to total adipose tissue is necessary. When evaluating
several indices derived from VAT volume, VAT/m3 appears to provide a good marker
4 Imaging in Precision Medicine for Diabetes 91
Superficial
subcutaneous
Subcutaneous adipose tissue
adipose tissue Deep
subcutaneous
adipose tissue
Adipose tissue Intrathoracic Cardiac

compartments
Visceral
Hepatic
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])
of metabolic disturbances as it was identified to correlate best with insulin sensitiv-

ity and glycemic control [18].
Furthermore, recent data provide evidence for differences in metabolic activity
between deep subcutaneous adipose tissue (DSAT) and superficial subcutaneous
adipose tissue (SSAT) [21], which are separated by Scarpa’s fascia [22]. This struc-
ture is particularly visible using ultrasound imaging techniques [21].
SSAT volume negatively associates with levels of glycated hemoglobin (HbA1c)
and positively with high-density lipoprotein (HDL) cholesterol concentration in
type 2 diabetes [23], therefore rather suggesting that SSAT volume is a marker of
metabolic health [24] (Fig. 4.2). In contrast, DSAT volume showed a positive asso-
ciation with insulin resistance, similar to visceral VAT volume [22]. Furthermore,
DSAT volume, similarly to VAT, might be a good predictor of fasting insulin levels
[19]. These imaging parameters may add to the in-depth metabolic characterization
of patients with diabetes allowing a more precise stratification [3, 6, 7, 25].
Assessment of whole-body adiposity can be performed by different techniques
including bioimpedance, hydrostatic weighing, air displacement plethysmography,
densitometry (DXA), computed tomography (CT), and magnetic resonance imag-
ing (MRI). Of note, the different techniques assess different aspects of adipose tis-
sue. Hydrostatic weighing and air displacement only provide whole-body density
from which fat percentage can be deduced. If detailed information of adipose tissue
distribution is desired without exposure to ionizing radiation, MRI is the most reli-
able choice.
Air displacement plethysmography uses whole-body densitometry to determine
body volume and can accommodate a wide range of populations. This method is
specifically relevant for humans with contraindications for other noninvasive mea-
suring tools such as MRI [26]. Based on tissue density, body composition (body fat
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])
and fat-free mass) can be estimated by air displacement plethysmography and

hydrostatic weighing.
Dual-energy X-ray absorptiometry (DXA) is a means of measuring body compo-
sition using spectral imaging. However, as it is a projection method, anterior-
posterior information is lost. Nevertheless, thanks to the association of data within
big data bases and new algorithms, the differential estimate of subcutaneous and
intra-abdominal visceral fat content is possible [27].
In CT, the contrast between adipose tissue and non-adipose tissue is less pro-
nounced, and as the technique uses X-rays, it is not indicated for all applications. An
advantage of CT with respect to MRI is that image homogeneity is superior, which
makes the threshold-based image segmentation much easier for CT. Studies using
CT to assess metabolic syndrome and diabetes revealed that accumulation of vis-
ceral adipose tissue and fat distribution are relevant markers of metabolic risk.
MRI based on T1-weighted, T2-weighted, or Dixon images provide high con-
trast between adipose tissue and non-adipose tissue, making segmentation possible.
This provides a reliable basis for interindividual comparison of the body fat distri-
bution and allows a fast and reliable quantification of total body adipose tissue and
the distribution of different adipose tissue components as subcutaneous and visceral
fat in different body regions.
The coefficients of variation for adipose tissue measurements by MRI are 3–18%
compared to CT where the variations are around 2% [28–30]. The signal intensity
of MRI pixels from the same tissue may vary from region to region due to magnetic
field heterogeneity. There may also be some sequence-related artifacts with MRI,
such as chemical shift and blood flow artifacts. These effects collectively lower the
accuracy and precision of MRI adipose tissue estimates, particularly as image anal-
ysis requires establishing the irregular boundaries between VAT and other tissues
and organs.
I maging Tools for Assessing Skeletal Muscle Tissue Structure

and Metabolism
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.
Intramyocellular Lipid Content
Accumulation of intramyocellular lipids (IMCL) is associated with insulin resis-

tance in muscle, and interestingly, this IMCL accumulation appears to be a very
early event in the development of insulin resistance, as IMCL is already found to be
increased in insulin-resistant offspring of patients with diabetes, which are healthy
but have an increased risk to develop type 2 diabetes [31]. Increased IMCL accumu-
late, when the supply of fatty acids to skeletal muscle exceeds the capacity and need
for muscular fat oxidation. On the other hand, accumulated fatty acids and their
derivatives in IMCL may interfere with muscle insulin signaling. The imbalance
between supply and oxidation of fatty acids can be induced by a positive energy
balance due to overnutrition or physical inactivity or a reduced capacity for muscu-
lar fat oxidation (i.e., reduced mitochondrial oxidative capacity), as observed in the
elderly [16, 32]. Strikingly, this negative relationship between IMCL and insulin
sensitivity, however, has not been found in well-trained endurance athletes, who
exhibit high IMCL, yet are highly insulin sensitive [33, 34]. This has been termed
the “athlete’s paradox,” and it was shown that there is a U-shaped relationship
between IMCL content and oxidative capacity (which is low in diabetic patients and
is increased as an adaptation to physical exercise training in endurance trained indi-
viduals) [35]. While initial observations focused on intramuscular triglycerides and
their impact on insulin resistance [36], it soon became clear that not the triglycer-
ides per se, but rather bioactive lipid species, in particular diacylglycerols (DAG)
and ceramides, have a role in mediating lipid-induced insulin resistance via inhibi-
tion of insulin signaling by increasing insulin receptor substrate (IRS)-1 tyrosine
phosphorylation or by decreasing AKT activity, respectively [37, 38].Biochemical
quantification of lipid content in muscle biopsies does not confer a true quantifica-
tion of IMCL as contamination of the biopsy specimen by lipids from adipose tissue
that infiltrates muscle (also called extramyocellular lipid (EMCL) is almost impos-
sible to prevent, leading to large variation in IMCL determination. It has been dem-
onstrated that magnetic resonance spectroscopy (MRS) techniques are capable of
distinguishing IMCL from EMCL in vivo, thereby offering the potential to derive
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].
Assessment of Mitochondrial Function in Skeletal Muscle
In order to investigate energy metabolism, phosphorous MRS can be used, and a

decreased mitochondrial function was reported as an early hallmark of type 2 dia-
betes mellitus [44] in skeletal muscle by phosphorous spectroscopy, either by using
saturation transfer [44] or PCr recovery measurements [45]. The saturation transfer
measurements quantify the ATP synthetic flux, however, tend to overestimate the
flux because the unidirectional flux (rather than the net flux) is determined and the
measurement is not restricted to mitochondrial ATP synthesis, but also includes
cytoplasmatic components, making the interpretation as a marker of mitochondrial
function rather difficult [46]. PCr recovery measurements assume that the kinetic of
PCr resynthesis reflects mitochondrial capacity, as it is largely fuelled by aerobic
metabolism. These assumptions were validated, and generally, PCr recovery is
accepted to be a robust measure of skeletal muscle oxidative capacity and therefore
in vivo mitochondrial function [47].Initial reports on decreased in mitochondrial
function in diabetes that were found with saturation transfer were confirmed by PCr
recovery measurements [48].
Assessment of Metabolic Fluxes
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.
I maging Tools for Assessing Hepatic Tissue Function

and Metabolism
Hepatocellular Lipid Content
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
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
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.
Measurement of Metabolic Fluxes
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].
I maging Tools for Assessing Cardiovascular Function

and Metabolism
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
prevention and diagnosis may be therefore of high clinical relevance in the context
of precision diabetology.
Myocardial Lipid Contents
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].
Myocardial Mitochondrial Function
Also in the heart, decreased mitochondrial function was suggested to be involved in

diabetic cardiomyopathy and heart failure (as reviewed in [71] and in line with a
diminished mitochondrial capacity, the energy status of the heart (determined as
PCr/ATP) was found to be decreased in diabetes in some, but not all studies
[72–74]).
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)
Diabetes-Associated Vascular Disease
Noninvasive techniques provide information on macrovascular anatomy, as well as

on functional parameters concerning blood flow in large vessels, tissue perfusion,
and microcirculation, all of which may be affected in humans with diabetes.
Ultrasonography (US) is mainly used to assess the atherosclerotic burden in non-
coronary arteries. Doppler US has been successfully employed for an early and
accurate characterization of the vasculopathy of lower limb arteries [75], thus con-
tributing to the prevention or delay of foot complications, especially amputation.
Moreover, the measurement of the carotid intima-media thickness (IMT) by US has
been demonstrated a useful marker of the progression of atherosclerosis throughout
the body and an excellent predictor of cardiovascular events even in diabetic popu-
lation [76, 77]. Furthermore, carotid IMT can be used to evaluate the efficacy of
new treatments and is often referred to as a primary outcome in cardiovascular
research in patients with diabetes [78–80].
Endothelial dysfunction is frequent in patients with diabetes mellitus and is asso-
ciated with the burden of cardiovascular risk in long-standing diabetes [81].
Endothelial dysfunction is characterized by a reduced flow-mediated vasodilation
due to decreased nitric oxide (NO) bioavailability [82]. Vasodilation is mainly
driven by NO production from the endothelium which is susceptible to changes in
the glucometabolic milieu. Several mechanisms of endothelial dysfunction have
been reported in relation to diabetes, including impaired release of NO as well as
signal transduction and substrate availability, enhanced release of endothelium-
derived constricting factors, and decreased sensitivity of the vascular smooth mus-
cle to NO signaling [83]. Investigation of the flow-mediated dilatation of the brachial
artery is a noninvasive technique to measure endothelial NO release during reactive
hyperemia after blood flow restriction of the brachial artery [81] (Fig. 4.5).
Endothelium-independent nitroglycerin-mediated dilatation can assess further
mechanisms involved in early atherosclerotic changes [84].
In the presence of endothelial dysfunction, there is a blunting and delay of the
hyperemic response, which can be measured noninvasively using a variety of MRI
methods. Recent developments in non-contrast, proton MRI ensure for dynamic
quantification of blood flow and oxygenation, for example, by detecting the blood
oxygenation-level dependent signal that reflects a combined effect of blood flow
and capillary bed oxygen content; arterial spin labeling for quantification of regional
perfusion; phase contrast to quantify arterial flow waveforms and macrovascular
blood flow velocity and rate; high-resolution MRI for luminal flow-mediated dila-
tion; and dynamic MR oximetry to quantify oxygen saturation. Overall, results sug-
gest that these dynamic and quantitative MRI methods can detect endothelial
dysfunction both in the presence of overt cardiovascular disease and in subclinical
settings [85].
Moreover, metabolic abnormalities that are common in diabetes, particularly
hyperglycemia, increased free fatty acids, and insulin resistance [1] can further
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
contribute to the alteration of the endothelial function and structure. Consequently,

it is of great clinical relevance to identify patient groups at risk and implement early
detection methods of endothelial dysfunction in patients with diabetes.
Blood supply to the pancreas may be of specific relevance in diabetes. Recently
studies using MRI in experimental studies on rodent diabetes models [86] evaluated
pancreatic vascular volume, microvascular flow, and permeability as possible patho-
physiological backgrounds for the development of diabetes and the heterogeneity of
clinical manifestations [87].
In addition, novel imaging techniques have been investigating in the character-
ization of atherosclerotic plaques by MRI among others by using negative contrast
agents (decreasing signal intensity) based on superparamagnetic iron oxides: SPIO
(superparamagnetic iron oxide) and USPIO (ultrasmall superparamagnetic iron
oxide) [88, 89].
Further new approach for in vivo visualization of inflammatory processes by
MRI uses biochemically inert nanoemulsions of perfluorocarbons (PFCs). PFCs can
serve as “positive” contrast agent for detection of inflammation by 19F-MRI, permit-
ting a spatial resolution close to the anatomical 1H image and an excellent degree of
specificity due to lack of any 19F background. Since PFCs are nontoxic, this
approach may have a broad application in the imaging and diagnosis of numerous
inflammatory states [90] with relevance for atherosclerosis and cardiovascular com-
plications in diabetes.
I maging Tools for Assessing Pancreatic Steatosis

in the Context of Diabetes
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.
I maging Tools for Assessing and Monitoring

Diabetic Nephropathy
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].
I maging Tools for Assessing and Monitoring

Diabetic Retinopathy
Diabetic retinopathy is a common microvascular complication of diabetes mellitus.

Fundus photography can be used to document retinal disease over time and may be
increasingly helpful in screening of diabetic patients for retinopathy (Fig. 4.6). It
has the advantage of being cost- and time-effective and is noninvasive and easy to
Fig. 4.6 Fundus

photography of diabetic
retinopathy. Fundus
photography of mild
diabetic retinopathy
showing hard exudates
implement in a clinical setting. B-scan ultrasonography can be helpful in patients

with media opacity, such as vitreous hemorrhage or cataract.
Optical coherence tomography angiography (OCTA) has been developed to
visualize the retinal microvasculature and choriocapillaris based on the motion con-
trast of circulating blood cells. OCTA enables quantification of microvascular alter-
ations in the retinal capillary network, in addition to the detection of classical
features associated with diabetic retinopathy, including microaneurysms, intrareti-
nal microvascular abnormalities, and neovascularization [98]. Furthermore, OCTA
can identify preclinical microvascular abnormalities preceding the onset of clini-
cally detectable diabetic retinopathy. This is particularly relevant for patients with
severe insulin-deficient diabetes who have been shown to present with higher preva-
lence of diabetic retinopathy [7]. Advancement of OCTA technology in clinical
research will ultimately lead to enhancement of targeted management and preven-
tion of visual impairment in patients with diabetes.
In patients with diabetic retinopathy, fluorescein angiography can show microan-
eurysms, which manifest as punctate areas of hyperfluorescence [99]. Patchy areas
of hypofluorescence can signify ischemia in retinal capillaries. Fluorescein can also
show abnormal blood vessels in the eye such as intraretinal microvascular abnor-
malities or retinal neovascularization and can leak out of incompetent blood vessels.
Retinal neovascularization also can cause fluorescein leakage, and fluorescein angi-
ography is a useful test to confirm the diagnosis of neovascularization in prolifera-
tive diabetic retinopathy but also for the diagnosis of macular edema [100, 101].
As these technologies have continued to evolve, their importance in the diagnosis
and management of diabetic retinopathy has become increasingly evident.
Concluding Remarks
Precision medicine in diabetes requires accurate profiling of individuals belonging

to a given sub(pheno)type (subgroup, cluster), by integrating imaging data to the
advances already made in clinical classifications. Presently, there is a diverse array
of imaging techniques at the disposal of clinicians and researchers aiding the com-
prehensive assessment of metabolic features in humans with diabetes. Most relevant
to current translational objectives in precision diabetology are the potential implica-
tions of imaging techniques for preventive and therapeutic strategies for the man-
agement of diabetes and its complications.
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Chapter 5
Implementation of Precision Genetic
Approaches for Type 1 and 2 Diabetes
Ronald C. W. Ma and Juliana C. N. Chan
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
Hong Kong, China
e-mail: [email protected]; [email protected]

112 R. C. W. Ma and J. C. N. Chan
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
“Traditional” biomarkers (e.g. HbA1c, microalbuminuria)

with clinical subphenotypes (e.g. C peptide, autoantibodies)
Risk models/equations using clinical markers (e.g.

UKPDS Risk Engine, RECODe, JADE algorithms and technology)
Genetic polymorphisms (e.g. SNPs from GWAS,

polygenic risk scores)
“Novel” biomarkers (e.g. omics including proteomics,

metabolomics and transcriptomics) and other data
analytics (e.g. continuous glucose monitoring, heart rate,
blood pressure from wearables, imaging data, retinal
vessels on fundus photos etc).
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
Diagnostic tests Nutrigenomics Pharmaco- Risk stratification

genomics for disease
management
Fig. 5.2 The pillars of precision medicine as applied to Precision Medicine in Diabetes
medicine in diabetes, as well as thinking ahead in terms of implementation of preci-

sion medicine. As illustrated in Fig. 5.2, these pillars of precision medicine include
the following:
(i) Precision diagnosis – using a broad range of information to facilitate more
precise diagnosis and sub-classification of diabetes.
(ii) Precision prevention – predicting the onset of diabetes by incorporating infor-
mation for designing tailor-made prevention strategies such as modifying diet/
exercise according to biological makeup. This may also include precision
monitoring, which is focused on implementing strategies to monitor patterns
of glucose excursion and other risk factor control based on the individu-
al’s makeup.
(iii) Precision treatment – selecting and modifying doses of medications based on
personalized clinical information, biological characteristics and treatment
responses.
(iv) Precision prognostics – predicting the onset and progression of diabetes com-
plications based on biomarkers and treatment responses for formulating per-
sonalized strategies.
In addition to these individualized biomedical information relevant to the predic-
tion, prevention and personalized care in diabetes, clinical acumen including the
recognition of secondary causes of diabetes (e.g. endocrine disorders, pancreatic
diseases [5]), other population-relevant factors (e.g. chronic low-grade infections
[6]), external factors that can affect glucose metabolism (e.g. concomitant
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.
Potential for Precision Medicine in Type 1 Diabetes (T1D)
Precision Diagnosis in T1D
Whilst the diagnosis of T1D in children and adolescents is usually straightforward,

the recognition of adult-onset T1D is comparatively more challenging. Given the
large majority of adults with newly diagnosed diabetes have T2D, the small propor-
tion who have underlying autoimmune diabetes are sometimes missed, leading to
delayed initiation of insulin and suboptimal glucose control. Whilst different bio-
markers including anti-glutamic acid decarboxylase (Anti-GAD) or other auto-
antibodies have been used in the diagnosis of T1D, they also have their limitations,
including false positivity, and potential for misdiagnosis in a population that is in
general at low risk for T1D [9]. The development of PRS for T1D, based on findings
from GWAS, provides opportunities to identify those at risk and has been found to
be of help to differentiate adults with T1D versus T2D and identify individuals who
require early insulin therapy [10].
Precision Prevention in T1D
One of the major breakthroughs in our understanding of the pathophysiology of

T1D is its progressive nature. The onset of beta-cell destruction, insulin deficiency
and hyperglycaemia is often preceded years earlier by gradual appearance of
markers of autoimmunity, including anti-islet antibodies. This has given rise to a

large number of clinical trials to investigate the possibility to delay the onset or
progression of T1D, for example, in at-risk individuals with family history of
T1D. These are summarized in several excellent reviews, and the details are beyond
the scope of this chapter [11]. Suffice to say, the use of agents to modify the poten-
tial development and progression of T1D is a prime example of implementing preci-
sion prevention in T1D. The most successful example to date is use of the Anti-CD3
antibody, teplizumab, which was associated with a 60% reduction in development
of T1D in at-risk relatives in a phase 2 trial [12]. Future efforts to use non-
pharmacological measures (e.g. vitamin D or other agents) and drugs to delay
development of T1D, guided by individual genotypes or biomarkers, appear prom-
ising. For example, a recent study incorporating genetic, clinical and immunologi-
cal factors was found to dramatically improve T1D prediction at 2–8 years compared
to autoantibodies alone. This multicomponent strategy may be used to facilitate
population-based newborn screening program to prevent ketoacidosis in childhood
and identification of high-risk subjects for prevention trials [13].
Precision Monitoring in T1D
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.
Precision Treatment in T1D
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
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.
Precision Prognostics in T1D
There is considerable heterogeneity in the development of complications in patients

with T1D, such as retinopathy, nephropathy and neuropathy. Whilst hyperglycae-
mia is a shared pathogenetic factor, other pathways may also be implicated in these
complications. Thus, the ability to predict future risk of specific complications will
facilitate risk stratification for management based on these personalized risks of
diabetes-related complications. Several studies have sought to identify genetic vari-
ants associated with diabetes complications, though few have attained genome-wide
association threshold, or have been consistently replicated [19–21]. Some success-
ful examples from recent large consortia-based studies have identified variants asso-
ciated with diabetic kidney disease in T1D, including a common missense mutation
in the collagen type IV alpha 3 chain (COL4A3) gene [22]. In addition, the hapto-
globin genotype has been demonstrated to be associated with risk of cardiovascular
complications in T1D. In the Epidemiology of Diabetes Complications Study, indi-
viduals with the haptoglobin 2/2 genotype had approximately twofold increased
risk of incident coronary artery disease (CAD) compared to those with haptoglobin
1/1 genotype during 18 years of follow-up [23]. Incorporating these genetic
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.
Potential for Precision Medicine in Type 2 Diabetes (T2D)
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].
Precision Diagnosis in T2D
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
different prognosis. Individuals with “severe insulin-deficient diabetes” had the

highest risk of incident diabetic retinopathy, whereas those with “severe insulin-
resistant diabetes” were mostly likely to develop chronic kidney disease (CKD)
compared to the other subtypes [25]. The clinical and prognostic significance of
these diabetes subtypes has subsequently been replicated in various studies from
different populations. An alternative “soft clustering” approach, based on GRS for
five different pathophysiological pathways associated with T2D (e.g. beta-cell, pro-
insulin, obesity, lipodystrophy, liver/lipid), has likewise facilitated the classification
of individuals with T2D according to underlying pathophysiology and the opportu-
nity to better tailor treatment according to underlying pathophysiological
defects [26].
Precision Prevention in T2D
Driven by the identification of genetic variants associated with T2D, different

research studies have explored the potential to use PRS for T2D to identify indi-
viduals at increased risk of T2D and to investigate strategies to empower prevention
of T2D. Incremental improvement in the development of PRS for T2D has improved
the ability to stratify risk. The use of phenotypes may also increase the validity of
PRS. For example, in the InterAct study, the relative risk of a T2D PRS was greater
among young and lean individuals. The 10-year cumulative incidence of T2D rose
from 0.25% to 0.89% across extreme quartiles of the genetic score in normal-weight
individuals, compared to 4.22% to 7.99% in obese individuals. Given the over-
riding effect of obesity at any level of genetic risk, this result suggests that
population-based approach to create a health-enabling environment to promote
healthy lifestyle would be more cost-effective [30, 31]. However, within this con-
text, there is a need to identify those people who are genetically at risk, especially
those who are young and lean, in whom PRS may identify those who require phar-
macological treatment to halt the disease progression. In this light, in the Diabetes
Prevention Programme (DPP), among 823 individuals with pre-diabetes who were
randomized to the intensive lifestyle intervention (ILS) arm and remained free of
diabetes 1 year after enrolment, genetic risk for T2D identified individuals with dif-
ferential risk of T2D despite achieving ILS goals of 7% weight loss, 150 min/week
leisure-time physical activity, and <25% weekly dietary calories from fat, highlight-
ing that achieving weight loss does not completely ameliorate the genetic risk [32].
Precision Monitoring in T2D
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
interpretation of HbA1c in relation to genetic makeup. For example, a multi-ethnic

study of 159,940 individuals identified 60 common variants associated with HbA1c.
Of note, a common X-linked G202A variant in the glucose 6 phosphate dehydroge-
nase (G6PD) gene present in 11% of African Americans was associated with
approximately 0.81% units lower HbA1c and hence gives rise to falsely low HbA1c
in carriers. This highlights the potential need to screen for the G6PD variant when
using HbA1c to diagnose diabetes in populations with high prevalence of G6PD
deficiency to provide more precision in monitoring glycaemic control using
HbA1c [33].
Precision Treatment in T2D
The aforementioned efforts of sub-classifying T2D, in part by delineating underly-

ing pathophysiological defects, lend themselves to precision treatment of T2D. Thus,
patients with predisposition to beta-cell defect would benefit from earlier insulin
treatment, whilst those with obesity-related diabetes should be targeted for weight-
reduction intervention, including very-low-calorie diet, for diabetes remission [34].
In a proof-of-concept study, using C peptide to define insulin sufficiency, Chinese
patients with T2D with low C peptide value treated with insulin had the lowest mor-
tality incidence compared with the highest rate in those with high C peptide and
treated with insulin, in part due to long disease duration [35]. Similarly, in a pro-
spective cohort of Chinese patients with young-onset T2D, 8% of patients had latent
autoimmune diabetes in adult (LADA) with positive anti-GAD antibodies. Among
the insulin-treated patients, patients with LADA had 1.7% reduction in HbA1c
compared with 0.8% in the non-LADA patients. Importantly, these patients with
LADA had threefold increased risk of end-stage kidney disease than their peers
with classical T1D presentation, raising the possibility that delayed diagnosis and
treatment in patients with LADA might have contributed to these prognostic differ-
ences [36]. In a similar vein, the use of Homeostatic Model for Assessment of insulin
resistance and beta cell function (HOMA-IR and HOMA-Beta) derived from fasting
plasma glucose and C peptide have also been shown to predict incident diabetes in
high risk individuals and, insulin requirement in patients with diabetes [37]. These
observational studies have provided the support to develop strategies of matching
treatment to underlying pathophysiology. However, randomized clinical trials are
needed to incorporate such algorithm-guided treatment to examine long-term clini-
cal outcome.
The need to tailor treatment to clinical characteristics was also highlighted by
earlier clinical trials on intensive glucose control. Clinical trials such as the Action
to Control Cardiovascular Risk in Diabetes (ACCORD) have highlighted that inten-
sive glucose control (targeting a HbA1c of below 6.0%) in specific patient popula-
tions with T2D may be hazardous and was associated with increased mortality
among patients randomized to the intensive-therapy group [38]. Some of these
patients with severe hypoglycaemia, often unmasked by intensive treatment or
failure to adjust treatment, exhibited a “frail” phenotype with multiple morbidities

notably chronic kidney disease (CKD) disease with some of them at increased risk
of premature death due to multiple causes including cancer [39, 40]. Findings from
these studies, together with results from other trials of intensive glucose lowering,
have highlighted the need for individualizing treatment targets and led to the recom-
mendation of proposing treatment algorithms for T2D taking into consideration
patient profile and co-morbidities [41, 42]. Interestingly, in a subsequent GWAS
utilizing the ACCORD cohort, 2 loci, rs9299870 near O6-Methylguanine-DNA
Methyltransferase (MGMT) and rs57922 near LINC01333, were found to be asso-
ciated with increased risk of cardiovascular mortality among participants in the
intensive glucose-lowering arm, but not in participants in the standard arm [43]. The
modulatory effect of a GRS composed of these two SNPs on association between
glycaemic control and cardiovascular mortality was confirmed in an independent
cohort from the Joslin clinic [43], highlighting the potential to use biomarkers to
identify subjects who may have altered risk-benefit ratio from intensive glucose
control.
Another application of precision treatment in T2D is the use of biomarkers or
other information to guide treatment selection, including strategies utilizing phar-
macogenomics. For example, clinical risk factors including low and high BMI, ear-
lier age at onset, elevated triglyceride and low HDL concentration were found to be
associated with increased risk of glycaemic progression and need for insulin in
different populations with T2D [44, 45]. Several genetic variants have also been
identified to be associated with sulphonylurea and metformin response and may be
used to guide treatment dosing [46–49]. In two cohorts of Chinese patients with
T2D in Hong Kong, PRS including genetic variants associated with T2D or metfor-
min response were found to show association with glycaemic progression and need
for insulin therapy [45].
Precision Prognostics in T2D
There is marked inter-individual variation in the risk of susceptibility to different

diabetes complications as well as other emerging comorbidities such as dementia
and cancers. Several risk scores or algorithms have been developed to predict risk
of cardiovascular and other complications, including the United Kingdom
Prospective Diabetes Study (UKPDS) risk engine [50] and the Risk Equations for
Complications Of type 2 Diabetes (RECODe) [51]. Several validation studies have
suggested that the UKPDS risk engine tend to overestimate risk for CAD in contem-
porary cohorts [52, 53], thus highlighting the need for additional algorithms and
population-specific adaptions.
Using data from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort and
the Jackson Heart Study, the Risk Equations for Complications of Type 2 Diabetes
(RECODe) provided improved risk stratification compared to the UKPDS outcome
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).
Macrovascular complications
Microvascular complications
β-cell function
Insulin
resistance
Blood
glucose
Pre-diabetes Type 2 diabetes
Application Usage Examples
Moleuclar Sequencing
diagnosis for MODY
genes
Risk prediction T2D genetic

of DM risk scores
Risk prediction Complications

DM risk scores
complications
PGx panel
Pharmaco for drug
genetics selection
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])
Another example of a biomarker-based strategy for risk stratification is the use of

CKD risk scores based on proteomic measurement of 273 urinary peptides
(CKD273-classifier), which has been shown to predict microalbuminuria during
follow-up [68]. In a recent multicentre, prospective, observational study with
embedded randomized controlled trial (PRIORITY), patients with T2D and normal
urinary albumin excretion were recruited from 15 European centres and stratified
for CKD risk using the CKD273-classifier. Patients identified as high risk for CKD
were randomized in 1:1 ratio to receive spironolactone or placebo. The study con-
firmed the utility of the CKD273-classifer in identifying increased risk of progres-
sion from normoalbuminuria to microalbuminuria, though spironolactone did not
reduce the risk among high-risk subjects randomized to receive spironolactone [69].
Implementation of Precision Medicine for Diabetes
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
The path to precision medicine in type 2 diabetes.
Understanding Vertical
the disease integration of
(risk factors, Biomarkers and
mechanisms, Generation of Patient Clinician Patient
natural history) Algorithms engagement education HEA feedback
Identifying disease- Regulatory Testing single Regulatory Clinical

specific Biomarkers engagement biomarkers or approval translation
Biomarker Sets in (continued clinician
Diagnostic, Monitoring,
intervention trials education and decision
Predictive, Prognostic, support)
Pharmacodynamic / Response,
Safety, Susceptibility, Surrogate
End Point
Hugo Fitipaldi et al. Diabetes 2018;67:1911-1922

American
Diabetes
©2018 by American Diabetes Association Association
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])
summarized in a review article [70](Fig. 5.4), requires a concerted effort of integrat-

ing the biomarkers and other relevant data into actionable algorithms, engaging
approval agencies, empowering clinicians for the appropriate clinical use, generat-
ing the evidence of utility in biomarker-driven clinical trials, obtaining regulatory
approval, educating users such as patients and high-risk individuals as well as seek-
ing reimbursement from payers, in order for such strategies to be widely adopted by
the clinical community (Fig. 5.3). The roadmap described thus highlights the differ-
ent hurdles and barriers that need to be overcome at different stages of the imple-
mentation plan. Among these steps are the need to demonstrate utility of
incorporating these strategies compared to traditional approach of diabetes manage-
ment. Furthermore, both patients and clinicians need to acquire a certain degree of
“biomarker” or “genetic literacy” in order to fully utilize these information to make
decisions, change behaviours and improve outcomes. Given the complexity of the
information being provided, there is also a need to design care models to gather,
analyse and communicate this wealth of information relating to risk, or disease sub-
classification, in order to educate, empower and engage both patients and care pro-
viders in accepting these new approaches to diabetes management. Most importantly,
these models need to be sustainable with full alignment among patients, providers,
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
technologies (e.g. biogenetic markers, CGMS, HbA1c, artificial intelligence, etc.),

we are now in a much better position to integrate these wealth of data to reclassify
diabetes and make better prediction for personalized prevention and treatment strat-
egies. It is anticipated that the next few years will witness exciting developments in
the delivery of precision medicine in diabetes, which would go hand in hand with
the rapid technological developments in big data analytics, large-scale biomarker
profiling and artificial intelligence, to bring diabetes care to the forefront of twenty-
first-century genomic medicine and care management.
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).
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Chapter 6
Precision Genetics for Monogenic Diabetes
Andrea O. Y. Luk and Lee-Ling Lim
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
L.-L. Lim
Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia

132 A. O. Y. Luk and L.-L. Lim
Epidemiology of Monogenic Diabetes
The majority of population-based studies on the prevalence of monogenic diabe-

tes have been conducted in Europe and North America. In most of these studies,
only the common MODY forms were considered. The prevalence of MODY var-
ies between studies depending on the criteria used for case finding. From a large
Germany and Austria clinical database of over 40,000 youth aged below 20 years
with diabetes, 0.8% were classified to have MODY by their physicians [4]. The
Norwegian Childhood Diabetes Registry, which accrued 2756 children aged
below 15 years, detected monogenic diabetes in 1.1% through genetic screening
of individuals without autoimmune antibodies [2]. In a Swedish cohort of 3933
people aged 1–18 years with recently diagnosed diabetes, the minimal prevalence
of MODY was 1.2% [5]. The US SEARCH for Diabetes in Youth Study consecu-
tively sequenced 586 diabetic youth who were negative for autoimmune antibod-
ies and had preserved beta-cell function based on detectable fasted C-peptide
level for mutations in the three common genes reported prevalence of 8% of the
tested sample or 1.2% of the whole diabetes youth population [6]. In a UK-based
study, 3.6% of 1365 people with diabetes diagnosed at age below 30 years had
monogenic diabetes including both common MODY forms and rare mutations
[1]. As these studies mainly reported disease prevalence among young people
with diabetes, the prevalence across the full age spectrum of diabetes population
is not known.
Classification of Monogenic Diabetes
There is no consensus for classification or nomenclature of monogenic diabetes. It

is generally recognized that monogenic diabetes may present as neonatal diabetes
(NDM) (diabetes presenting before the age of 6 months), MODY, monogenic diabe-
tes with multisystem syndromes, mitochondrial diabetes, or monogenic diabetes
associated with severe insulin resistance or with lipodystrophy [7].
Earlier literatures assigned MODY subtypes according to the order by which the
disease-causing mutation was discovered. For example, diabetes due to mutation in
the HNF4A has been referred to as MODY1, diabetes related to GCK mutation as
MODY2, etc. This nomenclature scheme is problematic because of the increasing
number of genes being incriminated. An alternative classification scheme combin-
ing the implicated gene and clinical presentation has been proposed. Under this
classification, HNF4A-MODY will replace MODY1, GCK-MODY will replace
MODY2, and so forth. Table 6.1 lists the common monogenic diabetes types based
on implicated genes and clinical manifestation.
6
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
(comparable to the general

population)
HNF1A Transcription Autosomal Progressive deterioration in Nil First line: Neonatal hyperinsulinemia,
factor dominant beta-cell function Low-dose hypoglycemia, and macrosomia: Rare
Glycosuria due to a low renal sulfonylureas or Maternal glycemia determines fetal
glucose threshold meglitinides outcomes
Enhanced sensitivity to Second line: Two options with shared
sulfonylureas Insulin, GLP1-RA, decision-making:
Normal body weight DPP-4 inhibitors (a). Stop sulfonylurea and transition
Normal lipid levels to insulin therapy before pregnancy
(b). Continue sulfonylurea during
early pregnancy, and transition to
insulin therapy in the second
trimester (only for mothers with
optimal glycemic control before
pregnancy)
(continued)
133
134
Genetic Function on Extra pancreatic

defect beta-cell Inheritance Clinical features features Treatment Implications on pregnancy
HNF4A Transcription Autosomal Similar to that seen in Nil First line: Neonatal hyperinsulinemia,
factor dominant HNF1A-MODY Low-dose hypoglycemia, and macrosomia: More
Sequencing for HNF4A sulfonylureas common than HNF1A-MODY
mutations is indicated if Second line: Fetal genotype determines fetal
HNF1A mutations are absent Insulin, GLP1-RA outcomes
Same treatment approaches as in
HNF1A-MODY
HNF1B Transcription Autosomal Catabolic symptoms: 47% Pancreatic First line: If both the mother and offspring have
factor dominant Ketoacidosis: Rare exocrine Sulfonylureas or HNF1B-MODY: Birth weight is
HbA1c ≥13% (119 mmol/ dysfunction meglitinides increased
Mol) Multi-organ 49% required If the mother is unaffected and the
BMI <25 kg/m2: 80% developmental insulin therapy at offspring has HNF1B mutations: Low
43% had ≥4 coexistent abnormalities diagnosis birth weight is common
cardiovascular risk factors (e.g., kidney, Insulin therapy is a conservative
Decreased insulin sensitivity genitourinary approach
compared with tract, liver)
HNF1A-MODY
Footnotes: BMI, body mass index; DPP-4, dipeptidyl peptidase-4; GCK, glucokinase; GLP1-RA, glucagon-like peptide-1 receptor analogues; HNF1A, hepa-
tocyte nuclear factor 1-alpha; HNF1B, hepatocyte nuclear factor 1-beta; HNF4A, hepatocyte nuclear factor 4-alpha; OGTT, 75-gram oral glucose tolerance test
A. O. Y. Luk and L.-L. Lim
6 Precision Genetics for Monogenic Diabetes 135
Diagnosis of Monogenic Diabetes
Correct identification of monogenic diabetes is a prime example of precision medi-

cine as molecular confirmation of this condition will affect medical therapy, direct
investigations for possible extra-pancreatic features, and prompt screening in other
family members. Depending on the incriminated monogenic diabetes gene, response
to glucose-lowering drugs varies, and prognosis with respect to the risks of vascular
complications differs. For example, GCK mutation, which is linked to a shift in the
glucose-sensing threshold of pancreatic beta-cell resulting in mild fasting hypergly-
cemia, is associated with extremely low risks of vascular complications from diabe-
tes and does not require pharmacological treatment [8, 9]. In contrast, people with
mutations in HNF1A and HNF4A have significant post-meal glucose excursions
which are sensitive to the action of sulfonylureas [10, 11]. Unlike people with muta-
tions in GCK, those with HNF1A, HNF4A, and HNF1B mutations are susceptible to
kidney and retinal complications at an early age, and close monitoring and preven-
tive measures instituted in a timely manner can minimize irreversible end-
organ damage.
Diagnosis of monogenic diabetes requires molecular testing using either Sanger
sequencing or next-generation sequencing (NGS). Sequencing is the process of
determining the order of nucleotides in a gene fragment. The Sanger method
sequences one gene at a time, whereas NGS is a high-throughput method and is able
to uncover variants in a larger pool of genes simultaneously. Sanger sequencing
remains the most frequently used method in clinical practice for identifying com-
mon MODY mutations in people with specific phenotypes. With narrowing in the
cost differential between Sanger sequencing and NGS, there is gradual trend toward
using NGS to screen for genetic variants. In a study of 82 individuals with suspected
MODY or neonatal diabetes in whom mutations could not be identified using tradi-
tional methods, 17% were found to harbor mutations within the less common mono-
genic diabetes genes using NGS [12]. In another study in which people with
evidence of endogenous insulin secretion and negative islet autoantibodies were
sequenced using NGS, mutations in rare genes contributed to about half of all cases
of monogenic diabetes [1]. Many facilities have developed targeted NGS gene pan-
els for monogenic diabetes. However, one should be cognizant of the possibility of
revealing variants of uncertain clinical significance or those that have little informa-
tion available in the medical literature. Determining whether these variants are
disease-causing poses major challenges even among experts. Recently, the American
College of Medical Genetics and Genomics and Association for Molecular
Pathology have standardized the procedures for assigning pathogenicity to genetic
variants [13]. The Clinical Genome Resource funded by the National Human
Genome Research Institute is an expanding knowledge base that is accruing genetic
and clinical information from researchers and clinicians from across the globe with
the overarching aim to develop consensus methods for interpreting genetic variants
in the clinical context [14]. In the case of finding variants associated with
extra-pancreatic manifestations, inappropriate interpretation may lead to unneces-

sary investigations and anxiety for both the affected individual and their family
members.
Challenges with Diagnosing 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].
Risk Calculator and Screening Algorithm for MODY
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
diagnosis or having a parental history of diabetes increased MODY detection rate to

33% and captured over 90% of all MODY cases.
It should be highlighted that these risk calculators or algorithms may not be gen-
eralizable to non-White ethnic groups. Firstly, the distribution of diabetes types
among youth or young adults with diabetes differs by ethnicity. For example, in
Chinese people, type 2 diabetes contributes to over half of youth (aged <20 years)
with diabetes, whereas type 1 diabetes is the predominant diabetes type in White
people [17]. Screening methods that differentiate between type 2 diabetes and
monogenic diabetes may be more relevant in non-White populations. Secondly,
there are huge variations in BMI distribution between ethnic groups. As such, the
usual correlation between BMI and diabetes types may not apply equally. Thirdly,
the types and frequencies of monogenic diabetes gene mutation may be dissimilar
between people of different ethnicities. Differences in genetic makeup will also
influence clinical expression of these variants. In a study of predominantly White
people, mutations in common MODY genes were detected in 51% of people with
age of diabetes onset below 25 years, with at least one affected parent and not insu-
lin treated [15]. In a Chinese diabetes cohort, however, only 10% of individuals
fulfilling similar clinical criteria were found to have mutations, leaving the majority
undefined [26].
ommon Subtypes of MODY: Clinical Phenotypes,

C
Management, and Implications on Pregnancy
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
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
Compared with GCK-MODY, people with HNF1A-MODY have progressive beta-

cell dysfunction with marked symptomatic hyperglycemia. Similar to that seen in
type 2 diabetes, people with HNF1A-MODY tend to develop microvascular and
macrovascular complications that are strongly related to glycemic control (Table 6.1)
[37, 38]. In a UK cohort, a lower proportion of people with HNF1A-MODY reported

any degree of retinopathy than age-, BMI- and diabetes duration-matched patients
with type 1 diabetes (13.5% versus 50.0%) [39]. Compared with non-mutation car-
riers, individuals with HNF1A-MODY had 1.9 and 2.6 times increased risk of all-
cause and cardiovascular deaths, respectively, after adjusting for sex and smoking
status [40]. Hence, annual screening for diabetes-related complications is recom-
mended [31].
First-line treatment for people with HNF1A-MODY is low-dose sulfonylureas,
which act via potassium-sensitive ATP channels to increase insulin secretion [39].
Given its increased sensitivity to sulfonylureas with a risk of hypoglycemia, sulfo-
nylureas should be initiated at a low dose and slowly titrated to target with dose
reduction or discontinuation of concurrent insulin therapy [38]. Despite treatment
with sulfonylureas, glycemic control continues to deteriorate after 3 to 25 years due
to progressive beta-cell dysfunction [37]. In an observational study in which 21
people with either HNF1A- or HNF4A-MODY switched from metformin and/or
insulin therapy to diet alone or sulfonylurea alone. At 2 years, about 60% achieved
target glycemic control of HbA1c ≤7.5% (58 mmol/mol). The major predictors for
response to sulfonylureas included short diabetes duration, low pre-treatment
HbA1c, and low BMI, highlighting the importance of early diagnosis [41].
Nateglinide has also been shown to reduce postprandial glucose levels with a lower
risk of hypoglycemia compared with glyburide [42].
Apart from insulin therapy, glucagon-like peptide-1 receptor analogues (GLP-1
RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors have been investigated as poten-
tial adjuvant therapies in HNF1A-MODY [43–45]. In a 6-week randomized, double-
blinded, crossover trial involving 16 individuals with HNF1A-MODY (mean age
39 years, HbA1c 6.4% (46 mmol/mol) and BMI 24.9 kg/m2), both liraglutide
(1.8 mg weekly) and glimepiride (1.0–4.0 mg daily) reduced fasting plasma glucose
without significant between-group differences [44]. Compared with liraglutide,
glimepiride was associated with a 10 times increased risk of mild hypoglycemia
[44]. In another 36-week randomized, double-blinded, crossover trial involving 19
people with HNF1A-MODY (mean age 43 years, HbA1c 7.4% (57 mmol/mol) and
BMI 24.8 kg/m2), the addition of linagliptin to glimepiride improved glycemic vari-
ability, insulin sensitivity, and HbA1c by 0.5% without increasing the risk of hypo-
glycemia [46]. By contrast, the use of sodium-glucose co-transporter-2 (SGLT2)
inhibitors in HNF1A-MODY is cautioned against due to reports of severe volume
depletion and diabetic ketoacidosis [31, 47, 48].
Majority of pregnancies affected by HNF1A-MODY are not associated with an
increased risk of fetal hyperinsulinemia, hypoglycemia, and macrosomia [49].
Maternal glycemia determines fetal outcomes, but there is limited data on the best
treatment approach during pregnancy. Although sulfonylureas (especially glyburide
as it has been extensively studied in pregnancy) are a reasonable treatment for
HNF1A-MODY during pregnancy, recent reports about transplacental transfer of
glyburide [50] with 2–3 times increased risk of neonatal hypoglycemia and macro-
somia have raised safety concerns [51]. In this light, there are two potential treat-
ment approaches, namely, [1] stop glyburide and transition to insulin therapy
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
Given HNF1A-MODY and HNF4A-MODY have similar phenotypes, sequencing

for HNF4A mutations should be performed when HNF1A mutations are absent [52].
Likewise, annual screening for diabetes-related complications is recommended.
People with HNF4A-MODY may present with transient neonatal hyperinsulinemia
and hypoglycemia, followed by diabetes during adolescence or early adulthood
[37, 53].
Similar to HNF1A-MODY, first-line treatment for HNF4A-MODY is sulfonyl-
ureas (Table 6.1) [52, 54]. However, most will require insulin therapy due to more
rapid deterioration of beta-cell function [37, 38]. Substantial glycemic improvement
with the use of GLP-1 RA has been reported in a father-son pair with HNF4A-
MODY who have failed either sulfonylureas or basal-bolus insulin therapy [55].
Nearly half of the offspring of pregnant women with HNF4A-MODY experience
fetal hyperinsulinemia, transient hypoglycemia, and macrosomia [49, 56]. In con-
trast to HNF1A-MODY, the fetal genotype is the key determinant of fetal outcomes
in pregnancies with HNF4A-MODY [57]. Compared with non-mutation carriers,
offspring with HNF4A mutations had a median increase in birthweight by 790
grams and a higher incidence of macrosomia (56.0% versus 13.0%) [49]. Treatment
approaches are the same as previously described for pregnancies with HNF1A-
MODY [57].
HNF1B-MODY
Hepatocyte nuclear factor 1-beta is a transcription factor expressed in embryonic

development of multiple organs [57]. In a European registry, 40% of individuals
with HNF1B-MODY reported extra-pancreatic features [58] including develop-
mental kidney disease (e.g., renal cystic disease, renal hypoplasia), chronic kidney
disease/end-stage kidney disease, liver dysfunction (e.g., unexplained transaminitis,
neonatal cholestasis), genital tract malformations (e.g., rudimentary uterus, cryptor-
chidism), hyperuricemia, and early-onset gout [59, 60]. Screening for these abnor-
malities at diagnosis is warranted.
Although first-line treatment for HNF1B-MODY can be either sulfonylureas or
meglitinides (repaglinide), people with HNF1B-MODY have decreased insulin sen-
sitivity than those with HNF1A-MODY [61]. In a multicenter retrospective cohort
study involving 201 individuals with HNF1B-MODY, 49% of them were treated
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.
KCNJ11-NDM and ABCC8-NDM
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
(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
A diagnosis of diabetes can adversely influence an individual’s life. Although

monogenic diabetes is relatively uncommon accounting for less than 5% of diabetes
in young people, early and accurate detection allows us to project clinical course,
steer the choice of glucose- lowering drugs, and guide screening of at-risk family
members. Timely recognition of MODY also influences antenatal care as maternal-
offspring genotype concordance or discordance can affect pregnancy outcomes.
Given the low diagnostic rate, there is a need to improve the scope and the efficiency
to test. This may be achieved by providing education for physicians and/or system-
atic screening guided by validated screening algorithms.
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Chapter 7
Diabetic Kidney Disease: Identification,
Prevention, and Treatment
M. Luiza Caramori and Peter Rossing
Abbreviations
ACR Albumin-to-creatinine ratio

CKD Chronic kidney disease
CVD Cardiovascular disease
DKD Diabetic kidney disease
ESKD End-stage kidney disease
eGFR Estimated glomerular filtration rate
GBM Glomerular basement membrane
GFR Glomerular filtration rate
KDIGO Kidney Disease: Improving Global Outcomes
RAS Renin-angiotensin system
T1D Type 1 diabetes
T2D Type 2 diabetes
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
P. Rossing
Steno Diabetes Center Copenhagen, Herlev, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

150 M. L. Caramori and P. Rossing
Introduction and Epidemiology
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
obesity-related glomerulopathy. Kidney biopsy studies in patients with T2D indi-

cate that IgA nephropathy, acute tubular necrosis, and others may also be present in
these patients [17–19]. Their frequency is related to the frequency of these condi-
tions in the background population as well as to reasons for a kidney biopsy indica-
tion, which often include atypical course [17–19]. Other causes of reduced GFR or
albuminuria should be considered if proteinuria in patients with T1D for <5 years,
in the presence of active urinary sediment, and if other systemic diseases that can
cause renal dysfunction are present.
Screening, Diagnosis and Stages, and Monitoring
CKD in diabetes is diagnosed by the presence of abnormal kidney function, namely,

estimated glomerular filtration rate (eGFR) and albuminuria [20]. The pathogenic
mechanisms associated with these findings may be distinct.
Screening
Multiple guidelines recommend annual CKD screening of patients with diabetes,
starting about 5 years after T1D diagnosis and at diagnosis in patients with
T2D. Screening tests should include both albuminuria measurements and esti-
mates of GFR.
Albuminuria
First-morning-void urinary albumin-to-creatinine ratio (ACR) measurement is the
test of choice. It is less cumbersome than timed urine collections and has lower day-
to-day variability compared to other methods [21]. If the results are abnormal, this
needs confirmation by collecting another urine sample, ideally within 1–3 months.
At least two out of three measurements should be abnormal before a diagnosis of
albuminuria is made. Acute illnesses, acute hyperglycemia, exercise, and upright
posture can transiently increase albuminuria.
GFR
GFR is usually estimated using equations that include patient’s age, sex, race, and
serum creatinine. Many laboratories currently calculate the eGFR using the serum
creatinine CKD-EPI equation [22] (https://www.mdcalc.com/ckd-epi-equations-
glomerular-filtration-rate-gfr), with race being now optional on this equation.
Importantly, serum creatinine should be measured by an accredited and standardized
assay (isotope dilution mass spectrometry reference method (IDMS)-traceable).
Diagnosis and Stages
CKD is diagnosed when two eGFRs (at least 3 months apart) are <60
mL/min/1.73 m2 and/or two out of three ACR measurements are ≥30 mg/g [20].
CKD staging considers both eGFR and albuminuria values (Fig. 7.1). This heat map
serves as an indicator of risk of progression to ESKD and is also a good indicator of
cardiovascular morbidity and mortality [20].
Persistent albuminuria categories

description and range
Prognosis of CKD by GFR A1 A2 A3

and albuminuria categories:
KDIGO 2012 Normal to
Moderately Severely
mildly
increased increased
increased
<30 mg/g 30-–300 mg/g >300 mg/g
<3 mg/mmol 3–30 mg/mmol >30 mg/mmol
GFR categories (mL/min per 1.73 m2)
G1 Normal or high >90
G2 Mildly decreased 60–89

description and range
Mildly to
G3a 45–59
moderately decreased
G3b Moderately to 30–44

severely decreased
G4 Severely decreased 15–29
G5 Kidney failure <15
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])
Monitoring Kidney Disease

Once urinary albumin excretion is abnormal, ACR should be measured every
3 months and eGFR every 3–6 months, depending on the CKD stage.
Structural Kidney Lesions in Diabetes
DKD manifests as a constellation of structural changes considered unique to this

disease [15, 23–25]. In patients with T1D, glomerular lesions can be demonstrated
after diabetes has been present for about 5 years, while in T2D, they can be present
at diagnosis, probably reflecting delayed T2D diagnosis. The severity of these
lesions is related to diabetes duration, glycemic control, and genetic factors and cor-
relates with functional abnormalities (albuminuria and decreased GFR). Renal
hypertrophy is the earliest renal structural change in T1D. Thickening of the glo-
merular basement membrane (GBM), mesangial expansion, and arteriolar hyalino-
sis follow. Kimmelstiel-Wilson nodules or nodular mesangial expansion is observed
in 40–50% of patients with proteinuria. Tubular atrophy and interstitial fibrosis,
common to most chronic renal disorders, can be present at later stages. Foot
processes (podocyte) changes can be observed by electron microscopy, and the

severity of these abnormalities has been associated with kidney function [26].
Relationships Between Kidney Structure and Function
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].
Albuminuria and GFR

Albuminuria and eGFR levels are associated with CKD development and progres-
sion [46, 64]. Baseline albuminuria strongly predicts ESKD [65]. Higher levels of
normoalbuminuria [66] and lower eGFR [67] predict a faster decline in
eGFR. Conversely, a short-term reduction in albuminuria with intervention suggests
reduced progression of kidney and cardiovascular complications [68, 69].
Comorbidities and Associated Complications
Patients with diabetic nephropathy often have other microvascular complications.

Significant retinopathy is almost always present in individuals with T1D and albu-
minuria [70]. This relationship is less strong among patients with T2D [71].
Peripheral neuropathy is also more common in diabetic nephropathy and associated
with both albuminuria and declining GFR [72]. Autonomic neuropathy, diagnosed
by loss of nocturnal blood pressure dipping, is frequently present [73, 74], and it
predicts decline in kidney function [75].
Albuminuria and reduced GFR contribute independently and synergistically to
the increased cardiovascular risk and are associated with increased morbidity and
mortality [4, 76–79]. While individuals with T1D and normoalbuminuria do not
have a higher risk of premature death [80, 81], those with moderately elevated albu-
minuria have a two- to threefold higher risk, those with severely increased albumin-
uria have a ninefold higher risk, and those with ESKD have an 18-fold increased
risk of premature death versus the non-diabetic population [80]. CVD is 1.2-fold
more common in patients with diabetes and moderately increased albuminuria [82]
and tenfold higher in those with severely increased albuminuria compared with
those with normoalbuminuria [83].
Similarly, in T2D, CVD risk is increased two- to fourfold with moderately
increased albuminuria [84, 85] and ninefold in severely increased albuminuria [86].
Once serum creatinine is outside the normal range, cardiovascular risk increases
exponentially [87].
Prevention and Treatment
The Kidney Disease Improving Global Outcomes (KDIGO) guideline on manage-

ment of diabetes in CKD emphasizes a holistic approach for the management of
cardiorenal risk factors, including lifestyle modification (diet, exercise, and cessa-
tion of smoking); glucose, blood pressure, and lipid control; use of agents blocking
the renin-angiotensin-aldosterone system; and use of SGLT2 inhibitors in patients
with T2D (Fig. 7.2) [88]. This is supported by data from the Steno 2 trial, where
patients with T2D randomized to intensive lifestyle intervention (weight loss,
Some
patients
Anti-platelet
therapies
Most
patients
SGLT2 RAS
inhibitors blockade
All
patients
Blood
Glycemic pressure Lipid
control control management
Exercise Nutrition Smoking cessation
Diabetes with CKD
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
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
primary outcome was a composite of ESKD, doubling of the serum creatinine, or

death from renal or cardiovascular causes. The study was stopped early as cana-
gliflozin showed a benefit effect with 30% reduction in the rates of the primary
outcome. These data were confirmed and extended by the DAPA-CKD study includ-
ing individuals with CKD with or without diabetes [111]. Small studies in T1D
show an increased risk of diabetic ketoacidosis, particularly among ambulatory
insulin pimp users. There are no studies in diabetic nephropathy in T1D. In patients
with T2D with CKD, SGLT2 inhibitors are recommended, independent of HbA1c,
for organ protection [88, 112, 113] (Fig. 7.3).
GLP1-RA
Cardiovascular benefits in individuals with T2D and pre-existing atherosclerotic
CVD have also been demonstrated for some (liraglutide, semaglutide, and dulaglu-
tide) but not all glucagon-like peptide 1 receptor agonists (GLP1-RA) [112, 113].
Benefit on CVD outcomes was also demonstrated in CKD populations, and thus
GLP1-RA are recommended for patients with T2D and CKD when metformin and
SGLT2 inhibition cannot control glucose levels [88, 114](Fig. 7.3).
RAS Inhibition
Intensive control of blood pressure drastically improves the prognosis in diabetic
nephropathy. RAS inhibitors do not prevent albuminuria in normotensive individu-
als with T1D [115–117]. There is also no evidence that control of hypertension in
T1D with normoalbuminuria prevents kidney disease progression; however, this
seems highly likely. Once albuminuria is present, RAS inhibition is clearly indi-
cated and associated with decreased likelihood of progression and increased likeli-
hood of regression to normoalbuminuria levels [118]. RAS inhibitors should be
offered to all individuals with T1D and albuminuria, regardless of blood pressure.
Physical activity
Lifestyle therapy Nutrition
Weight loss
Metformin SGLT-2 inhibitor

First-line
therapy eGFR eGFR Kidney eGFR Kidney
+
< 45 < 30 failure < 30 failure
Reduce dose Discontinue Discontinue Do not initiate Discontinue
GLP-1 receptor agonist

(preferred) • Guided by patient preferenes,
comorbidities, eGFR, and cost
Additional drug therapy as DPP-4 inhibitor Insulins • Includes patients with eGFR
needed for glycemic control Sulfonylurea TZD < 30 ml/min/1.73 m2 or treated
with dialysis
Alpha-glucosidase inhibitors • See Figure 12
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])
An often-overlooked concept is the importance of titrating these agents up to the

maximum recommended or tolerated dose, to obtain maximal antiproteinuric effect.
Studies indicate that the rate of GFR decline can be reduced from 10–12 mL/min/
year to <5 mL/min/year if blood pressure levels are controlled [119]. Often multiple
blood pressure-lowering agents are needed in patients with CKD stage 3 and beyond.
Data in patients with T2D also indicates that control of hypertension reduces the
risk of increased albuminuria [120–123]. Inhibition of the renin-angiotensin system
may be of particular benefit [124–126], but lowering blood pressure is the key. Most
guidelines suggest a blood pressure target of 130/80 mmHg in patients with T2D.
Systolic blood pressure levels below 120–130 mmHg were associated with increased
mortality and ESKD in patients with T2D [127]. In T2D, RAS inhibition is clearly
indicated in the presence of albuminuria [119, 121]. In more advanced CKD, RAS
inhibition with angiotensin receptor blockers (ARB) reduces kidney disease pro-
gression, ESKD, or death [128, 129]. With worsening of CKD, hyperkalemia is a
common problem [130], and general measures to lower potassium levels, such as
dietary changes, diuretics, and use of potassium binders, should be considered [88].
Introduction of a RAS inhibitor often leads to an acute decline in GFR, which then
stabilizes. Individuals with the greatest initial fall in GFR have the slowest subse-
quent decline in kidney function [131]. Dual blockade of the RAS is not recom-
mended [132–137].
Mineralocorticoid Receptor Antagonists (MRA)
Short-term studies indicate that spironolactone or eplerenone reduces albuminuria
by about 30% in patients with CKD [138]. However, a longer-term study (3-year
intervention) including high-risk patients with T2D did not show a benefit of spi-
ronolactone on the progression of kidney disease [139]. A novel nonsteroidal MRA,
finerenone conferred an 18%reduction in progression to kidney failure, decrease of
eGFR ≥40%, or kidney death among patients with T2D and CKD [140]. In a sepa-
rated RCT, finerenone reduced the risk of cardiovascular death or nonfatal cardio-
vascular events (myocardial infarction, stroke, or heart failure hospitalization) by
13% [141]. MRA are associated with an increased risk of hyperkalemia, and potas-
sium levels should be carefully monitored and managed in these patients.
Other Agents
Atrasentan, an endothelin receptor A antagonist, showed kidney but no major
adverse cardiovascular events benefit, with a tendency to increased heart fail-
ure [142].
Additional Agents Modifying Cardiovascular Risk and Their Potential
Impact in the Kidneys
Lipid-lowering therapy is recommended to reduce the risk for CVD in patients with
CKD. There is also some evidence that lipid-lowering agents may be potentially
beneficial to the kidney [143].
Aspirin is indicated in patients with established CVD and should be considered
for prevention in high-risk patients. Patients with diabetes and CKD not only have
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.
regnancy in Women with Diabetes and Chronic

P
Kidney Disease
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.
Intensive
Kaplan-Meier Estimates Survival Conventional
1.00
Survival Probability
0.75
HR 0.55
p = 0.005
0.50
0.25
0.00 7.9 years

0 4 8 12 16 20
Number at risk: Years since randomization
Intensive 80 76 66 58 54 43
Conventional 80 78 65 45 34 24
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).
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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
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Chapter 8
Precision Medicine for Diabetic
Neuropathy
Long Davalos, Amro M. Stino, Dinesh Selvarajah, Stacey A. Sakowski,

Solomon Tesfaye, and Eva L. Feldman
iabetic Peripheral Neuropathy: Clinical Evaluation

D
and Epidemiology
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
L. Davalos · A. M. Stino · S. A. Sakowski · E. L. Feldman (*)

Department of Neurology, University of Michigan, Ann Arbor, MI, USA
e-mail: [email protected]; [email protected]; [email protected];
[email protected]
D. Selvarajah
Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK
S. Tesfaye (*)
Diabetes Research Unit, Sheffield Teaching Hospital, Sheffield, UK

172 L. Davalos et al.
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]
initial clinical and epidemiologic observations [11–14]. Despite decades of costly

and failed clinical trials (Table 8.1), spanning antioxidants, lipid-lowering agents,
aldose reductase inhibitors, neurotrophic factors, and GABA analogues, to name a
few, we now stand on the cusp of a targeted therapeutic approach to diabetic neu-
ropathy, one that encompasses interventions such as exercise, dietary control, and
more targeted and novel drug therapies [15–17]. Advances in DPN pain research
have also refined DPN pain management approaches through more focused sensory
and imaging phenotyping.
8 Precision Medicine for Diabetic Neuropathy 173
ype 1 Versus Type 2 Diabetic Peripheral Neuropathy: Towards

T
a More Precise Understanding
DPN is most frequently a distal symmetric sensory predominant neuropathy, which

is the most common complication of both type 1 diabetes (T1D) and T2D [18–20].
The incidence of T2DPN (6100 per 100,000 person-years) is higher than T1DPN
(2800 per 100,000 person-years) [21–23]. However, the prevalence of neuropathy is
similar in T2DPN (8–51%) [18–20] and T1DPN (11–50%) [18, 24]. The observed
difference in incidence with similar prevalence in both might be related to multiple
factors, including the underlying pathophysiology, as well as differences in age and
onset of diabetes.
In T1DPN, hyperglycemia is the major contributor to the development of neu-
ropathy. Intensive glycemic control reduces the risk of developing T1DPN by 60%,
and the beneficial effects persist for over 16 years [25, 26]. Other smaller studies
reached similar conclusions, evidence that improved glycemic control preserves
nerve function and/or decreases likelihood of developing DPN [27].
On the other hand, in T2DPN, hyperglycemia does not seem to be the primary
mechanism. Large studies have demonstrated little to no effect of glycemic control
on T2DPN, indicating that factors independent of glycemic control are critical in
the development of neuropathy [28, 29]. In fact, there is growing evidence that the
MetS components (central obesity, dyslipidemia, hypertension) accelerate T2DPN
progression and might have equal or greater import than glycemic index alone [9].
Such pathophysiologic differences require distinct management approaches tar-
geted to T1DPN and T2DPN. Improving glycemic control should be the main focus
in patients with T1DPN, while lifestyle interventions, specifically diet and exercise,
coupled with optimal lipid and blood pressure control, are the optimal therapeutic
approaches for patients with T2DPN.
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,
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].
Metabolic Syndrome, Obesity, and Peripheral Neuropathy
MetS revolves around dyslipidemia (elevated triglycerides and/or reduced high-

density lipoproteins (HDLs), central obesity, insulin resistance (diabetes or predia-
betes), and hypertension) and afflicts over one-third of adults in the United States
[35]. Seven international population-based studies have now firmly identify MetS as
a driver of peripheral neuropathy and highlight the intimate association between
central obesity and neuropathy [1–6, 36].
Obesity has emerged as the second most influential metabolic risk factor for
neuropathy after diabetes, independent of glycemic status. Recent studies in the
United States have shown that obese normoglycemic individuals have a higher prev-
alence of neuropathy compared to lean controls [37]. In fact, waist circumference is
associated with the greatest number of neuropathy outcome measures compared to
other metabolic factors [1, 2]. Studies conducted in China and Europe have reached
similar conclusions, highlighting that obesity is independently associated with neu-
ropathy, regardless of glycemic status [3–6]. Global population-specific differences,
however, are worthy of consideration, as a recent study of South Asian Indian
patients found that MetS components or waist circumference did not associate with
peripheral neuropathy [38]. In addition, hypertriglyceridemia correlates with CSPN,
IENFD loss, sural nerve myelinated fiber loss, and the likelihood of lower limb
amputation [31, 39–41].
The optimal disease-modifying approach in obese patients with and without dia-
betes is to target obesity and its downstream effects. Lifestyle interventions such as
diet and exercise are inexpensive and accessible strategies to combat obesity and
promote nerve restoration, as highlighted in the Look AHEAD trial [42, 43].
However, since poor exercise and dietary compliance are a natural limitation, the
role of alternative strategies, such as pharmacotherapy and bariatric surgery, has

become a topic of interest in MetS-related neuropathy. Although initial observations
suggested that lipid-lowering therapy reduces DPN development risk and lower
limb amputation, a recent population-based Danish study showed that statin therapy
did not mitigate DPN risk in T2D patients (9% of whom were obese) [44]. Bariatric
surgery, however, seems to improve neuropathic outcome measures in patients with
obesity and T2D and is the focus of ongoing evaluation in a randomized controlled
clinical trial [45, 46]. Even though these interventions have shown promising
results, larger studies are needed to evaluate their cost-effectiveness [47, 48].
Prediabetes and Peripheral Neuropathy
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.
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.
Pediatric Diabetic Peripheral Neuropathy
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,
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
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].
iabetic Peripheral Neuropathy: Pathogenesis

D
and Therapeutic Targets
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
dysfunction in both neurons and Schwan cells [84]. Furthermore, peroxisome

proliferator-activated receptors (PPARs) are highly dysregulated in T2D [85]. In
addition, oxidized cholesterol – oxysterol – a byproduct of reactive oxygen species
and low-density lipoproteins (LDLs), binds to various neuronal cell membrane
receptors, including oxidized LDL receptor 1 (LOX1), toll-like receptor 4 (TLR4),
and receptor for advanced glycation end products (RAGE), triggering further down-
stream pro-inflammatory signaling via IL-6, COX-2, and TNF-α [86–88]. Nuclear
transcription factors upregulate NF-κB expression and free fatty acid β-oxidation,
further adding to a pro-inflammatory state [89].
Toll-like receptors (TLRs) also play a key role in DPN, particularly TLR 4 in
pain and TLR 2 and 4 in disease pathogenesis, neuropathy progression, and meta-
bolic dysfunction, particularly lipopolysaccharide binding protein (LPB) and
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB). In
a recent study, TLR 2 and 4 knockout mice placed on a high-fat diet were evaluated
alongside wild-type mice on a high-fat diet and wild-type mice on a standard diet.
TLR 2 and 4 knockout mice developed neuropathy at a later time point compared to
high-fat diet wild-type mice [90]. The study suggested that TLR signaling impacts
early sensory neuron injury in DPN and is mediated via immune modulation.
Potential Therapeutic Avenues
As much as our understanding of pathogenesis has shed led on DPN complexity, it

has also opened the door to more precise therapies (Fig. 8.1). Dietary reversal from
a high-fat diet to a standard diet or to a diet consisting of a higher ratio of mono- or
polyunsaturated fatty acids (relative to long-chain saturated fatty acids) prevents
peripheral neuropathy development and restores IENFD in murine models [11]. In
addition, such dietary changes improve thermal responsiveness and large fiber sen-
sory nerve conduction velocities [91]. Pioglitazone, a PPAR-γ agonist, improves
DPN in T2D db/db mice [92]. In addition, sodium glucose cotransporter 2 (SGLT2)
inhibitors represent another area of therapeutic interest. SGLT2 inhibitors increase
renal glucose excretion and lower blood glucose levels and are thought to lessen
microvascular complications. A 10-week regimen of empagliflozin, an SGLT2
inhibitor, improved neuropathy in streptozotocin-induced T1D mice, but not in db/
db T2D mice [93]. There was also a trending improvement of empagliflozin on reti-
nopathy in T1D animals, but no effect on nephropathy and no effect on either reti-
nopathy or nephropathy in T2D mice. The study emphasized two important
aspects – first, that T1DPN differs in pathology than T2DPN since empagliflozin
exerts differential effects and, second, that tissue-specific treatments for the various
macrovascular complications could be necessary. With regard to inflammatory tar-
gets, polyunsaturated fatty acids inhibit NF-κB activation and nuclear translocation,
while both pioglitazone and acipimox offer additional mechanisms that block the
NF-κB pathway [12]. Pioglitazone is a PPAR-γ agonist that alters glucose and lipid
metabolism gene expression and increases insulin sensitivity. Acipimox is a niacin
MUFA supplementation Cell body

or dietary reversal
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].
Diabetic Peripheral Neuropathy: Pain
Painful Diabetic Peripheral Neuropathy
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
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
Quantitative 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,
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].
Two Distinct Pain Phenotypes: The Nonirritable and Irritable Nociceptor
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.
Phenotype-Driven Therapeutic Experience in Painful DPN
Examples of studies that focused on painful DPN include an open-label retrospec-

tive study using the DFNS protocol, which evaluated key phenotypic differences in
sensory profiling associated with response to intravenous lidocaine in patients with
severe, intractable painful DPN [111]. Patients with the irritable nociceptor pheno-
type were more likely to respond to intravenous lidocaine, which inactivates sodium
channels, compared to the nonirritable nociceptor phenotype [111]. In fact, dynamic
mechanical allodynia and pain summation to repetitive pinprick stimuli were the
only evoked “gain-of-function” QST parameters that informed treatment response.
The presence of these sensory gain parameters suggests aberrant central processing
with hyperexcitable neurons driven by abnormal sodium channel regulation, gener-
ating ectopic impulses and amplifying afferent sensory inputs. In another painful
DPN study by Campbell et al. of topical clonidine, sensory profiling was performed
using the capsaicin challenge test [112]. The post hoc analysis demonstrated a sig-
nificant reduction in pain in the patient subgroup with increased spontaneous pain
following cutaneous capsaicin administration, indicating the presence of function-
ing and sensitized nociceptors. Bouhassira et al. published post hoc analysis data of
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.
Sensory Phenotyping to Predict Therapeutic Response
In a randomized, double-blind, placebo-controlled, and phenotype-stratified study

of patients with painful DPN, Demant et al. reported that oxcarbazepine was more
efficacious for relief of peripheral neuropathic pain in patients with the irritable vs
the nonirritable nociceptor phenotype (Fig. 8.2). Based on this and other recent
studies, current opinion with regard to neuropathic pain clinical trials recommends
a detailed sensory profiling of participants at baseline; and even if there is no signifi-
cant separation of a drug with placebo, a subgroup analysis can be performed to see
if the drug was efficacious in a particular subgroup. If there is a clear signal that this
NON-IRRITABLE NOCICEPTOR (N=52) IRRITABLE NOCICEPTOR (N=31)
1 NNT 13 NNT 3.9

Change in pain NRS
–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])
Human surrogate Pain generating New therapeutic

model mechanisms/symptoms agents
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
was the case, a further, adequately powered, phenotype-stratified trial would be

designed (Fig. 8.3).
Sensory profiling can also identify subgroups with altered endogenous pain
modulation to predict treatment outcomes of drugs and other interventions that
affect a given mechanism. In a study of pain modulation in DPN, individuals were
assessed using QST for conditioned pain modulation (CPM), a psychophysical par-
adigm in which central pain inhibition is measured via the phenomenon of “pain
inhibiting pain,” via the simultaneous administration of a conditioning painful stim-
ulus at a distant body site. The pain in participants with abnormal CPM was more
receptive to duloxetine, which is believed to increase descending inhibitory pain
pathway activation, than individuals with normal pain modulation, although there
was no comparison to placebo in this open-label study [115].
Taken together, these studies support the notion that mechanism-based approaches
to pain management may be feasible in painful DPN. However, in an elegant mech-
anistic study, Haroutounian et al. examined 14 patients with neuropathic pain of
mixed etiology [unilateral foot pain from nerve injury (n = 7) and distal polyneu-
ropathy (n = 7)] to determine the contribution of primary afferent input in maintain-
ing peripheral neuropathic pain [116]. Each patient underwent randomized
ultrasound-guided peripheral nerve block with lidocaine versus intravenous lido-
caine infusion. They found that peripheral afferent input was critical for maintaining
neuropathic pain, but improvement in evoked hypersensitivity was not related to
improvements in spontaneous pain intensity. This suggests that further studies are
needed to rationalize sensory phenotyping in order to optimize clinical trial out-
comes in painful DPN. Moreover, given the rarity of the irritable nociceptor pheno-
type, as determined by QST, a single assessment modality may be unlikely to help
stratify patients, and combining with additional modalities may be necessary (e.g.,
brain imaging).
Brain Imaging in Painful Diabetic Peripheral Neuropathy
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
a Ectopic activity
Periphery Cell body
Axon
Axon Schwann cell
Terminal Node of Ranvier Cell body

Nav
Cav3.2 glycosylation Nav1.7
Nav Cell
Methylglyoxal membrane
O TRPA1 ¯ kv ¯ kv
H CH Nav1.8
3 Vesicle
O
Nav
b Ascending pathways Descending pathways

Somatosensory
cortex
Potential reorganization
Ventrobasal medial
and lateral areas
Hypothalamus Ongoing and enhanced activity

3
in sensory and affective areas
Amygdala
Periaqueductal grey
Locus
Increased pain signalling, anxiety,
coeruleus 1 depression, prior experience and
Parabrachial descending facilitatory control
Locus
nucleus 2
coeruleus
Nucleus gracilis
Cuneate nucleus A7 nucleus
Autonomic changes and

sleep disturbances
Rostroventral
Peripheral nerve medial medulla
AS
Dorsal root nucleus
Aβ fibre 4
ganglion Aδ fibre Peripheral nerves
C fibre Altered properties, transduction
and transmission
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])
stimulation tasks. During a typical RS-fMRI examination, the hemodynamic

response to spontaneous neuronal activity (blood oxygen level-dependent (BOLD))
signal is acquired while subjects are instructed to simply rest in the MR scanner
[123]. The data acquired is used in brain mapping to evaluate regional interactions
or functional connectivity, which occur in a resting state. Most studies use a machine
learning approach to identify patterns of functional connectivity, which differenti-
ates patients from controls. RS-fMRI experiments in painful DPN have reported
greater thalamic-insula functional connectivity and decreased thalamic-
somatosensory cortical functional connectivity in patients with the irritable versus
nonirritable nociceptor phenotype (Fig. 8.5) [111]. There was a significant positive
correlation between thalamic-insula functional connectivities with self-reported
pain scores [111]. Conversely, there was a more significant reduction in thalamic-
somatosensory cortical functional connectivity in those with more severe neuropa-
thy. This demonstrates how RS-fMRI measures of functional connectivity relate to
Non lrritable Nociceptor Irritable Nociceptor
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])
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.
iabetic Peripheral Neuropathy: Future Directions

D
and Moving Toward Precise Treatments
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
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
Fig. 8.6 Precision medicine-based approach to diabetic peripheral neuropathy. A precision-based

medicine approach to DPN calls for the subclassification of the general DPN population into more
specific subgroups, classified by clinical and pain phenotype. Such classification is guided by
patient clinical presentation, QST, functional MR imaging, and genetic profile, which lead to more
targeted pain management and disease-modifying interventions. (Created in part with
BioRender.com)
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
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Chapter 9
Inpatient Precision Medicine for Diabetes
Georgia Davis, Guillermo E. Umpierrez, and Francisco J. Pasquel
Introduction
The pursuit of precision medicine in diabetes surrounds numerous efforts to assem-

ble and understand complex genetic, phenotypic, and environmental data and its
associated impact on disease risk, progression, and therapeutic responses [1, 2].
There has been significant movement along the path from personalized to precision
diabetes management, but many current diagnostic, risk stratification, and treatment
strategies have yet to fully integrate genomic factors and other “-omics” data into
targeted precise therapies for diabetes management, including in the hospital setting
[3]. However, continued advancement of precision diagnostics, monitoring, and
pharmacologic therapy for diabetes applicable to the outpatient setting can inform
individualized management for hospitalized patients. Additionally, the inpatient set-
ting may confer unique insight into other dimensions of precision diabetes care,
including (1) patient stratification by metabolic phenotype and severity of illness on
admission, (2) optimal inpatient glucose monitoring strategies, and (3) individual-
ized glycemic targets and pharmacologic therapy. The next evolution in inpatient
precision diabetes care surrounds the ability to leverage the diverse networks of
patient-specific phenotypic background data, dynamic inpatient clinical data, and
large-scale public data to guide hospital diabetes management.
Extraordinary advances in diabetes pharmacotherapeutics and technology have
emerged over the past two decades, allowing for more personalized care particularly
in the outpatient setting. These more individualized management strategies have
moved into the inpatient setting and include the use of non-insulin antihyperglyce-
mic agents, as well as the implementation of diabetes technology for inpatient
G. Davis · G. E. Umpierrez · F. J. Pasquel (*)

Division of Endocrinology, Department of Medicine, Emory University School of Medicine,
Atlanta, GA, USA
e-mail: [email protected]; [email protected]

200 G. Davis et al.
glucose monitoring. Existing background phenotypic data in combination with data

obtained during treatment of acute illness (i.e., biomarker changes, glycemic con-
trol trends) may provide a deeper understanding of the dynamic clinical and meta-
bolic conditions underlying an individual’s disease process and response to diabetes
therapy. Expansion of the inpatient knowledge base moving forward will allow for
the generation of more comprehensive data sets applicable to inpatient diabetes
management. To date, true precision medicine has not been realized for inpatient
diabetes care, but with continued data acquisition, we are moving toward this goal.
atient Heterogeneity and Complexity in Factors

P
Affecting Metabolism
Glucose metabolism is influenced by multiple factors in the hospital, including

intrinsic patient factors, severity of illness, and hospital treatment. Intrinsic patient
characteristics such as background metabolic status (obesity, prediabetes, type 1 or
type 2 diabetes) significantly influence insulin-dependent glucose disposal. In
patients with diabetes, the complexity of the home management regimen and the
duration of diabetes, as well as relevant comorbidities (e.g., chronic kidney disease),
can also significantly influence inpatient glycemic control. Furthermore, glucose
metabolism is influenced by the severity of illness, which is associated with hor-
monal activation (cortisol, catecholamines) and an immunometabolic response
mediated by cytokines and other tissue injury-related factors associated with
changes in insulin sensitivity [4–6].
Even though hyperglycemia and diabetes are primarily considered disorders of
glucose metabolism, analyses of large cohorts using high-resolution metabolomics
(HRM) techniques have reported positive associations of branched-chain amino
acids (BCAAs) and products of fatty acid metabolism (i.e., acylcarnitines) with
insulin resistance, insulin secretion defects, and incident diabetes [7–12]. These
relationships suggest that circulating and increased release of amino acids and acyl-
carnitines during hormone-mediated catabolism during stress could mediate insulin
resistance and beta-cell dysfunction.
Furthermore, common hospital factors including the type of nutrition (oral,
enteral, parenteral) or medications (e.g., steroids, vasopressors) can significantly
influence glucose metabolism. Figure 9.1 shows the complexity of glucose metabo-
lism in the hospital related to intrinsic patient factors, severity of illness, and hospi-
tal factors (nutrition, medications).
Automated evaluation of clinical data through deep learning with medical appli-
cations is becoming a recent reality [13] and is laying the groundwork for the inte-
gration of clinical data, computation, and likely systems biology data in the near
future. Integrating underlying metabolic phenotypic information, severity of illness
biomarkers, glucose metabolism biomarkers (glucose, A1c, CGM-derived metrics),
hospital factors (nutrition, medications), individual- and population-derived data,
9 Inpatient Precision Medicine for Diabetes 201
Metabolic phenotype Acute Illness
Counterregulatory Hormones Tissue Injury

(gulcagon, epinephrine, norepinephrine, cortisol)
Cell stress
Proteolysis Lipolysis Inflammation Immune System Activation
Pro-thrombosis
Ceramides,
BCAA Acyl-carnitines
TNF-a, IL-6
Glycogenolysis Insulin Beta-cell End organ damage

Gluconeogenesis Resistance Dysfunction
Hospital Factors Stress Hospital

Hyperglycemia Morbidity/Mortality
Enteral Nutrition
Parenteral Nutrition
Exogenous steroids, Antihyperglycemic latrogenic
vasopressors therapy Hypoglycemia
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).
Hospital Glucose Monitoring and Data Acquisition
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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annotation diabetes care in
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EHR data Individualized

integration and therapy and
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analysis
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
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.
I ndividualized Management Strategies: Glycemic Targets

and Pharmacotherapy
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
Mild hyperglycaemia Medical and surgical

Consider low-dose basal insulin or OAD* (100–180 mg/dL)
• BG <200 mg/dL
• Give correction doses with rapid-acting
• £2 antidiabeti agents†
insulin before meals or every 6 h
• Insulin naive
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
Severe hyperglycaemia Basal-bolus regimen

Inpatient Precision Medicine for Diabetes
• 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
As precision medicine continues to advance through ongoing initiatives for those

living with diabetes, it must also include the expansion of inpatient knowledge
bases and data analytics to inform more comprehensive, patient-specific hospital
diabetes management. Although there have been significant advances made in
understanding individual-level genetic, metabolic, environmental, and lifestyle
factors pertaining to diabetes risk, glycemic control, and responses to pharmaco-

logic therapy, there are opportunities to develop more complete inpatient-specific
data to guide care during acute illness. It is important to understand not only how
baseline patient phenotypes can be employed to guide inpatient diabetes therapy but
also how the interplay of other clinical parameters, such as illness severity, can
modify metabolism and therapeutic response. Future efforts need to ensure this
extensive knowledge can be translated into meaningful treatment strategies associ-
ated with improved clinical outcomes in the hospital setting.
Developing inpatient precision diabetes medicine includes aspects of precision
diagnostics (characterization of unique individual-level genetic, metabolic, and
clinical phenotypes for more accurate disease-state classification and inpatient risk
stratification), precision monitoring (real-time continuous glucose data with remote
monitoring capabilities and patient-specific glycemic control targets), and precision
therapeutics (addition of non-insulin agents with associated benefits beyond glyce-
mic control, computer-based decision algorithms, and automated insulin delivery).
To date, there is advancing but limited application of these concepts of precision
medicine in the hospital setting, but also a clear need to combine acute and chronic
disease-state data to better comprehend individual-level responses to diabetes treat-
ment and help guide care during acute illness.
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Chapter 10
Precision Medical Management Strategies
for Diabetes Remission
Sangeetha R. Kashyap and Saif M. Borgan
Definition of Remission in Type 2 DM
Remission of type 2 diabetes mellitus refers to normalization of blood glucose lev-

els to levels below the threshold at which diabetes is diagnosed, in the absence of
active pharmacological agents, for a period of at least 6–12 months [1]. The dura-
tion of normalization has been an area of controversy, which has caused some
degree of heterogeneity across studies [2]. The term remission is usually adopted,
rather than cure, as the genetic and environmental factors that led to the develop-
ment of this chronic disease still exist in many patients who achieve remission.
Thus, the risk of redeveloping diabetes is still considered greater than in the general
population [1]. Partial remission refers to patients whose hyperglycemia improves
to the prediabetic but does not reach normal glucose threshold, while those who
achieve normal glucose parameters have complete remission [1].
win Cycle Hypothesis and Remission Window:

T
Clinical Inertia
Grasping the pathophysiology and timeline underlining the development of type 2

DM is crucial to understanding proposed mechanisms for its reversal [3]. According
to the “twin cycle hypothesis,” in the right environment, usually a prolonged posi-
tive energy balance with genetic predisposition, the developing insulin resistance at
S. R. Kashyap (*)
Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
S. M. Borgan
Endocrinology and Metabolism Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

212 S. R. Kashyap and S. M. Borgan
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.
egative Energy Balance, How It Can Induce Remission,

N
and Clinical Trials Showing Practicality
A negative energy balance either through medically supervised hypocaloric diet or

facilitated through bariatric surgery has been the most successful intervention in
inducing remission from type 2 diabetes mellitus. During a hypocaloric diet, the
mobilization of liver fat occurs at a disproportionately greater rate than subcutane-
ous and visceral fat [8]. Thus, the reduction in liver overall size and fat content is
expected to begin within days of negative energy balance diet [9, 10]. The change in
hepatic fat corresponds to normalization of hyperglycemia. As demonstrated in a
trial of hypocaloric diet (330 calorie/day) in 30 subjects with type 2 diabetes mel-
litus, 87% of the plasma glucose reduction happened in the first 10 days of the trial,
compared with 13% additional decline in hyperglycemia across the remaining
30 days [11]. Interestingly, the degree of plasma glucose reduction was not
10 Precision Medical Management Strategies for Diabetes Remission 213
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
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].
harmacotherapy with Oral Hypoglycemics, Insulin,

P
and Appetite Suppressants
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.
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14. McInnes N, Smith A, Otto R, Vandermey J, Punthakee Z, Sherifali D, Balasubramanian K,
Hall S, Gerstein HC. Piloting a remission strategy in type 2 diabetes: results of a randomized
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Chapter 11
Surgical Management for Diabetes
Remission
A. Maria Daniela Hurtado and Maria Collazo-Clavell
Introduction
Diabetes mellitus type 2 (DM2) is a multifactorial, complex, and progressive dis-

ease. In 2017, the worldwide prevalence of DM2 was 6.3%, which was equivalent
to a staggering 462 million people [1]. A significant proportion of patients with
DM2 has disease-related comorbidities and overall decreased lifespan. The underly-
ing chronic hyperglycemia characteristic of this disease leads to macrovascular and
microvascular complications. As a matter of fact, diabetes is the leading cause of
amputations of the lower extremities, kidney failure, and blindness. As such, DM2
is the ninth leading cause of death globally [2, 3]. DM2 also poses an economic
burden: in the United States alone, the estimated cost of DM2 in 2017 was $327
billion [4]. Consequently, DM2 is recognized as a global public health problem.
Excess weight is one of the most important risk factors for DM2. The prevalence
of overweight and obesity among patients with DM2 is almost double compared to
the overall prevalence of these conditions in the general population (90% vs 50%,
respectively) [2]. This health crisis is known as the “twin pandemic.” Lifestyle inter-
ventions with the goal of weight reduction are the cornerstone of DM2 manage-
ment. Weight loss of 5–10% of the total body weight with intensive lifestyle
modification has been associated with improved glycemic control and even DM2
A. Maria Daniela Hurtado

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine,
Mayo Clinic Health System, La Crosse, WI, USA
Mayo Clinic, Rochester, MN, USA
M. Collazo-Clavell (*)
Mayo Clinic, Rochester, MN, USA

218 A. Maria Daniela Hurtado and M. Collazo-Clavell
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.
DM2 Cure Versus 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
of developing microvascular and macrovascular complications, and an overall

decreased mortality, protection that is carried over even if patients experience
relapse of their DM2 [15, 16].
Bariatric Surgeries Associated with DM2 Remission
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
Roux-en-Y Adjustable Vertical sleeve Biliopancreatic diversion

bypass gastric band gastrectomy with duodenal switch
© MAYO CLINIC
Fig. 11.1 Bariatric surgeries associated with DM2 remission

proximal duodenum that is then anastomosed to the ileum resulting in a bypass of

most of the duodenum, the jejunum, and a portion of the ileum.
At present, the most commonly utilized bariatric surgeries are the VSG and the
RYGB [17].
DM2 Remission After Bariatric Surgery
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

Mean or median
Type of time of follow-up Rate of DM2
Study surgery Definition of DM2 remission time (years) remission
Wentworth LAGB FPG <16 mg/dL and less 2 52%
et al. (2014) than <200 mg/dL 2 h after
[27] oral glucose
Courcoulas RYGB and ADA criteria for complete 1 17% for RYGB
et al. (2014) LAGB remissiona 23% for LAGB
[25]
Halperin et al. RYGB FPG <126 mg/dL and HbA1c 1 58%
(2014) [26] <6.5% ± medications
Courcoulas RYGB and ADA criteria for complete 3 15% for RYGB
et al. (2015) LAGB remissiona 5% for LAGB
[30]
Ding et al. LAGB HbA1c <6.5% and FPG 1 33%
(2015) [28] <126 mg/dl ± medications
Mingrone et al. RYGB and ADA criteria for partial 5 37% for RYGB
(2015) [21] BPD remissiona 63% for BPD
Yska et al. RYGB, ADA criteria for complete 2.4 94.5/1000
(2015) [18] VSG, and remissiona person-years
LAGB
Cummings RYGB ADA criteria for complete 1 60%
et al. (2016) remissiona
[29]
Purnell et al. RYGB and ADA criteria for partial 3 69% for RYGB
(2016) LAGB remissiona 30% for LAGB
Ikramuddin RYGB ADA criteria for complete 3 17%
et al. (2016) remissiona
[23]
Gulliford et al. RYGB, ADA criteria for partial 2 34% for RYGB
(2016) [44] VSG, and remissiona 38% for VSG
LAGB 20% for LAGB
Schauer et al. RYGB and ADA criteria for complete 5 22% for RYGB
(2017) [22] VSG remissiona 15% for VSG
Madsen et al. RYGB HbA1c <6.5% on no 1 74%
(2019) [39] medications or <6% on
metformin only
Jans et al. RYGB and ADA criteria for complete 2 and 5 58% at 2 years
(2019) [32] VSG remissiona 47% at 5 years
Abbreviations used: ADA American Diabetes Association, BPD biliopancreatic diversion, DM2
type 2 diabetes mellitus, FPG fasting plasma glucose, HbA1c hemoglobin A1c, LAGB laparo-
scopic adjustable gastric banding, RYGB Roux-en-Y gastric bypass, VSG vertical sleeve
gastrectomy
a
ADA criteria: Complete remission is defined as an HbA1c below 6% or <42 mmol/mol on no
medications and maintained for at least 1 year; Partial remission is defined by an HbA1c below
6.5% or <48 mmol/mol on no medications and maintained for at least 1 year
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].
Mechanisms Driving DM2 Remission
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
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
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).
I mportant Considerations of Bariatric Surgery in DM2

Remission and Future Directions
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.
There is a substantial body of evidence demonstrating that in addition to caloric

restriction and massive weight loss, other important mechanisms are involved in
DM2 remission, some of which remain to be fully characterized. Some of these
mechanisms include increased levels of GLP-1, PYY, and GIP, impaired ghrelin
secretion, improved bile acid metabolism, and changes in the microbiome.
The utilization of bariatric surgery is hindered by the small, albeit existent, risk
of complications and its cost. With the mounting evidence showing that gastrointes-
tinal modifications from bariatric surgery influence glucose metabolism through
multiple mechanisms, research has focused on developing less invasive gastrointes-
tinal procedures. Likewise, bariatric surgery and these experimental gastrointestinal
procedures have helped gained insight into the physiologic role of the different parts
of the gastrointestinal system on glucose homeostasis. Eventually, this knowledge
could lead to the development of pharmacologic therapies and metabolic proce-
dures aimed at DM2 treatment and not necessarily focused on weight loss.
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Chapter 12
Precision Nutrition for Type 2 Diabetes
Orly Ben-Yacov and Michal Rein
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
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

234 O. Ben-Yacov and M. Rein
T2DM is a heterogeneous disease from a genetic, pathophysiological, and clinical

point of view [9]. Current understanding of the pathophysiological mechanisms of
T2DM remains insufficient to explain the large variability between individuals in
both the development and the clinical manifestations of the disease [10, 11].
Moreover, individual responses to dietary, lifestyle, and pharmaceutical interven-
tions vary considerably [12–16].
Recently, the concept of precision nutrition (also known as personalized nutri-
tion) has gained a great deal of interest in the scientific community and the general
public [17–20]. Similar to precision medicine, the key mission of precision nutrition
is to tailor dietary recommendations to individuals or population subgroups based
on their unique characteristics, including genome sequence, microbiome composi-
tion, medical history, lifestyle, diet, and other personal factors, to prevent and man-
age chronic diseases. Recent advances in omics technologies [21–24], wearable
devices [25, 26], and mobile technologies [27, 28] have broaden the possibilities of
applying precision nutrition for prevention and management of T2DM. Integrated
data from these emerging technologies along with traditional nutritional assessment
allow deep phenotyping of individuals and monitoring of their metabolic state, thus
promoting the development of innovative approaches in precision nutrition
(Fig. 12.1). This comprehensive profiling of individuals will ultimately promote the
achievement of several goals: (a) better understanding of the mechanisms underly-
ing the variability between individuals in response to dietary exposures or interven-
tions, (b) better assessment of dietary intakes and nutritional status in free-living
populations, (c) identification of novel biomarkers that are more effective than tra-
ditional biomarkers at predicting risk of disease and its health complications, (d)
identification of new targets for lifestyle and pharmacological interventions, and
Fig. 12.1 The core

components for IONAL ASSESS
comprehensive nutritional TRIT ME
assessments of individuals NU ITORING NT
and design of precision AL MO
N
EP
N
nutrition approaches for

IO
OTYPING
DE
EN
DIT
prevention and
management of T2DM PH
TRA
EP
NUTRITIO
DE
N
PRECISIO
BIO M E
IE S
RO
M
IC
for T2D
OG
M
*M
ET
AB
OL
OL CS
OM MI
HN
EA IC S * G E N O
W
RA TE
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ED
E VIC E S * M O B
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.
Determinants of Precision Nutrition in T2DM
Deep Phenotyping (Omics Technologies)

Nutrigenetics and Nutrigenomics
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
formulate effective dietary recommendations to improve nutritional status of indi-

viduals, including those with T2DM or at risk to develop the disease. This is the
case for hypolactasia [39], celiac disease [40], and phenylketonuria [41] diagnoses,
for example, which allowed the implementation of tailored dietary advices based on
genetic makeup for years. Other, more recent, discoveries include genetic variants
related to caffeine metabolism [42–44], predisposition to weight gain by saturated
fat intake [45, 46], increased risk of developing hypertension by high salt intake [47,
48], zinc transport [49], alcohol metabolism [50], macronutrient intake [51], and
predisposition to obesity by macronutrient intake [52], among others. On the private
sector, many companies are already offering genetic tests to customize dietary rec-
ommendations based on individual response to specific nutrients, such as those
mentioned above. However, the scientific community generally agrees that the
future of precision nutrition cannot rely solely on nutrigenetics/nutrigenomics [53]
and other factors beyond genetics must be considered in order to establish compre-
hensive and dynamic nutritional recommendations based on shifting, interacting
parameters in a person’s internal and external environment throughout life. In this
regard, two large randomized controlled trials initiated about a decade ago,
PREDIMED [54] and Food4Me [55], were among the most stimulating wide-scale
approaches which aimed to broaden the knowledge about factors involved in the
different response to a given nutritional intervention, utilizing a constellation of
omics technologies (transcriptomics, genomics, epigenomics, and metabolomics),
deep phenotyping and genotyping, and robust dietary adherence assessment.
Taken together, it seems that precision nutrition approaches must include, in
addition to genetics, other deep phenotyping factors such as omics technologies
(e.g., microbiome, metabolomics) and comprehensive assessment of dietary habits,
food behavior, and physical activity to establish a comprehensive framework for
prevention and management of T2DM [56–58].
Microbiome
The gut microbiota, which consists of trillions of bacterial microorganisms, has a

central role in human health and disease. Emerging evidence suggests that the gut
microbiome profile, which is unique to each individual, should be included as a key
feature of precision nutrition [59, 60]. Specifically, the role of microbiome in the
interpersonal variability of host metabolism and glycemic status is being under
intense research in the last decade [12, 13]. In that sense, it was shown that part of
the variability between people in postprandial glucose responses (PPGR) to foods
can be explained by microbiome features in both healthy individuals and subjects
with an elevated glycemic status [13, 61].
Gut bacterial abundances are influenced by dietary intakes and are representative
of the habitual diet and metabolic state of individuals. A recent study by Asnicar
et al. suggested that many significant associations between gut microbes and specific
dietary components are driven by the presence and diversity of healthy and
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
signature which enabled risk classification and prediction of T2DM, suggesting a

functional link between circadian rhythms and the microbiome in T2DM [75].
Several other nutritional studies identified some metabolic phenotypes related to
glycemic control and diabetes, typically in response to a dietary intervention, which
were associated with some aspects of the gut microbiome. For example, in an RCT
of a dietary intervention in subjects with T2DM, Zhao et al. found that adopting a
high-fiber diet promoted the growth of a select group of 15 bacterial strains that
produce short-chain fatty acids (SCFA), while other potential SCFA producers were
either diminished or unchanged. The high-fiber diet induced changes to the entire
gut microbiome that correlated with elevated levels of glucagon-like peptide-1
(GLP-1), a reduction in HbA1c and improved blood-glucose regulation [69].
Importantly, the production of SCFA through bacterial fermentation of dietary car-
bohydrates is considered beneficial to the host since it provides an energy substrate
to colonocytes, mitigates inflammation, and regulates satiety [76, 77]. Deficiency in
SCFA production has been repeatedly associated with various metabolic conditions,
including T2DM [65–67, 78]. Notably, in the context of a fiber-type intervention,
various studies have highlighted several associations of microbiome features with
response to dietary fiber, including the ratio of Prevotella to Bacteroides (P/B ratio)
or enterotype, diversity and richness, functional gene content within groups of taxa,
abundance and diversity of SCFA-producing bacteria, and abundance of certain
groups of taxa such as Bifidobacteria, Bacteroides, Ruminococcus, Dialister and
Coriobacteriaceae, Eubacterium, Clostridium, and Coprobacter fastidiosus and
Lachnospiraceae [79].
Another pioneering work, which indicates causality of the microbiome in deter-
mining host metabolic phenotype, is the work by Kootte et al. which showed that
fecal microbiota transplantation (FMT) from lean donors to obese patients with
metabolic syndrome improved insulin sensitivity, a transient effect associated with
changes in microbiota composition and fasting plasma metabolites. Furthermore,
the researchers demonstrated that baseline fecal microbiota composition in recipi-
ents was able to predict the response to lean donor FMT [80]. This important result
suggests that individual microbiome-targeting dietary interventions prior to FMT
may potentially improve treatment success.
Taken together, there is considerably increasing evidence that gut microbiome
represents an important factor in precision nutrition and that targeted promotion of
certain microbiome features via precision nutrition may present a novel ecological
approach for manipulating the gut microbiota to prevent or manage T2DM and its
metabolic manifestations.
Metabolomics
Metabolomics, defined as the comprehensive assessment of small molecules in bio-

logical specimens (usually blood or urine), is based on high-throughput metabolite
profiling technologies such as mass spectrometry (MS) and nuclear magnetic reso-
nance (NMR) for individual assessment of dietary intake and metabolic state [81,
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].
Overall, metabolomics platform may serve as a complementary tool, in parallel

to other traditional tools, for more accurate and objective assessment of disease
progression and patient response to a nutritional treatment. As such, metabolomics
may help to attain the goal of precision nutrition to usefully tailor dietary advice
based on anticipated individual responses to a nutritional intake.
Deep Monitoring
In addition to deep phenotyping by different types of omics data, precision nutrition

should integrate patients’ information from both traditional sources (validated ques-
tionnaires, standard clinical tests, etc.) and modern sources (electronic health
records and deep monitoring from mobile applications and wearable devices). This
integration of data from multiple disparate sources requires the use of bioinformat-
ics tools, such as big data analytics, to be able to analyze and interpret the high
volume and complexity of available data. However, the field is still in its infancy,
and researchers using these methods face different challenges, such as incomplete
and unreliable input data as well as misleading interpretations of findings owing to
a lack of expert knowledge.
Mobile Technologies for Nutritional Assessment and Diabetes Management
Mobile applications have the potential to improve real-time assessment of dietary

intake and provide feedback, thus encouraging individuals to actively participate in
their own behavior change and disease management. Therefore, it may provide a
useful tool for monitoring and implementing precision nutrition for improving gly-
cemic control among individuals with prediabetes or T2DM. Diabetes mobile phone
applications (hereafter referred to as diabetes apps) are defined as mobile phone
software that accept data (transmitted or manual entry) and provide feedback to
patients on improved management (automated or by a healthcare professional
[HCP]). In a systematic review and meta-analysis, which included ten studies that
examined diabetes app use in individuals with T2DM (n = 586), a significant mean
reduction of 0.49% in HbA1c was reported among participants using diabetes apps
as compared with controls (95% CI 0.30, 0.68; I2 = 10%). Subgroup analyses indi-
cated that younger patients were more likely to benefit from the use of diabetes
apps, and the effect size was enhanced with HCP feedback [27]. Indeed, recent
healthcare concerns are rapidly expanding the use of technology-based services,
including mobile applications, to advance traditional approaches of diabetes self-
management education and support (DSMES) [104]. This issue also deserved a
specific highlight in a recent expert consensus report [105] and in the 2021 ADA’s
Standards of Medical Care in Diabetes [106].
The use of mobile apps for food logging and real-time assessment of dietary
intake has been utilized in several research settings. Large-scale population-based
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.
Wearable Devices for Metabolic Assessment
Wearable devices for real-time assessment of physiological variables are emerging

as potential valuable tools for discovering authentic physiological and behavioral
patterns that are relevant for accurate tailoring of personalized diets. In particular,
physiological variables such as blood-glucose levels, heart rate, physical activity,
and sleep quality, traditionally tested in clinical settings only, are now available for
use in free-living populations. The integration of deep and continuous data collected
by wearable devices with comprehensive nutritional assessments can be used to
discover metabolic and behavioral patterns [108, 109], estimate predicted physio-
logical responses to specific lifestyle interventions [12, 13, 110], and potentially
help individuals in adopting better lifestyle habits and dietary choices [111–113].
Together with recent advances in technologies and the fact that wearable devices are
relatively inexpensive, it is not surprising that the use of wearable devices has
become more prevalent in research and clinical settings as well as personal use in
the private sector.
Wearable devices for tracking physical activity are commonly used for continu-
ous measurement of activity levels and intensity, which provide the ability to calcu-
late energy expenditure and improve lifestyle habits [114]. Other widely used
wearable devices are continuous glucose monitoring (CGM) sensors, which esti-
mate blood-glucose levels with high accuracy through measurement of interstitial
glucose concentrations in several minute intervals [115]. The data extracted from
CGMs provide the ability to identify undetected glucose dysregulations, like
hypoglycemia and hyperglycemia, and unveil individual responses to a variety of

foods or meals [13, 68]. For example, by grouping nondiabetic individuals into
subgroups of glucose fluctuation patterns, based on CGM data, Hall and colleagues
could define “glucotypes” (low, moderate, and severe) which were correlated with
other metabolic parameters such as fasting plasma glucose, HbA1c, and BMI [109].
Likewise, by using 7-day-long CGM data from 1000 individuals, Zeevi and col-
leagues were able to predict with high accuracy personalized PPGRs of individuals
to any meal [13]. In the PREDICT 1 study, participants were connected to several
wearable devices, including physical activity sensors, CGM, and sleep monitors, as
part of the study design. Interestingly, dietary and lifestyle features extracted from
these wearables and from food recordings in a mobile logging application, such as
meal composition and timing, physical activity, and sleep were reported as core
determinants in prediction of glucose responses to meals [12]. Another unique
wearable device is seeking to track eating patterns such as nocturnal eating, overeat-
ing, and snacking habits, which may also help to assess energy intake and add a
different point of view on lifestyle behaviors. The device is a wrist motion sensor
coupled with a micro-electro-mechanical gyroscope that estimates caloric intake by
monitoring food bites and provides information about individuals’ eating habits or
adherence to a given dietary intervention [20, 25]. Despite its potential to provide
accurate assessments of energy intake, further studies are needed to validate its
accuracy and overcome different confounders in measurement such as eating speed
of different food types.
Taken together, wearable devices measure physiological parameters in a real-
time and continuous manner, thus providing complementary information about
individuals’ lifestyle habits and physiological responses. Integrating data from
wearable devices with other deep phenotyping methods allows in-depth exploration
of human physiological responses in research settings and may facilitate decision-
making by HCPs in clinical care settings, both highly valuable for promoting preci-
sion nutrition solutions in T2DM.
From Science to Practice: Clinical Translation
As described thoroughly in the previous sections of this chapter, the cutting-edge

omics technologies and ever developing mobile applications and wearable devices
are emerging as promising tools for advancing the field of precision nutrition toward
the design of personalized and unbiased nutritional solutions for prevention and
management of T2DM. The translation of the growing evidence emerging from
basic nutritional science into meaningful and clinically relevant dietary advices rep-
resents nowadays one of the main challenges of clinical nutrition.
While mobile apps and wearable devices are already implemented to some extent
in clinical care and facilitate decision-making by HCPs for T2DM management, the
use of omics technologies in clinical practice is still scarce, due to cost-effectiveness
considerations and lack of sufficient clinical evidence base. In particular, the omics
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
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.
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Chapter 13
Precision Exercise and Physical Activity
for Diabetes
Normand G. Boulé and Jane E. Yardley
Definitions and Considerations
Physical Activity Definitions
Movement comes in a variety of forms. The most basic of these is referred to as

physical activity, which essentially includes all movement that increases energy use
above that of a resting body. The subcategory of “activities of daily living” encom-
passes all of the movements required to care for oneself independently and includes
such things as eating, dressing, and bathing (basic activities of daily living) [1]. It
can also include such things as cleaning, laundry, shopping, meal preparation, and
other household tasks. Physical activity can also include any type of active transpor-
tation (walking, cycling, etc.). Finally, the term “exercise” is used to describe physi-
cal activities that are planned and structured.
Aerobic exercise includes activities such as walking, swimming, cycling, and
jogging where large muscle groups are involved in repeated and continuous move-
ment [2]. Regular moderate aerobic exercise enhances insulin sensitivity, increases
the muscles’ ability to burn fuels in the presence of oxygen (due to a greater avail-
ability of enzymes and mitochondria), improves several aspects of lung function,
and boosts the immune system (provided that exercise duration is not extensive). In
N. G. Boulé
Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
J. E. Yardley (*)
Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada
Augustana Faculty, University of Alberta, Edmonton, AB, Canada
Women’s and Children’s Health Research Institute, Edmonton, AB, Canada
252 N. G. Boulé and J. E. Yardley
addition, it increases cardiovascular health, by augmenting cardiac output, while

also improving the reactivity and compliance of blood vessels. Further benefits can
include improved nerve conduction, muscle mass, and bone mineral density,
depending on the type of activity selected [3]. This type of activity is generally con-
sidered “aerobic,” where much of the fuel provided to the working muscles is pro-
duced through oxidation of glucose and fatty acids.
Resistance exercise, also referred to as strength training, can include any type of exer-
cise that involves the contraction of muscles against a moveable or immovable force.
This type of exercise can include lifting, pushing, or pulling of weights (free weights,
body weight, or machines) or working against an elastic resistance band [4]. Regular
resistance exercise improves body composition by increasing muscle mass and decreas-
ing fat mass, enhances strength, promotes mental health, increases bone mineral density,
improves blood pressure, ameliorates lipid profiles, and generally benefits cardiovascu-
lar health [3]. This type of activity is usually considered “anaerobic” or high intensity,
where much of the fuel provided to the working muscles is produced through glycolysis.
During high-intensity interval exercise (HIIE), the participant will alternate short
bursts of high to maximal intensity activity with periods of recovery. The recovery
intervals can consist of rest or a certain amount of time spent performing low- to
moderate-intensity aerobic exercise. The duration and intensity of the work and
recovery periods vary greatly depending on the desired training response. These
types of programs tend to enhance cardiovascular health, insulin sensitivity, and
muscle oxidative aerobic capacity to a greater extent than aerobic exercise if an
equal amount of work is performed [5].
Precision Medicine
The concept of “precision medicine” generally involves an understanding that the

right therapy should be provided for the right patient, at the right time [6], and that
a one-size-fits-all solution does not exist. The same can be said with exercise/physi-
cal activity as an essential part of management for individuals with diabetes. A great
deal more success will result if the right treatment, in this case exercise and/or
physical activity, is provided to individual patients with recommendations for
appropriate type, timing, duration, and intensity based on their goals, preferences,
and physiology. In order to be as precise as possible in these prescriptions, it will be
essential to understand the acute and training effects associated with different types
of exercise for both type 1 and type 2 diabetes, along with the individual patient
characteristics that might mediate some of these short- and long-term outcomes.
Type 1 Diabetes
Type 1 diabetes is an autoimmune condition in which the immune system attacks

the insulin-producing beta cells of the pancreas. The destruction of these cells
leads to a need for insulin replacement, either via multiple daily injections or
13 Precision Exercise and Physical Activity for Diabetes 253
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].
he Right Treatment: Adaptations to Exercise Training

T
and Habitual Physical Activity in People with Type 1 Diabetes
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
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.
he Right Treatment: Acute Glycemic Effects of Exercise

T
in Individuals with Type 1 Diabetes
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
hyperglycemia. Where endogenously produced insulin has a half-life of approxi-

mately 5 minutes, even the fastest-acting synthetic insulins used for blood glucose
management among individuals with type 1 diabetes take over an hour to hit their
peak and several hours to be cleared from the system [46]. As a result, most people
with type 1 diabetes undertake exercise in a hyperinsulinemic state. Depending on
the type, intensity, or duration of exercise performed, excess insulin can increase the
risk of hypoglycemia either during or after activity. In order to individualize exer-
cise recommendations, a clear understanding of the acute effects of each type of
exercise on blood glucose and any factors that might mediate these effects is
essential.
Lipids are the primary source of fuel for low-intensity aerobic exercise [47], with
its relative contribution to the fuel mix decreasing as exercise intensity increases.
The secondary source of fuel at low intensity is glucose, but more specifically blood
glucose, with the reliance on muscle glycogen as a fuel source increasing in propor-
tion to exercise intensity. In people without diabetes, a delicate balance between
insulin and its functional antagonist, glucagon, is maintained in order to ensure
adequate blood glucose levels. As a result, both sympathetic nervous system signal-
ing [48] and a small decline in blood glucose [49] are among the signals that lead to
a decrease in insulin secretion from the pancreatic beta cells once activity has
started. The naturally short half-life of endogenous insulin ensures a decrease in
circulating insulin, with a concomitant increase in glucagon release by the alpha
cells in the pancreas. Glucagon is then able to exert its effects on the liver to ensure
release of glucose from storage and maintain blood glucose levels in a tight range
for up to 2 hours of activity, even in the absence of carbohydrate intake.
In individuals with type 1 diabetes, the amount of insulin in circulation is depen-
dent on the most recent bolus (either by injection or by infusion) along with the
basal insulin that has been administered to manage blood glucose levels. To have
appreciably lower insulin in circulation, preparation at least 90 minutes to 2 hours
before exercise is necessary (discussed in section “Insulin Management”). As a
result, most individuals with type 1 diabetes will start exercise in a hyperinsulin-
emic state, which is often exacerbated by the fact that the accompanying elevation
in blood flow can also increase the absorption of insulin (particularly short- and
intermediate-acting) from subcutaneous depots [50–53], resulting in even higher
levels of insulin during activity. Consequently, it is common for large declines in
blood glucose to be experienced during aerobic exercise [54, 55], unless an effort to
decrease circulating insulin has been made in advance or unless exercise is per-
formed in the fasting state (see section “Timing of Exercise: Fasting Versus Fed
Exercise”). To complicate the situation further, these declines in blood glucose dur-
ing exercise are often followed by a resurgence in blood glucose levels to the point
of hyperglycemia in the hours postexercise [54], followed by an elevated risk of
late-onset hypoglycemia [56], particularly if exercise is performed later in the day.
It is often suggested that individuals with type 1 diabetes either decrease their basal
insulin overnight, eat a low-glycemic index snack before bedtime, or combine both
of these strategies to decrease the risk of nocturnal hypoglycemia after performing
physical activity/exercise late in the day.
Studies to date would indicate that increasing exercise intensity is associated

with smaller declines and potentially even increases in blood glucose during anaero-
bic activity in individuals with type 1 diabetes [57–59]. Activities, such as resis-
tance exercise [54, 60], HIIE [55, 61–63], and subsequently several team sports,
often result in smaller changes in blood glucose during exercise, thereby carrying a
lower risk of hypoglycemia during activity and often necessitating smaller insulin
adjustments (if any) prior to exercise. In addition to these types of exercise using
muscle glycogen as a fuel source (which is used less during aerobic exercise), the
smaller declines and/or increases in blood glucose in individuals with type 1 diabe-
tes are often attributed to higher circulating levels of catecholamines, and in particu-
lar epinephrine, stimulating hepatic glycogenolysis [58, 62, 64]. While there is
some disagreement among studies to date, it is likely that anaerobic activities carry
a greater risk of late-onset postexercise hypoglycemia [54, 65, 66], due to the need
to replenish glycogen stores used to fuel the activity. Similar to aerobic activities,
this risk is likely higher if exercise takes place later in the day (see section “Timing
of Exercise: Late Afternoon/Evening Exercise”) and may be prevented by decreas-
ing pre-bedtime insulin doses or eating a bedtime snack.
The knowledge that high-intensity activities can have a glucose-stabilizing effect
has led to the suggestion that these types of activities can be included before, during,
or after aerobic exercise to decrease the acute risk of hypoglycemia during exercise.
One small study involving 12 individuals with type 1 diabetes demonstrated that
performing resistance exercise (3 sets of 8 repetitions of 7 different exercises,
involving all major muscle groups) can delay the declines in blood glucose during
subsequent aerobic exercise [67]. Similarly, other studies have shown that 4-second
maximal sprints performed every 2 minutes during a low-intensity aerobic exercise
session [62] or even a single 10-second sprint at the end of 20 minutes of low-
intensity aerobic exercise [68] can lead to smaller exercise-induced declines in
blood glucose during activity compared to aerobic exercise on its own.
The Right Patient
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
(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
is the ability to lower basal rates overnight postexercise (especially if exercise is

performed late in the day) without causing next-day hyperglycemia. The consensus
statement by Riddell et al. [45] provides a great deal more details about the size of
insulin adjustments recommended for different types, intensities, and durations of
exercise for individuals using CSII.
A recent randomized crossover trial also showed that using a combination of
CSII and MDI (referred to as the “untethered” approach) can be effective for man-
aging blood glucose levels around both aerobic and HIIE sessions [73]. The hybrid
approach consisted of a single daily injection of long-acting insulin (basal dose)
while using an insulin pump to deliver bolus insulin throughout the day. The com-
parator was usual CSII treatment. Insulin infusion was suspended 60 minutes prior
to exercise. Compared to standard CSII therapy, the hybrid regimen was associated
with more time in a euglycemic range during and after lab-based aerobic exercise
and HIIE sessions, along with more time in euglycemia and less time in hypergly-
cemia during and after four high-intensity and two moderate-intensity home-based
exercise sessions [73]. The authors argue that this particular approach to insulin
management may offer more flexibility while still effectively managing blood glu-
cose levels in physically active individuals with type 1 diabetes [73].
Recently developed closed-loop systems are very effective at managing blood
glucose levels both overnight and for most day-to-day activities in individuals with
type 1 diabetes of all ages [70, 74]. Exercise and physical activity, however, are still
a challenge for closed-loop systems where blood glucose management is concerned.
These single hormone systems [available in both commercial and do-it-yourself
(also known as “looping”) forms] use interstitial glucose data sent from a CGM
system to adjust insulin infusion via an insulin pump with minimal input from the
user. As mentioned above, however, simply having insulin infusion shut off at the
beginning of exercise (if the system were able to detect the activity) often fails to
prevent large declines in blood glucose during exercise [55, 72]. Companies produc-
ing commercial closed-loop, single hormone systems will thus recommend setting
a higher blood glucose target (which subsequently reduces insulin infusion) 90 to
120 minutes before exercise, which should be maintained until the end of exercise
[75]. Bihormonal systems (using both insulin and glucagon) are predicted to have
greater success with respect to glucose management during exercise, with studies to
date showing successful prevention of almost all hypoglycemic episodes [76–79].
The progress of these systems, which have not met with commercial approval to
date, continues to be hampered by the lack of a stable glucagon solution and rela-
tively little safety data surrounding the effects of the long-term use of injected
glucagon.
Pancreatic islet transplantation is a less often used means of recovering endoge-
nous insulin secretion in individuals with type 1 diabetes. One small study found
that those who had undergone transplantation and were independent of exogenous
insulin were still likely to experience greater declines in blood glucose and overall
lower blood glucose levels during exercise compared to control participants without
diabetes matched for height, weight, age, sex, and physical activity level [80].
Hypoglycemia, however, was no more common in the transplant recipients than it
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].
Continuous Glucose Monitoring/Intermittently Scanned Continuous

Glucose Monitoring (CGM/isCGM)
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
A majority of the studies of exercise responses in individuals with type 1 diabetes

were performed with younger individuals who were habitually physically active
and, for the most part, male. As such, very little is known about the impact of age,
sex, or physical fitness on blood glucose responses to exercise and related hypogly-
cemia risk in this population [43]. What little we know comes from observational
studies or secondary analyses of data that were collected for different purposes.
Among individuals with type 1 diabetes, one large observational study
(n = 18,028) found that the frequency of self-reported exercise decreased with age
[16]. In the youngest patients (aged 18 to <30 years), 25.8% reported exercising at
least twice per week, compared to only 10.0% of individuals (p < 0.0001) in the
oldest age group (45 to <80 years). Older individuals who were more physically
active, however, also reported higher rates of severe hypoglycemia than younger
individuals with similar activity levels. Those who were most active were also likely
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
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].
The Right Time
In discussing the “right time” for exercise, it is important to consider benefits of

regular exercise throughout disease progression and the life span, in addition to the
acute effects of exercise timing throughout the day. With much of the focus in the
area of exercise and type 1 diabetes being on acute hypoglycemia prevention, the
effects of exercise timing throughout the day and with respect to food intake have
been the focus of a great deal more research. There are, however, some important
points to be made about exercise through different stages of life and diabetes
progression.
The “Honeymoon” Phase
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
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.
Children and Adolescents with Type 1 Diabetes
It is generally recommended that children and adolescents acquire at least twice as

much weekly physical activity as adults (60–90 minutes/day for toddlers,
90–120 minutes/day for preschoolers, and 60 minutes/day for school-aged children
and adolescents) [108]. A meta-analysis of exercise studies involving children and
youth with type 1 diabetes found that potential benefits of exercise included lower
A1c [109, 110], decreased BMI [109], and improved triglyceride levels [109].
While the benefits of physical activity with respect to mental health are well-
documented in children and adolescents without diabetes [111, 112], these benefits
have not been well-researched in youth with diabetes. There is observational evi-
dence from studies using CGM that physical activity, particularly if it is performed
in the afternoon, is associated with an increase in hypoglycemia for youth with T1D
[113, 114]. Conversely, intervention studies promoting an increase in physical
activity have generally not found an increase in hypoglycemic events with increas-
ing activity levels [109].
The risk of cardiovascular disease is much higher in individuals with type 1 dia-
betes than in people without diabetes and is higher for those who are diagnosed with
type 1 diabetes at a younger age [115]. There is also evidence that children and
youth with type 1 diabetes may already possess cardiovascular risk factors [116]. As
the cardiovascular benefits of physical activity and exercise are well-established in
individuals with type 1 diabetes [13, 16, 17, 117] and physical activity patterns from
youth tend to track into adulthood [118], developing regular physical activity habits
in children and youth with type 1 diabetes will be essential to their long-term health.
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
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.
Timing of Exercise: Fasting Versus Fed Exercise
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
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.
Timing of Exercise: Late Afternoon/Evening Exercise
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.
Timing of Exercise Relative to Meals/Snacks
As previously mentioned, the timing of exercise with respect to previous meals

and snacks is an important consideration where exercise is concerned. It is generally
recommended to avoid exercise when circulating insulin will be at its peak (usually
within 1 to 3 hours of a bolus, depending on the type of insulin administered). If
exercise is taking place during this window and adjustments have not been made to
basal insulin in advance, carbohydrate consumption will likely be required to pre-
vent hypoglycemia during exercise, regardless of exercise intensity. As mentioned
above, another option for maintaining blood glucose levels during the postprandial
period is to consume a pre-exercise snack with a reduced insulin bolus. The size of
this reduction will depend on how close to exercise the snack is being consumed and
what type of activity the individual is about to undertake [142]. A more comprehen-
sive discussion on this topic is provided by Riddell et al. [45].
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.
The Right Treatment
General Considerations
Compared to type 1 diabetes, the acute risk of hypoglycemia or hyperglycemia dur-

ing or following exercise is typically less of a concern in type 2 diabetes. In the
latter, a much larger number of exercise trials have been conducted from the per-
spective of improving longer-term indicators of glycemic management (e.g., A1c)
[144, 145] and cardiovascular risk factors [146, 147]. Different forms of exercise
training (e.g., aerobic, resistance, HIIE) have often been found to have relatively
similar effects on A1c [145, 148]; however, other considerations may make one
form of exercise preferable over others.
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
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].
High-Intensity Interval Exercise (HIIE)
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
some people. Most organizations recommend additional screening for cardiovascu-

lar risk before performing such activities [44, 152]. In terms of benefits, it is clear
that HIIE training can result in greater improvements in aerobic fitness [156].
Aerobic fitness is often low in people with type 2 diabetes and can be important to
facilitate activities of daily living. Aerobic fitness is also one of the strongest inde-
pendent predictors of all-cause mortality [159, 160].
Breaking Sedentary Time
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].
The Right Patient
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
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).
Age and/or Duration of Diabetes
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
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].
Obesity, Body Fat Distribution, and Sarcopenia
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
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].
Other Treatments (e.g., Medications or Nutrition)
Even though regular exercise or physical activity is considered a frontline therapy

for the management of type 2 diabetes, it is rarely prescribed in isolation. When
combining multiple therapies, it is possible that their effects are simply additive,
that they have synergistic interactions (i.e., the benefits of combined treatment are
superior to the additive effect of each treatment), or that one interferes or compli-
cates another (i.e., negative interaction). Given the great number of options in regard
to interventions such as glucose-lowering medications, dietary approaches, and bar-
iatric surgeries, it would not be feasible to discuss all potential interactions with
exercise (and, in many cases, these have not been studied). Consequently, we will
discuss one example each of a likely additive, synergistic, and interference effect
from combining other therapies with exercise.
Example 1: Additive Effect – Benefits of Combining Aerobic and Resistance

Training In the Diabetes Aerobic and Resistance Exercise (DARE) trial, participants
with type 2 diabetes were randomly assigned to a control group, resistance training,
aerobic training, or fourth group that completed both the aerobic and resistance train-
ing protocols [151]. At both 3 months and 6 months, the effects of the combined
training group seemed additive when compared to the groups that performed aerobic
and resistance training alone. Although speculative, it would seem that only the two
groups performing aerobic training (i.e., the aerobic and combined training groups)
showed beneficial changes in A1c during the first 3 months, whereas the two groups
that completed resistance training (i.e., the resistance and combined training groups)
were the only ones who saw beneficial changes from months 3 to 6 [151].
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].
Example 2: Potential Synergistic Interaction – High-Protein Diet and

Exercise Reductions in muscle mass are common with aging, particularly in those
with type 2 diabetes. Exercise can contribute to increasing lean body mass or mus-
cle mass, and there is evidence that this effect can be improved with the consump-
tion of higher amounts of dietary protein. Evidence to support this premise has been
at times correlative in nature, such as in one study where greater habitual protein
intake was associated with greater improvements in strength and skeletal muscle
mass following only 8 weeks of resistance training in elderly women [190].
However, when participants with type 2 diabetes are randomly assigned to different
protein intakes, the results have not been fully consistent. In a recent study by
Memelink et al. [191], an enriched protein drink, which included leucine and vita-
min D, or isocaloric control drink was provided in the morning and immediately
following combined HIIE and resistance exercise sessions performed 3 times per
week over 13 weeks. Total lean mass and insulin sensitivity increased to a greater
extent in the group that received the protein-enriched drink [191].
Wycherley et al. [192] used a factorial design in which an energy-restricted diet
included random assignment of participants with type 2 diabetes to resistance train-
ing or no exercise with and without a high-protein diet. Reductions in body weight
and total fat mass were largest in the combined resistance training and high-protein
group. However, contrary to Memelink et al. [191], this group did not experience
the most favorable changes in fat-free mass. Differences among studies may be due
to factors such as the amount of energy restriction or the timing of protein intake.
Indeed, larger improvements in lean body mass and in strength have been shown in
older adults assigned to consume a protein supplement immediately after, as
opposed to 2 hours after, resistance training sessions [193].
Example 3: Negative Interaction – Metformin and Exercise Unlike type 1 diabe-

tes where the interactions between exercise and insulin treatments are often studied,
little is known regarding the effect of glucose-lowering medications on responses to
exercise in type 2 diabetes. For example, in the previously discussed DPP, partici-
pants were randomly assigned to placebo, an intensive lifestyle intervention, or met-
formin, but there wasn’t a combined lifestyle intervention plus metformin group
[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.
The Right Time
Unlike some glucose-lowering medications, increasing physical activity, including

participation in structured exercise, is indicated at all stages (healthy, prediabetes,
new-onset diabetes, and long-duration diabetes) of disease progression.
Consequently, most people receive advice at all stages, and we are not aware of any
studies, comparing exercise to delayed exercise prescription in people with type 2
diabetes. Some such studies exist in other chronic conditions such as severe obesity,
which did not suggest advantages of delaying the addition of physical activity to an
energy-restricted diet [198]. On the other hand, there are recent trials addressing
issues pertaining to the timing of individual bouts of exercise in relation to the time
of day or other factors such as meal or medication intake.
Speculations on When Delaying Exercise Interventions (or

Co-Interventions) Could Be Considered
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
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.
Exercise Timing (e.g., Time of Day)
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.
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.
THE RIGHT TREATMENT

-Type (e.g., aerobic, resistance, HIIT)
-Acute vs. chronic effects of exercise
-Outcomes (Risks and Benefits)
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
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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
In their comprehensive review of precision medicine, Mering and Florez conclude

that “Clinical decision-making is, by necessity, dichotomous: on the basis of com-
plex and often continuous information, the practitioner needs to decide whether to
act or not to act, to intervene or to merely observe. One course must be taken among
several possible options, and the key question is whether modern omics technolo-
gies will be able to capture enough biological variation to enable the construction of
sensible discrete categories to facilitate rational decision analysis, or this will remain
the province of ‘boutique’ rare forms of diabetes” [1]. They, of course, were writing
about the contributions of genomics, proteomics, metabolomics, and glycomics as a
means of characterizing individuals with diabetes in order to identify effective treat-
ments. They conclude that “Treatment personalisation requires initial identification
of key characteristics of the patient with diabetes” [2]. Gloyn and Drucker, in their
review of type 2 diabetes, agree, arguing that genetics helps to distinguish between
subtypes and thereby provides more precision in diagnosis and treatment [3]. An
alternative view advanced by Dennis and associates suggests that “The known het-
erogeneity in type 2 diabetes, together with the differences we have observed in
clinical outcomes, raises the possibility of a practical clinical application of
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

290 R. S. Mazze et al.
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].
Changing the Precision Medicine Paradigm
Clearly, while advancing “omics,” credence must be given to clinical observations.

Two of the most promising and far-reaching technologies in clinical practice which
enable the collection and application of accurate, reliable, and verifiable data are
often overlooked in terms of their contributions to precision medicine, specifically
continuous glucose monitoring (CGM) and continuous subcutaneous insulin infu-
sion (pump). These technologies have the potential of revolutionizing precision
medicine if the paradigm underlying their use shifts. If these technologies are
employed for the “… comprehensive capture of multiple data points across orthogo-
nal axes of information [to develop] … analytical methods that permit the interpre-
tation of complex data [this will] … enable the construction of more refined
categories, and concomitant advances in targeted therapeutics“ [1].
The question is whether glucose sensing and insulin delivery systems have an
expanded role in precision medicine. Can the use of CGM for the management of
diabetes be extended to encompass improving diagnostic and treatment precision by
identifying with greater specificity the underlying metabolic abnormalities that
characterize diabetes? Currently, CGM is employed to measure glucose in an effort
to guide and assess treatment. When optimized, CGM provides a diurnal profile of
glucose perturbations which may uncover defects that otherwise go undetected.
Similarly, can the insulin pump functionality go beyond attempting to mimic physi-
ologic insulin delivery in type 1 diabetes? These traditional practices of CGM and
pump technologies have stifled the myriad purposes both technologies may serve in
precision medicine. This chapter addresses three areas: (1) how these technologies
function, (2) optimization of their current roles in clinical practice, and (3) their
potential contributions to precision medicine.
A change in the paradigms that have guided the use of CGM and pump technolo-
gies since their introduction is needed if their roles in precision medicine are to be
maximized. Both technologies were originally introduced without a clear understand-
ing of their purpose. As with many technological advances in diabetes, the focus was
on how these technologies functioned and their accuracy and reliability. In general,
their purpose in clinical practice was left to the physician’s and/or patient’s preroga-
tive. Consequently, for many years, the implementation of these technologies in clini-
cal practice has been stilted. Accordingly, for both technologies, it is important to
understand their purpose, so that their potential usage in terms of precision medicine
14 Diabetes Technology for Precision Therapy in Children, Adults, and Pregnancy 291
can be explored. What is the purpose of continuous glucose monitoring (CGM)?

CGM is used to provide a means of accurate and verifiable glucose data in order to
make clinical decisions that improve the diurnal glucose profile with the goal of mim-
icking normal glucose metabolism [5]. Insulin pumps are employed to mimic normal
glucose metabolism by infusing insulin in response to diurnal glucose patterns.
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
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.
CGM Clinical Outcomes
CGM’s primary contribution to precision medicine is the provision of verifiable and

unbiased continuous data. CGM can generate between 96 and 288 measurements
per day (dependent upon the system). It has been shown that CGM helps to improve
diabetes care in terms of reduction of hypoglycemic episodes and glycated hemo-
globin (HbA1c), lessen glycemic variability, and improve quality of life in people
with type 1 and type 2 diabetes receiving different treatment regimens [16]. The use
of CGM also helps to reduce diabetes-related complications [17].
As a component of precision medicine, CGM is complementary to HbA1c. As a

general marker of glycemic control and prognostic indicator of incident diabetes-
related complications, HbA1c cannot address an individual’s glycemic excursions
and does not provide insights regarding the adjustment of the treatment regimen on
a personalized basis; whereas, CGM provides a means of assessing diurnal glucose
patterns under conditions of daily living to guide clinicians and patients in making
decisions related to treatment. With the standardization of the reporting format and
inclusion of key metrics from CGM data through international consensus and clini-
cal targets specific for CGM from international experts, the interpretation of CGM
data has become more straightforward [13, 18, 19].
CGM and the Ambulatory Glucose Profile (AGP)
The myriad uses of CGM rely on an understanding of the innovative approaches

CGM employs to display glucose data. Figure 14.1 illustrates the scope of informa-
tion provided by CGM. It contains two ambulatory glucose profiles (AGPs), each
based on 2 weeks of continuous monitoring of the same individual with type 1
DM. AGP graphics are a means of representing continuous glucose data as a “typi-
cal” diurnal glucose pattern using five frequency distribution curves [20–22].
Figure 14.1 displays two consecutive time periods during which time estimated A1c
and mean glucose are stable. In this instance, the contribution to precision medicine
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
lies in the discovery of the frequency, duration, magnitude, and distribution of

hypoglycemic events. Depsite a stable average glucose (7.7–7.8 mmol/L), the inci-
dence of hypoglycemia increased threefold from 4 to 11%. In AGP 1, hypoglycemia
occurs between 16:00 and 19:00 hours and is mild, while in AGP 2, it begins at
noon and continues until near midnight. Furthermore, variability (interquartile
range) averages 7 mmol/L in AGP 1 and 11 mmol/L in the later AGP 2.
This level of specificity is only possible using CGM technology. It identifies
underlying dysglycemia that would otherwise have gone undetected. Since both
variability and stability have been identified as potential contributors to long-term
complications, their discovery and amelioration are critical. In this case, neither the
average glucose nor the eA1c would have detected these anomalies. Furthermore,
only through CGM can they be specified as to their magnitude, frequency, distribu-
tion, and duration.
Expanding the Role of CGM: Real-Life Applications
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.
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
Background and Rationale for Pump Therapy
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?
Blinded CGM (27-28 GW Open CGM (29-30GW)
GW27-29
and
an
a nd early
ear
e
ea
earl
arl
rly evening
rly eve
eve
ev en
nin
niing glucose
ing gluccos
gl ose levels.
ose leve
els
lss.
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.
Pumps with Integrated CGM
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
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.
ybrid Closed Loop in Clinical Practice: Following

H
the Principles of Precision Medicine
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.
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.
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
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.
Expanding the Role of Pumps
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
treatments rely on very limited data. This is especially problematic as diagnosis of

type 2 diabetes is often delayed until it becomes symptomatic.
In a study of individuals newly diagnosed with type 2 DM, subjects were hospi-
talized for 3 weeks during which time they underwent episodic pump therapy using
CGM before, during, and after pump therapy to “define the features of patients” in
order to determine whether long-term insulin therapy was required [27].
Hypothetically, if near euglycemia could be maintained using the pump, the precise
insulin regimen could be identified, and the decision could be made as to whether to
continue with pump therapy or MDI and, more importantly, whether insulin therapy
could be discarded if, for instance, a negligible amount of insulin were required to
achieve near euglycemia. At diagnosis, using pump therapy with CGM may foster a
“better understanding of the underlying mechanisms responsible for elevated fast-
ing versus postprandial glucose concentration, as well as knowledge about the
expected responsiveness to treatment in individuals with different clinical charac-
teristics at diagnosis, may contribute to optimising strategies for management of
hyperglycaemia in both pre-diabetes and type 2 diabetes” [28].
If glucose sensing technologies are to make a lasting contribution to precision
medicine, then we must understand: (1). how the current technology is related to the
underlying pathophysiology of diabetes, and (2). how this relationship can improve
clinical practice. The classifications, type 1 and type 2 diabetes, as well as diabetes
in pregnancy are placeholders suggesting that “one term fits all.” Genomics has iden-
tified numerous subtypes, suggesting that all diabetes within the same classification
are not the same. Metabolic profiling can take precision medicine one step further.
Using CGM can identify the distinguishing features within diabetes subgroups that
contribute to greater diagnostic specificity and consequently, improved therapeutics.
For example, informed treatment selection requires an understanding of glucose
exposure, variability, and stability, as well as the incidence of hypoglycemia and
how these characteristics reflect the underlying pathophysiology of diabetes.
The purpose of CGM is manifold. First, it characterizes patients in new and inno-
vative ways using recognized data patterns related to the disease pathophysiology.
Second, it assists in the interpretation of these patterns (AGPs) to better identify and
manage patients with diabetes. Third, because CGM provides a means of collecting
accurate, verifiable, and reliable glucose data under conditions of daily living that
cannot otherwise be obtained, it facilitates insights into the inter-relationships
between behavior and pathophysiology. Fourth, by providing diurnal and nocturnal
glycemic patterns vital to the detection of dysglycemic patterns, it aids in the selec-
tion and adjustment of therapies. Essentially, CGM technologies bring the goal of
achieving normal metabolic patterns closer.
The role of CGM in precision management of diabetes was recently enhanced by
the recommendation of the American Diabetes Association that CGM reports with
AGP graphic displays should be used to detect dysglycemic patterns and associate
these patterns with their underlying pathophysiology [29]. CGM allows greater
specificity in selecting the appropriate therapy to correct the underlying defect.
Essentially, when used in type 2 diabetes to detect fasting, postprandial and over-
night dysglycemia, CGM analytics provide clues related to their underlying causes.
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.
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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
Chiara Toffanin, Claudio Cobelli, and Lalo Magni
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
L. Magni
Department of Civil and Architecture Engineering, University of Pavia, Pavia, Italy

306 C. Toffanin et al.
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.
Impulse Response (IR) Models
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.
Constrained Optimization (CO) Models
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
measurements need to be prefiltered to be considered for identification; in this case,

a moving average filter showed good performances [32]; other techniques, like the
retrofitting process [36], could be considered. A substantial advantage of the CO
approach is represented by the fixed parametric structure of the identified model,
which results in a fixed implementation complexity of the control algorithm for any
patient. It has been shown in [32] that the CO approach is able to capture the glu-
cose-insulin dynamics of the patient by relying on shorter identification datasets,
which are more easily realizable in a real-life scenario where the patient would be
enrolled in a clinical study to produce historical input-output data for identification
purposes.
Nonparametric (NP) Models
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].
Neural Network (NN) Models
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.
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
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.
Conclusions
In this chapter, we have focused on two important problems related to AP control

algorithms which should allow an improved long-term glucose control, i.e. indi-
vidualization and adaptivity. Both issues are very relevant for precision medicine
since they would allow to tune glucose control to a specific person or to a subgroup
of people.
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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.
Automated Insulin Delivery
A true artificial endocrine pancreas (AEP), or a closed-loop automated insulin

delivery system, or, more precisely, a glucose-controlled automated insulin delivery
system, has been evolving over the past few decades. Initial systems used a bedside
apparatus and required intravenous access both for glucose measurement and for
insulin delivery [1]. Continuous subcutaneous insulin infusion (CSII) pumps were
introduced in the late 1970s [2–3] and used in clinical practice beginning in the
1980s [4–5]. An implantable system, using an intravascular glucose sensor and
intraperitoneal insulin delivery, was briefly used in clinical trials in the early 2000s
[6]. In the mid-2000s, continuous glucose monitoring (CGM) systems emerged, and
as their accuracy improved, they were coupled with CSII pumps [7–8]. With devel-
opment of sophisticated algorithms to control CSII delivery based on CGM input,
first emerged hybrid systems that controlled basal insulin, and subsequently more
sophisticated systems for AID that approach being a true AEP [9–13]. Further evo-
lution will likely be based on advanced data science methods to support diabetes
decision support, such as deep learning and big data analytics so that the control
J. S. Skyler (*)
Diabetes Research Institute, University of Miami Miller School of Medicine,
Miami, FL, USA

316 J. S. Skyler
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.
revention of Immune Destruction to Preserve Beta-Cell Mass

P
or Function
In genetically predisposed individuals, an environmental trigger initiates an

immune response directed against pancreatic islet beta cells, resulting in cellular
damage, impairment of function, and a potential decrease of beta-cell mass. There
16 Evolving Approaches to Type 1 Diabetes Management 317
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
Replacement of Insulin-Secreting Beta Cells
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].
Regeneration of Beta Cells
Beta-cell regeneration might be a way to improve function and potentially reverse

T1D. Although approaches to regeneration have been used in animal models, human
studies have not yet been successful [67, 68]. Nonetheless, many laboratories are
pursuing beta-cell regeneration, and the hope is that progress will be forthcoming.
Conclusions
My hypothesis is that the ideal therapeutic approaches to T1D, automated insulin

delivery (AID); prevention of immune destruction, to preserve beta-cell mass or
function; and replacement of insulin-secreting beta-cells and/or regeneration of beta
cells, are all approaches that will ultimately come to fruition. The time course of
success for each of these approaches is unpredictable. Many investigators, their
institutions, or their funders often issue press releases heralding their advances. One
must be cautious in reading these, as many overpromote the advances [69].
Nonetheless, there has been a great progress in both innovations and the scientific
breakthroughs needed to advance these ideas to clinical reality.
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Index
A Automated insulin delivery (AID), 206,

Action in Diabetes and Vascular Disease: 315, 316
Preterax and Diamicron MR Average glucose profile (AGP) report, 17
Controlled Evaluation (ADVANCE)
trials, 20
Action to Control Cardiovascular Risk in B
Diabetes (ACCORD), 20 BANDAID2, 33
Adenosine triphosphate-citrate lyase (ACL) Bariatric surgery, 8
inhibitors, 23 Basal insulin, 296
Adipose tissue compartments, 90–92 Bempedoic acid, 23, 67, 71, 72
Advanced biochemistry, 3 Ben-Yacov, O., 233–244
Aerobic exercise, 251, 252 Berry, S.E., 241
Aerobic training, 265, 266 Bezafibrate Infarction Prevention study, 73
AHEAD trial, 9 Bihormonal systems, 258
Ahlqvist, E., 267, 268 Biliopancreatic diversion (BPD), 219
Ambulatory glucose profiles (AGPs), 293, 294 Biobank, 4
American Association of Diabetes Biomarkers, epigenetics, 4
Educators, 29 Blankenship, J.M., 267
American Diabetes Association (ADA), 8, 244 Body composition, 90–92
Anti-islet autoimmune markers, 137 Body fat distribution, 269, 270
Appetite suppressants, 214, 215 Borgan, S.M., 211–215
Artificial intelligence (AI), 5 Bouhassira, D., 181
Artificial pancreas (AP) Boulé, N.G., 251–275
adaptivity, 309, 310 Branched-chain amino acids, aromatic amino
individualization acids (BCAA/As), 239
CO models, 307, 308 Breaking sedentary time, 267
CR-based models, 306, 307
impulse response models, 307
NN models, 308 C
NP approach, 308 Campbell, C.M., 181
technology, 206 Caramori, M.L., 150–160
ASCENDRCT, 32 Cardiovascular disease (CVD), 2
ASCOT study, 68 Cardiovascular function
Asnicar, F., 236 diabetes-associated vascular disease,
ASPEN study, 68 100, 101
Automated closed loop, 316 MRI, 98

https://doi.org/10.1007/978-3-030-98927-9
324 Index
Cardiovascular function (cont.) cytokine release and vasoconstriction, 54

myocardial lipid contents, 99 diabetic cardiomyopathy, 56, 58
myocardial mitochondrial function, 99 general population incidence, 54
transthoracic echocardiography, 98 glucagon-like peptide-1 receptor (GLP1)
Chan, J.C.N., 111–125 agonist, 60
Chen, D., 1–5, 8, 9, 14, 18–34 glycemic control, 58, 59
Cholesterol ester transfer protein (CETP) hyperlipidemia, 58
function, 66 hypertension, 56–58
Church, T.S., 271 incidence, 57
Cobelli, C., 305–311 morbidity and mortality, 53
Cochrane Database Review, 73 natriuretic peptide deficiency, 54, 60
Collaborative Atorvastatin Diabetes Study pharmacologic agents, 59
(CARDS) trial, 68 sodium glucose cotransporter 2 (SGLT2)
Collazo-Clavell, M., 217–226 inhibitors, 59, 60
Constrained optimization (CO) models, Diabetes apps, 240
307, 308 Diabetes mellitus type 2 (DM2) remission
Continuous glucose monitoring (CGM), 17, ABCD and DiaRem score, 222, 223
203, 315, 316 bariatric surgery, 219–222
AGPs, 293, 294 complications, 225
clinical outcomes, 292, 293 cure and, 218, 219
external systems, 291, 292 mechanisms, 222, 224
implantable system, 291 recurrence risk, 222
insulin pump therapeutic target, 225
background and rationale, 295, 296 Diabetes Prevention Program (DPP), 8,
HCL, 296–300 239, 268
open-loop systems, 296, 297 Diabetes self-management education and
role expansion, 300, 301 support (DSMES), 240
precision medicine paradigm, 290, 291 Diabetic cardiomyopathy, 56
real-life applications, 294 Diabetic kidney disease (DKD)
Continuous glucose monitoring/intermittently comorbidities and complications, 154
scanned continuous glucose diagnosis and stages, 151, 152
monitoring (CGM/isCGM), 259 epidemiology, 150
Continuous subcutaneous infusion (CSI), 214 kidney structure vs. function, 153
Continuous subcutaneous insulin infusion monitoring, 152, 159
(CSII), 257, 258, 315 organization of care, 160
Control algorithm, 308, 309 pathophysiology, 150, 151
Coronary heart disease (CHD), 65 pregnancy, 159
Coronavirus 2019 (COVID-19) pandemic, 203 prevention and treatment
C-peptide, 137 aspirin, 158, 159
Cure, definition, 218 dietary modification, 155, 156
GLP1-RA, 157
glycemic control, 156
D lifestyle modification, 154–156
Data acquisition, 201, 203 lipid-lowering therapy, 158
Davalos, L., 171–189 MRA, 158
Davis, G., 199–207 RAS inhibition, 157, 158
Deep subcutaneous adipose tissue (DSAT), 91 SGLT2 inhibitor, 156, 157
Defronzo, R.A., 268 risk factors, 153, 154
Demant, 182 screening, 151
Dennis, J.M., 289 structural kidney lesions, 152, 153
Diabetes and heart failure management Diabetic nephropathy, 103, 150
comorbidities, 54 Diabetic peripheral neuropathy (DPN)
coronary artery disease, 55–57 animal models, 177, 178
Index 325
brain imaging, 184–187 E

clinical approach, 173, 174 Electronic decision support tools, 28
clinical study findings, 187 Endothelial dysfunction, 100
disease prevention and management, 188 End-stage renal disease (ESRD), 2
epidemiological data, 171, 172 European Association for the Study of
genetic risk factors, 177 Diabetes (EASD), 244
high-throughput profiling datasets, European Medicines Agency (EMA), 180
188, 189 Ezetimibe, 23, 71
Kidney Precision Initiative, 188
MetS, 174, 175
obesity, 174, 175 F
painful DPN, 179, 180 Feldman, E.L., 171–189
pediatric DPN, 176, 177 Fenofibrate Intervention and Event Lowering
potential therapeutic avenues, 179 in Diabetes (FIELD) study, 19
potential therapy, 178, 179 Fibrate, 72
prediabetes, 175, 176 Flash glucose monitoring (FGM), 30
sensitivity and specificity, 188 Florez, J., 289
sensory profiling Flow-mediated dilatation, 100
irritable nociceptor phenotype, 181 Fulcher, Jordan, 1–5, 8, 9, 14, 18–34
nonirritable nociceptor
phenotype, 181
phenotypic differences, 181, 182 G
QST, 180, 181 Gaussian noise, 308
therapeutic response, 182, 183 Gene chip assays, 4
T1D vs. T2D, 173 Genetic risk score (GRS), 235
Diabetic retinopathy, 103, 104 Genome-wide association studies (GWAS), 4,
Diet and drugs, 2 188, 235
Dietary Approaches to Stop Hypertension GISSI Prevenzione study, 74
(DASH) diet, 9 GLOBES STRIVED mnemonic, 8
DiRECT trial, 15 antiplatelet agents, 32
Drucker, D.J., 289 arterial disease and heart failure
Drug-eluting stents, 33 management, 33
Duvivier, B.M., 267 education, 29
Dyslipidemia emotion, 27
bempedoic acid, 71, 72 fairly fast SA2A2B, 32
definition, 65 glucose monitoring
diabetes-specific medications devices, 30
GLP-1 receptor agonists, 76–78 glucose benefits, 32
metformin, 76 interstitial fluid glucose monitoring,
thiazolidinediones, 77 advantages and
ezetimibe, 71 disadvantages, 30, 31
JUPITER trial, 69 interstitial fluid glucose monitoring,
non-LDL directed medications, 72 treatment targets, 31
fibrates, 72–74 glucose-lowering medications, 21
omega-3 fatty acids, 74–76 glycemia
pathogenesis, 65, 66 CGM profile, 17
PCSK9 inhibitors, 69, 70 glucose variability (GV), 19, 20
treatment personalizing glucose targets, 18, 19
atorvastatin, 68 hypertension
moderate-intensity statin flow-chart, 26, 27
therapy, 68 individualizing BP targets, 26
secondary prevention, 67, 68 selecting BP-lowering drugs, 26
statins, 66, 67 white-coat hypertension, 25
326 Index
GLOBES STRIVED mnemonic (cont.) Hepatocellular lipids (HCL), 95, 96

inflammation/infections, 29 Hepatocyte nuclear factor 1-alpha
lipids and lipid drugs (HNF1A), 139–141
cardiovascular disease, 22 Hepatocyte nuclear factor 1-beta (HNF1B-
fibrates, 24 MODY), 141, 142
fish oils, 24 Hepatocyte nuclear factor 4-alpha
LDL-C-lowering drugs, 23, 24 (HNF4A), 141
lipid profiles, 21 High-intensity interval exercise (HIIE), 252,
microvascular disease, 22 254, 266, 267
statin therapy, 24 High-resolution metabolomics (HRM)
statins and new-onset diabetes techniques, 200
(NOD), 23 Hindgut hypothesis, 224
management of CVD, 33 “Honeymoon” phase, 261, 262
microvascular complications Hong Kong Diabetes Register, 4
management, 33 Human embryonic stem cells (hESCs), 318
novel glucose control agents, 10, 21 Hurtado, A.M.D., 217–226
obesity, 25 Hybrid closed-loop pump (HCL),
rationale for glucose targets, 20, 21 296–300, 316
screening, 28 Hyperglycemia, 200, 301
smoking, 28 Hypoglycemia, 258
treating to target, 28
vaccinations, 29
Gloyn, A.L., 289 I
GLP-1 receptor agonists (GLP-1Ras), 76–78 Imaging techniques
Glucagon-like peptide 1 receptor agonists body composition and adipose tissue
(GLP1-RA), 60, 157 compartments, 90–92
Glucokinase (GCK), 138, 139 cardiovascular function
Glucose metabolism, 200 diabetes-associated vascular disease,
Glucose, Lipids and lipid drugs, Obesity, 100, 101
Blood pressure and blood pressure MRI, 98
drugs, Emotion, and Smoking myocardial lipid contents, 99
(GLOBES), 8 myocardial mitochondrial function, 99
Glucotypes, 242 transthoracic echocardiography, 98
Glycemia, 17–21 diabetic nephropathy, 103
CGM profile, 17 diabetic retinopathy, 103, 104
glucose variability (GV), 19, 20 hepatic tissue function
glucose-lowering medications, 21 HCL, 95, 96
novel glucose control agents, 10, 21 metabolic fluxes, 98
personalizing glucose targets, 18, 19 mitochondrial function, 97
rationale for glucose targets, 20, 21 NAFLD, 96, 97
Glycemic index, 171 noninvasive imaging, 89, 90
Glycemic status, 236, 237 pancreatic steatosis, 102
skeletal muscle tissue structure
“ectopic” fat storage, 93
H IMCL, 93, 94
Hall, H., 242 metabolic fluxes, 95
Haroutounian, S., 183 mitochondrial function, 94
Helsinki Heart Study, 73 Immune intervention, 316, 317
Hepatic tissue function Impaired fasting glucose (IFG) group, 175
HCL, 95, 96 Impaired glucose tolerance (IGT), 175
metabolic fluxes, 98 IMPROVE-IT trial, 23
mitochondrial function, 97 Impulse response (IR) models, 307
NAFLD, 96, 97 Induced pluripotent stem cells (iPSCs), 318
Index 327
INITATION trial, 30 Magni, L., 305–311

Inpatient precision medicine Maturity-onset diabetes of the young
data acquisition, 201, 203 (MODY), 133–134
factors, 200–202 GCK-MODY, 138, 139
glycemic targets, 204–206 HNF1A-MODY, 139–141
hospital glucose monitoring, 201, 203 HNF1B-MODY, 141, 142
non-insulin antihyperglycemic HNF4A-MODY, 141
agents, 199 INS-NDM, 143
pharmacotherapy, 204–206 KCNJ11-NDM and ABCC8-NDM,
setting, 199 142, 143
Insulin, 214, 215 risk calculator and screening algorithm,
Insulin-to-carbohydrate ratio (CR) 137, 138
parameter, 306, 307 Mazze, R.S., 289–301
Intensive lifestyle intervention, 213 Memelink, R.G., 271
Intensive metabolic intervention, 213 Mering, J., 289
Intermittently scanned (isCGM), 291 Metabolic milieu of diabetes, 2
Interstitial glucose (ISG), 291, 292 Metabolic profiling, 301
Intraepidermal nerve fiber density (IENFD), Metabolic syndrome (MetS), 171, 174, 175
173, 174 Metabolomics, 238–240
Intramyocellular lipids (IMCL), 93, 94 Meta-transcriptomic methods, 243
Intraperitoneal (ip) insulin delivery, 305 Metformin, 76, 159, 271, 272
Isocaloric feeding, 213 Metformin-associated lactic acidosis
(MALA), 19
Microbiome, 236–238
J MicroRNAs, 4
Jenkins, A.J., 1–5, 8, 9, 14, 18–34 Microvascular and macrovascular damage, 56
Joint Asia Diabetes Evaluation (JADE) Mineralocorticoid receptor antagonists
system, 121 (MRA), 59, 158
JUPITER trial, 69 Mitochondrial function, 94, 97
Mnemonic to guide diabetes care, 8–9
Mobile technologies, 240, 241
K Model predictive control (MPC), 309, 310
Kashyap, S.R., 211–215 Molecular biology, 3
Kong, A.P.S., 289–301 Molecular medicine, 1
Kootte, R.S., 238 Monogenic diabetes, 4
challenges, 136
classification, 132
L diagnosis, 135, 136
Laparoscopic adjustable gastric banding epidemiology, 132
(LAGB), 219 history, 131
Latent autoimmune diabetes in adults MODY, 133–134
(LADA), 253 GCK-MODY, 138, 139
Lifestyle modifications, 8 HNF1A-MODY, 139–141
Lim, L.-L., 131–134 HNF1B-MODY, 141, 142
Low-density lipoprotein cholesterol HNF4A-MODY, 141
(LDL-C), 66 INS-NDM, 143
Low-glucose suspend, 316 KCNJ11-NDM and ABCC8-NDM,
Luk, A.O.Y., 131–134 142, 143
risk calculator and screening algorithm,
137, 138
M Mono-unsaturated FA (MUFA), 96
Ma, R.C.W., 111–125 Multiple daily injections of insulin (MDI),
MACE 3 endpoint, 74 214, 256–257
328 Index
Multiple model predictor (MMP), 310 children and adolescents, 262

Multiple risk factor control, 6, 9–32 classification, 252
lifestyle, 9, 15 exercise training and habitual physical
primary and secondary prevention of CVD activity, 253, 254
and microvascular complications, fasting vs. fed exercise, 263, 264
9, 11–17 “honeymoon” phase, 261, 262
Munan, M., 273 insulin management, 256–259
Murine models, 171, 177, 178 LADA, 253
Myocardial mitochondrial function, 99 late afternoon/evening exercise, 264
meals/snacks, 264
older adults, 263
N pregnancy, 262, 263
Narendran, P., 261 type 2 diabetes
National diabetes associations, 7 aerobic training, 265, 266, 270, 271
National/international guidelines, 5 age and duration of diabetes, 268, 269
Natriuretic peptide deficiency, 54, 60 breaking sedentary time, 267
Nerve conduction studies (NCS), 173 exercise timing, 273, 274
Neural network (NN) models, 308 heterogeneity, 268
Neuropathic pain, 180, 182–184 high-protein diet, 271
Neuropathic Pain Symptom Inventory (NPSI) HIIE, 266, 267
questionnaire, 182 hypoglycemia/hyperglycemia, 265
Non-alcoholic fatty liver disease identification, 265
(NAFLD), 95–97 Look AHEAD trial, 267
Nonparametric (NP) approach, 308 metformin, 271, 272
Nutrigenetics, 235, 236 obesity, body fat distribution, and
Nutrigenomics, 235, 236 sarcopenia, 269, 270
resistance training, 266, 270, 271
sex, 269
O speculations, 272, 273
Obesity, 174, 175, 269, 270 stages, 272
Omega-3 fatty acids, 74–76 Pories, W.J., 220
Oral glucose tolerance test (OGTT), 2 Postprandial glycemic response (PPGR),
Oral hypoglycemics, 214, 215 236, 237
Precision medicine, 2–5, 7
Precision nutrition, see Type 2 diabetes mellitus
P Prediabetes, 175, 176, 301
Pancreatic islet transplantation, 258 Pregnancy, 262, 263
Pancreatic steatosis, 102 Prevotella to Bacteroides (P/B ratio), 238
Pasquel, F.J., 199–207 Proprotein convertase subtilisin/kexin type 9
PCSK9 inhibitors, 23 (PCSK9) inhibitors, 69, 70
Personalized diets, 235, 241 Proton density fat fraction (PDFF), 96
Personalized medicine, 1
Personalized nutrition, see Type 2 diabetes
mellitus Q
Petrovski, G., 289–301 Quantitative sensory testing (QST), 180, 181
Pharmacotherapy, 214, 215
Physical activity
aerobic exercise, 251, 252 R
definition, 251 Real-time CGM (rt-CGM), 203, 291
HIIE, 252 REDUCE-IT trial, 74
resistance exercise, 252 Rein, M., 233–244
type 1 diabetes Reitmeier, S., 237
acute glycemic effects, 254–256 Relative risk (RR) reduction, 8
CGM/isCGM, 259 Renin-angiotensin system (RAS) inhibitors,
characteristics, 259–261 157, 158
Index 329
Resins, 23 GWAS, 111

Resistance exercise, 252 implementation, 122–124
Resistance training, 266, 270, 271 insulin-secreting beta cells, 318
Resting-state functional MR imaging monitoring, 115
(RS-fMRI), 184, 186, 187 physical activity
Riddell, M.C., 257, 258, 261, 264 acute glycemic effects, 254–256
Roden, M., 89–104 CGM/isCGM, 259
Roux-en-Y gastric bypass (RYGB), 219, 220 characteristics, 259–261
Run-to-run (R2R) approach, 309 children and adolescents, 262
classification, 252
exercise training and habitual physical
S activity, 253, 254
Sarcopenia, 269, 270 fasting vs. fed exercise, 263, 264
Saturated fatty acids (SFA), 96 “honeymoon” phase, 261, 262
Savikj, M., 273 insulin management, 256–259
Scandinavian Simvastatin Survival Study (4S LADA, 253
study), 67 late afternoon/evening exercise, 264
Schrauwen–Hinderling, V.B., 89–104 meals/snacks, 264
Scott, E.S., 1–5, 8, 9, 14, 18–34 older adults, 263
Screening, TReating to target, Infection, pregnancy, 262, 263
Vaccination, Education, and PMDI, 114
Devices (STRIVED), 8 prevention, 114, 115
Selvarajah, D., 171–189 prognostics, 116, 117
Short-chain fatty acids (SCFA), 238 treatment, 115, 116
Skyler, J.S., 315–319 Type 2 diabetes (T2D), 173, 300, 301
SMBG, 292 biomarkers, 112
Sodium-glucose cotransporter-2 (SGLT2) biomedical information, 113
inhibitors, 59, 60, 156, 157 consensus report, 112
Stino, A.M., 171–189 diagnosis, 117, 118
Subcutaneous insulin delivery, 310 GWAS, 111
Superficial subcutaneous adipose tissue implementation, 122–124
(SSAT), 91 monitoring, 118, 119
Systems biology, 200, 201 physical activity
aerobic training, 265, 266, 270, 271
age and duration of diabetes,
T 268, 269
T4DM trial, 8 breaking sedentary time, 267
Technology-mediated interventions, 8 exercise timing, 273, 274
Telomeres, 4 heterogeneity, 268
Tesfaye, S., 171–189 high-protein diet, 271
Thaiss, C.A., 239 HIIE, 266, 267
Thiazolidinediones, 77 hypoglycemia/hyperglycemia, 265
Toffanin, C., 305–311 identification, 265
Toll-like receptors (TLRs), 178 Look AHEAD trial, 267
Twin cycle hypothesis, 211, 212 metformin, 271, 272
Twin pandemic, 217 obesity, body fat distribution, and
2-aminoadipic acid (2-AAA), 239 sarcopenia, 269, 270
Type 1 diabetes (T1D), 173, 300 resistance training, 266, 270, 271
automated insulin delivery, 315, 316 sex, 269
beta-cell function, 316, 317 speculations, 272, 273
beta-cell regeneration, 319 stages, 272
biomarkers, 112 PMDI, 114
biomedical information, 113 prevention, 118
consensus report, 112 prognostics, 120–122
diagnosis, 114 treatment, 119, 120
330 Index
Type 2 diabetes mellitus (T2DM) V

challenges, 242–244 Van Proeyen, K., 274
clinical practice, 242 Vertical sleeve gastrectomy (VSG), 219, 220
deep monitoring Very-low-calorie diet (VLCD), 15
mobile technologies, 240, 241 Very-low-density lipoprotein (VLDL), 66
wearable devices, 241, 242 Veterans Affairs Diabetes Trial (VADT), 20
deep phenotyping Visceral adipose tissue (VAT), 90
metabolomics, 238–240
microbiome, 236–238
nutrigenetics, 235, 236 W
nutrigenomics, 235, 236 Weight loss, 215, 224
dietary recommendations, 243 Wu, H., 237
prevention and management, 243 Wycherley, T.P., 271
remission
definition, 211
narrow time window, 212 Y
negative energy balance, 212–214 Yardley, J.E., 251–275
pharmacotherapy, 214, 215 Yoyo effect, 239
twin cycle hypothesis, 211, 212
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

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Precision

ISBN 978-3-030-98926-2 ISBN 978-3-030-98927-9 (eBook)

© Springer Nature Switzerland AG 2022

Precision medicine is gaining a lot of attention in clinical practice, particularly with

Lastly, I wish to dedicate this book to my father, a dedicated physician himself

Charlottesville, VA, USA Rita Basu

1 Precision Medicine Approaches for Management

11 Surgical Management for Diabetes Remission���������������������������������������� 217

Ethan Alexander Divisions of Endocrinology, Metabolism and Genetics,

Claudio Cobelli Department of Woman and Child’s Health, University of Padova,

Emma S. Scott NHMRC Clinical Trials Centre, University of Sydney, Sydney,

Precision Medicine in Diabetes describes solid approaches to diagnosing and treat-

proportion of individuals starting kidney replacement therapy due to diabetes varies

functionality of continuous glucose monitoring (CGM) and continuous insulin infu-

David Chen, Jordan Fulcher, Emma S. Scott, and Alicia J. Jenkins

Personalized medicine, sometimes referred to as precision medicine, is defined as

© Springer Nature Switzerland AG 2022 1

Diabetes is pandemic, currently affecting 9.3% of the global population aged

The Metabolic Milieu of Diabetes

Precision Medicine: Now and Later

T2D with progressive

T2D with micro- and/or

Fig. 1.1 The metabolic milieu of Type 2 diabetes

- Lifestyle modifications including the use of technology-assisted tools[82]

Diabetes (no complications)

Glucose - Aim for HbA1c ≤7% in most patients[110]

Screening[14] - HbA1c 4 times a year

†Prescribe with caution, especially in patients on insulin or sulfonylureas

Fig. 1.2 (continued)

 argeted Screening for Type 2 Diabetes

Mnemonic to Guide Diabetes Care

In pre-diabetes or Type 2 diabetes, it is important to address more than just glucose

Benefits of Multiple Risk Factor Control

Table 1.3 Cardiac and renal effects of novel glucose-lowering drugs

Table 1.4 Prevention of CVD complications in patients with Type 2 diabetes

Primary prevention Secondary prevention

Table 1.5 Prevention of microvascular complications in patients with Type 2 diabetes

Calorie restriction diets In motivated patients with short-duration Type 2 diabetes,

Table 1.8 (continued)

prospective evidence linking CGM-related glucose metrics to future complications

Personalizing Glucose Targets

Meta-analyses have shown substantially reduced risk of microvascular complica-

independence, and types of medications. Less stringent HbA1c targets should be

Rationale for Glucose Targets

Personalization of the intensity of glucose control is supported by some clinical tri-

Microvascular disease benefit Multiple trials have demonstrated benefits of better

Novel Glucose Control Agents

Individualizing Glucose-Lowering Medications

Lipids and Lipid Drugs

 ssociations Between Lipids, Diabetes, and Chronic

Adverse traditional lipid profiles, including elevated triglycerides, LDL-cholesterol

Statins and Diabetes Complications

Microvascular disease Statins’ effects on microvascular complications are less

Other LDL-Lowering Drugs

Most predominantly LDL-C-lowering drugs also have some triglyceride-lowering

Suggested Lipid Drug Use in People with Type 2 Diabetes

Hypertension is common in many non-diabetic populations, and its incidence is

10 mmHg reduction in systolic BP lowered all-cause mortality by 13%, CVD events

Recommended BP targets vary depending on the Type 2 diabetic patient’s cardio-

Selecting BP-Lowering Drugs

In patients with existing CVD or renal or retinal disease, angiotensin-converting

Confirm diagnosis of HTN

Consider & exclude secondary causes of HTN (5−10%)

Charlottesville, VA, USA Rita Basu

1 Precision Medicine Approaches for Management

11 Surgical Management for Diabetes Remission�� 217

The Metabolic Milieu of Diabetes

Precision Medicine: Now and Later

argeted Screening for Type 2 Diabetes

Mnemonic to Guide Diabetes Care

Benefits of Multiple Risk Factor Control

Personalizing Glucose Targets

Rationale for Glucose Targets

Novel Glucose Control Agents

Individualizing Glucose-Lowering Medications

Lipids and Lipid Drugs

ssociations Between Lipids, Diabetes, and Chronic

Other LDL-Lowering Drugs

Suggested Lipid Drug Use in People with Type 2 Diabetes

Selecting BP-Lowering Drugs

In an American Association of Diabetes Educators systematic review, diabetes self-

Management of Type 2 Diabetes Patients with Known CVD

Management of Arterial Disease and Heart Failure

anagement of Microvascular Complications in Type 2

Cardiovascular and Metabolic Cross-talk

Cardiovascular Complications of Diabetes

Coronary Artery Disease

Epidemiology and Burden of Diabetes and Heart Disease

Coronary Artery Disease

Management of Diabetes and Heart Disease

Do Statins Increase Newly Incident Diabetes?

Non-LDL Directed Medications

Omega-3 Fatty Acids

GLP-1 Receptor Agonists

ole of Noninvasive Imaging Techniques

I maging Tools for Assessing Body Composition and Adipose