Chapter

Hypoglycemia: Essential Clinical

Guidelines
Thenmozhi Paluchamy

Abstract

Hypoglycemia is the acute complication of diabetes mellitus and the commonest

diabetic emergency and is associated with considerable morbidity and mortality.
It can be caused by too much insulin intake or oral hypoglycemic agents, too little
food, or excessive physical activity. The level of glucose that produces symptoms of
hypoglycemia varies from person to person and varies for the same person under
different circumstances. It characterized by sweating, tremor, tachycardia, palpita-
tion, nervousness, hunger, confusion, slurred speech, emotional changes, double
vision, drowsiness, sleeplessness, and often self-diagnosed which may leads to
serious symptoms of seizure, cognitive impairment, coma and death. The immedi-
ate treatment of hypoglycemia should be known by all the diabetic patients, so
that need for hospitalization could be avoided. Hypoglycemia and its severity can
be prevented by early recognition of hypoglycemia risk factors, self-monitoring
of blood glucose, selection of appropriate treatment regimens, appropriate educa-
tional programs for healthcare professionals. The major challenges of the treatment
of hypoglycemia are good glycemic control, minimize the risk of hypoglycemia and
thereby minimize long-term complications. Hence there is an urgent need to under-
stand the clinical spectrum and burden of hypoglycemia so that adequate control
measures can be implemented against this life-threatening complication.

Keywords: blood glucose, diabetes mellitus, glucagon, glycemic index,

hypoglycemia, insulin

1. Introduction

The blood sugar level, blood sugar concentration, or blood glucose level is the
amount of blood sugar level in the blood. Glucose is required for cellular respira-
tion and is the preferred fuel for all body cells. Plasma glucose concentration is the
balance between the rate of glucose entering the circulation and the rate of removal
of glucose from the circulation. Circulating glucose comes from intestinal absorp-
tion from the ingestion of carbohydrate during the fed state and by the process of
glycogenolysis, and gluconeogenesis in the fasting state. Glycogenolysis is the bio-
chemical breakdown of glycogen into glucose which takes place in the cells of the
muscle and liver in response to hormonal and neural signals. Gluconeogenesis is
the metabolic process of generation of glucose from non-carbohydrate substances
such as protein and fat which takes place in the liver and kidney in response to dia-
betogenic hormones. There are hormones involved in glucose regulation are called
glucoregulatory hormones which include insulin, glucagon, amylin, glucogan-like
peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), epinephrine,

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cortisol, and growth hormone. Among, insulin and amylin are secreted from the
β-cells of islets of Langerhans, glucagon from the α-cells of islets of Langerhans of
the pancreas, GLP-1 from the small intestine and colon, and GIP from upper small
intestine. If these glucoregulatory or counter-regulatory hormones fail to balance
the blood sugar level causes hypoglycemia or hyperglycemia.
Hypoglycemia, also called low blood glucose or low blood sugar, occurs when
the level of glucose in blood drops below normal. The term literally means “under-
sweet blood”. It may also be referred to as an insulin reaction, or insulin shock. This
condition typically arises from abnormalities in the mechanisms involved in glucose
homeostasis. Hypoglycemia is the commonest diabetic emergency and is associated
with considerable morbidity and mortality. The American Diabetes Association
defines the hypoglycemia as any abnormally low plasma glucose concentration
that exposes the subject to potential harm [1]. Hypoglycemia is common in insulin
dependent diabetic patients and may also occur in patients with non-insulin-
dependent diabetes mellitus. It can be caused by too much insulin intake or oral
hypoglycemic agents or too little food or excessive physical activity [2]. The other
causes or risk factors of hypoglycemia are dosage, combination of anti-diabetic
drugs, timing of consuming the drug and anti-diabetic drug with simultaneous use
of other interacting drugs. The symptoms of hypoglycemia depend on the level of
blood glucose and vary from one person to another person and also vary within the
same person under different circumstances [3]. It may range from a very mild with
minimal or no symptoms (60–70 mg/dl), to severe hypoglycemia, and neurological
impairment (<40 mg/dl) [4].

2. Prevalence of hypoglycemia in diabetes

Hypoglycemia is one of the most feared complications of diabetes treatment [5].

Individuals who take insulin, which includes all people with T1DM and some people
with type 2 diabetes, are prone to hypoglycemia [6]. Hypoglycemia commonly
occurs in clinical practice as approximately 90% of all patients who receive insulin
have experienced hypoglycemic episodes [7]. Furthermore, surveys investigating
the prevalence of hypoglycemia have provided some alarming results. The Diabetes
Control and Complication Trial (DCCT) reported a threefold increase in severe
hypoglycemia and coma in intensively treated T1DM patients versus convention-
ally treated patients [8]. A meta-analysis study reported that the prevalence of
hypoglycemia was 45% for mild/moderate and 6% for severe. Incidence of hypogly-
cemic episodes per person-year for mild/moderate and for severe was 19 and 0.80,
respectively. Hypoglycemia was prevalent among patients on insulin; among, the
prevalence of mild-moderate and severe hypoglycemia episodes was 50 and 21%,
respectively. Similarly, among patients on the treatment of sulfonylurea, the preva-
lence of mild-moderate and severe hypoglycemia was 30 and 5%. It was also found
5% of prevalence among those who did not include sulfonylureas in the treatment
regime [9].
A population-based study conducted in the UK to determine the frequency
and predictors of hypoglycemia in type one diabetic patients. The study findings
concluded that type 1 diabetes mellitus patients who are on intensive treatment
may experience up to 10 episodes of symptomatic hypoglycemia per week and
severe temporarily disabling hypoglycemia at least once a year [10]. It is estimated
that 2–4% of deaths occur in people with type 1 diabetes due to hypoglycemia [11].
Hypoglycemia is also equally common in type 2 diabetes, with prevalence rates of
70–80% [12]. Donnelly et al. who conducted a survey with 267 individuals with

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type 1 diabetes and insulin-treated type 2 diabetes to record hypoglycemic events

over a 4-week period and 155 individuals reported 572 incidents of hypoglycemia.
Of these, the rate of hypoglycemia events in type 1 diabetic was 43 per patient per
year whereas in type 2 diabetes was 16 events per patient per year. The predictor of
hypoglycemia for individuals with type 1 diabetes and insulin-treated type 2 diabe-
tes was a history of previous hypoglycemia and duration of insulin treatment [10].
Similarly other study findings also concluded that hypoglycemia occurs more often
than previously reported [12] in insulin-treated type 2 diabetes and with sufficient
frequency to cause significant morbidity.

3. Risk factors for hypoglycemia

Several factors influence an individual at risk (Table 1) for a hypoglycemic

episode. These include a mismatch in the timing, amount, or type of insulin,
skipping meals, eating small meal, irregular dietary pattern and lack of physical
activity. Additional factors such as alcohol consumption, obesity, elderly people,
liver disorders, renal disease, adrenal insufficiency (glucocorticoid or catechol-
amine deficiencies) and pituitary insufficiency and leukemia which increase the
risk for hypoglycemia. Other factors at risk are those who have ingested medi-
cation salicylates and those who have surgery with general anesthesia, which
places them in an altered state of consciousness and hyper-metabolic state [13].
Another potential risk for hypoglycemia is the use of β-blocker and ACE inhibi-
tor medication in cardiac and hypertensive patients which mask the symptoms of
hypoglycemia. β-Blockers inhibit the secretion of insulin and glycogenolysis due
to diminishing of adrenergic counter regulation and also conceal the symptoms
of catecholamine-mediated neurogenic hypoglycemia such as tremor, palpitation,
hunger, irritability and confusion. However sweating remains unmasked and may
be the only sign of patients treated with β-blockers [14].

Medical-related factors Lifestyle-related factors

• Strict glycemic control • Increased exercise (relative to usual)
• Previous history of severe hypoglycemia • Irregular lifestyle
• Long duration of type 1 diabetes • Alcohol
• Duration of insulin therapy in type 2 diabetes • Increasing age
• Lipohypertrophy at injection sites • Early pregnancy
• Impaired awareness of hypoglycemia • Breast feeding
• Severe hepatic dysfunction • No or inadequate blood glucose
monitoring
• Impaired renal function (including those patients requir-
Reduced carbohydrate intake/absorption
ing renal replacement therapy)
• Food malabsorption, e.g., gastroenteritis,
• Sepsis
coeliac disease
• Inadequate treatment of previous hypoglycemia
• Bariatric surgery involving bowel
• Terminal illness resection
• Cognitive dysfunction/dementia Other factors:
• Hypoglycemia unawareness
• Number of years since diabetes diagnosis
• Time since insulin initiated

Table 1.
Risk factors of hypoglycemia.

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4. Causes of hypoglycemia

Hypoglycemia is commonly occur in people with both type 1 and type 2 diabetes
taking insulin or certain oral hypoglycemic agents. The common causes of hypogly-
cemia are:

4.1 Insulin and oral hypoglycemic agents

Diabetes medications such as insulin and Sulfonylureas are the most common
causes of hypoglycemia in diabetic subjects [15]. Of these, Insulin is a definite
cause of low blood glucose. One reason why newer insulin are preferred over
NPH and regular insulin is that they are less likely to cause blood glucose lows,
particularly overnight. Insulin pumps may also reduce the risk for low blood
glucose. Accidentally injecting the wrong insulin type, too much insulin, or
injecting directly into the muscle instead of subcutaneous can cause low blood
glucose. The long-acting sulfonylureas such as glibenclamide and chlorprop-
amide are associated with more severe hypoglycemia than the shorter-acting
drugs [16]. Metformin was the most frequent used oral hypoglycemic agents
(66.4%) followed by sulfonylurea and the most prevalent combination therapy
was metformin/glibenclamide regimen (28.5%). The majority of patients treated
with metformin at the time when they were diagnosed with diabetes (45.3%).
Hypoglycemic episodes were most commonly reported adverse events with
insulin and gastric upset with oral hypoglycemic agents. 60.3% of the patients did
not follow regular blood glucose checkup [17]. Several reports reveal that various
pharmacological agents like metformin, rosiglitazone, etc., which have wide rang-
ing side effects, including weight gain, hypoglycemia and risk of coronary heart
disease [18]. Occasionally episodes of hypoglycemia may occur with metformin,
as the most commonly used anti-diabetic drug, due to an imbalance between food
intake and dose of metformin [19].

4.2 Food pattern

Eating foods with less carbohydrate than usual without reducing the amount of
insulin taken. Timing of insulin based on whether consumption of carbohydrates
is from liquids or solids which can affect blood glucose levels. Liquids are absorbed
much faster than solids, so timing the insulin dose to the absorption of glucose from
foods. The composition of the meal contains the amount of fat, protein, and fiber
which can also affect the absorption of carbohydrates.

4.3 Dietary habit

If meal is skip or delay, blood glucose could drop too low. Hypoglycemia also can
occur when asleep and have not eaten for several hours.

4.4 Drinking alcohol

Alcohol consumption increase the insulin secretion and makes the liver not to
release the glucose effectively into the blood circulation especially if have not eaten
enough food within around 6 h and also makes more difficulty to generate new glu-
cose by liver. Hypoglycemia occur overnight if fall asleep after consuming alcohol
without eating food among people with diabetes.

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4.5 Physical activity

Exercise has plays a vital role and has many potential health benefits. However
the exercise can lower blood glucose by utilizing glucose for energy. Nearly half
of the individual with diabetes mellitus who exercised an hour during the day
may experience a low blood glucose reaction overnight. The factors influencing
exercise induce hypoglycemia are the intensity, timing of exercise and dura-
tion. Hypoglycemia can occur during, 1–2 h after, or up to 17 h after exercise.
Endogenous insulin secretion is reduced up to 40–60% while doing moderate-
intensity exercise among non-diabetic individuals. Hence it is mandate that
decrease insulin dose or increase glucose intake is recommended before, during or
after exercise depending on the intensity of exercise to prevent exercise associated
hypoglycemia.
Additionally, recent studies have observed the cruel cycle of counter-regulatory
failure between exercise and hypoglycemia. Thus, subsequent two episodes of pro-
longed, moderate-intensity exercise can inhibit autonomic nervous system and neu-
roendocrine responses by 50%. Similarly, 40–50% of counter-regulatory responses
reduced during two episodes of antecedent hypoglycemia due to subsequent exercise
[20]. Hence, there is a greater risk of hypoglycemia during exercise among individu-
als who have had a previous episode of hypoglycemia. This may be prevented by
adjusting pre-exercise insulin dose, and consuming appropriate amounts of glucose.

4.6 Potential causes of in-patient hypoglycemia

Common causes of inpatient hypoglycemia are listed in Table 2. One of the most
serious and common causes of inpatient hypoglycemia are insulin prescription
errors including:

• Misreading poorly written prescriptions

• Confusing the insulin name with the dose

Treatment-related causes Glucose intake-related causes

• Inappropriate use of short acting insulin • Reduced carbohydrate intake than

normal
• Incorrect prescription and administration insulin or oral
hypoglycemic agent • Anorexia
• Mismatch between insulin/oral hypoglycemic therapy • Nausea and/or vomiting
and meal or enteral feed
• Nothing by mouth orders
• Acute withdrawal of long term steroid therapy
• Delay in serving food tray
• Recovery from stress of critical illness
• Poor coordination in meal and medica-
• Polypharmacy tion timing
• Mobilization after illness • Skipping of meal
• Amputation of limb
• Intravenous insulin infusion with or without glucose
infusion
• Failure to monitor blood glucose adequately especially on
Intravenous insulin infusion

Table 2.
Etiological factors of hypoglycemia.

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• Confusing the insulin strength with the dose

• Transcription errors

• Inappropriately withdrawing insulin using a standard insulin syringe

• Confusion between the prescription of a glucose and insulin infusion for

hyperkalemia and glucose and

• insulin infusion to blood glucose control

5. Physiology of glucose counter-regulation

The most metabolically active organ is brain and it is the first organ affected by
lower blood glucose level. The brain requires continuous supply of oxygen and glu-
cose to meet the needs of energy requirement as it does not store excess energy and
derives almost all of its energy from aerobic oxidation of glucose. Hence brain cells
are vulnerable to glucose deprivation and also cannot survive more than 5–6 min
without glucose. The sequence of counter-regulatory response will play significant
role when the blood glucose levels fall below 70 mg/dl to protect the brain from
further deterioration of effects of hypoglycemia.
Decline in Blood glucose levels below the physiological range may trigger hierar-
chically organized sequence of responses in the non-diabetic individual [21, 22]. It
includes release of neuroendocrine hormones or counter-regulatory or anti-insulin
hormones, stimulation of the autonomic nervous system (ANS), and manifestation
of neurogenic and neuroglycopenic symptoms. Pancreatic beta cells suppressed the
insulin secretion when blood glucose levels declines within the physiological range
results in reduction of peripheral glucose uptake and increase in hepatic glucose
production to prevent true hypoglycemia. In further, declining intra-islet insulin
plays an important role for the glucagon response to hypoglycemia by increase the
release of glucagon by pancreatic alpha cells [23–25] and pancreatic polypeptide
from the pancreas. Similarly catecholamines such as epinephrine secreted from
the adrenal medullae and norepinephrine from sympathetic postganglionic nerve
terminals and adrenal medulla. Cortisol from the adrenal cortex and growth
hormone from the anterior pituitary gland also triggered when blood glucose level
falls. The primary physiological fast acting hormones in response to hypoglycemia
are glucagon and epinephrine.
Glucagon hormones enhance endogenous glucose production by the process
of glycogenolysis and gluconeogenesis and generating glucose substrates such as
lactate, pyruvate, alanine, and glycerol. In addition, epinephrine also has similar
effects like glucagon in increase of endogenous glucose production and inhibition
of utilization of glucose in the peripheral tissue and converts the gluconeogenic
pathway. It can also stimulate net renal glucose production. However inhibition of
insulin secretion is the primary physiological defense against decrease blood glucose
and occurs at a plasma glucose concentration of less than 80 mg/dl. The response
of sympathetic nervous system against hypoglycemia is activated by both circulat-
ing catecholamines and direct innervation results in increased fat metabolism of
lipolysis in adipocytes which release free fatty acid. It is estimated that 25% of the
total defense against hypoglycemia by the contribution of free fatty acid. Cortisol
and growth hormone are metabolic defense which are released in response to pro-
longed hypoglycemia; but they have modest significant effect on glucose counter-
regulation during acute stage. The actions of these hormones are increasing glucose

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production and restraining glucose disposal after 4 h onset of hypoglycemia. It has

only 20% of counter-regulatory response compared to the action of epinephrine.
If counter-regulatory mechanism fails to maintain the glucose homeostasis and
blood glucose value of 3.0–3.5 mmol/l, may trigger the autonomic nervous system
mediated warning symptoms such as sweating, palpitation and hunger to warn sub-
jective awareness of hypoglycemia and provoke feeling of eating to improve blood
glucose level. If not consume adequate glucose during this stage, central nervous
deprives for glucose, neuroglycopenia develops and cognitive function declines.
Counter-regulatory responses to hypoglycemia also referred to as glycemic thresh-
olds and may be altered to higher plasma glucose levels following chronic hyper-
glycemia [26] or to lower plasma glucose levels following repeated hypoglycemia
[27–29]. On the whole, the magnitude of counter-regulatory function is decrease
with age 18 and is more obvious in male than in female [30].

6. Hypoglycemia and glycemic threshold

The glycemic threshold has a dynamic and significant role in the activation of
counter-regulatory physiological response against the low plasma glucose level [20].
Though the individuals have increased level of glycated hemoglobin (HbA1C) may
perceive the symptoms of hypoglycemia at higher blood individuals who undergo
intensive glucose level with diabetes [31]. It means sudden and rapid declines of
blood glucose from higher level to a lower but not too low and at this level brain
started reacting to change and release of counter-regulatory hormones. This
phenomenon is called “relative hypoglycemia” and it is self-limiting. Brain will
usually takes 2–4 weeks to readjust and to improve that relatively reduced circulat-
ing glucose levels [27, 31–34].
In contrast, among diabetic patients who are on the intensive treatment of
control of plasma glucose level may not perceive hypoglycemia until their plasma
glucose is considerably lower than the normal physiological glycemic thresholds
[33, 35]. The changes in this glycemic control are highly influenced chronically
by persistent hyperglycemia and acutely by antecedent hypoglycemia [12, 35–38].
Antecedent hypoglycemia is a condition caused by hypoglycemia itself which
impairs and reduces the reduced neuroendocrine and symptomatic responses
to subsequent hypoglycemia. An experimental study found that there is a sig-
nificant reduction in glucagon, epinephrine, cortisol, pancreatic polypeptide
responses to next-day of hypoglycemia among antecedent hypoglycemic patients
who experienced two episodes with the blood glucose level of 50 mg/dl. It was
also demonstrated that antecedent hypoglycemia reduced the neurogenic and
neuroglycopenic symptom responses [28]. In later another study investigated the
responses of metabolic and neuroendocrine on the effect of morning hypoglycemia
to subsequent afternoon hypoglycemia. The findings revealed that only one pro-
longed, moderate hypoglycemic episode can also blunt the substantial changes of
physiological counter-regulatory defense and the neurogenic and neuroglycopenic
symptom response to subsequent hypoglycemia [39].
This impaired counter-regulatory responses otherwise called as “hypoglycemia-
associated autonomic failure” causes reduced neuroendocrine counter-regulatory
responses to hypoglycemia and lowered glycemic thresholds for activation of physi-
ological defenses against hypoglycemia, which together lead to a condition called
hypoglycemic unawareness. During this stage, because of failure to trigger the
epinephrine secretion against severe drop in blood sugar, the individuals unaware of
hypoglycemic symptoms of sweating, palpitation, anxiety generated by epinephrine.
These symptoms are very significantly important to warn the individuals of the

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lowering blood glucose level. Same scenario happened in intensively treated type 1
and type 2 diabetic individuals due to shifting of glycemic threshold to lower plasma
glucose level [33, 39–42] which further limits the efforts to attain euglycemia [37, 38].

7. Clinical manifestations of hypoglycemia

Hypoglycemic signs and symptoms (Table 3) may occur unexpectedly and

suddenly depends on the blood glucose level and may also vary from one person to
another. The hyperglycemic individuals who have blood glucose level with 200 mg/dl
or greater may feel adrenergic hypoglycemic symptoms when blood glucose sud-
denly falls to 120 mg/dl or less. Whereas a person with usual blood glucose levels in
the low range may not experience symptoms when blood glucose slowly drops under
50 mg/dl and also patients who have had diabetes for many years have decreased
hormonal (adrenergic) response to hypoglycemia.
Hypoglycemic symptoms may manifest as neurogenic (autonomic) symptoms
and cholinergic-mediated symptoms. Low blood glucose level triggered the neu-
rogenic symptoms by activating the autonomic nervous system which releases
the catecholamines (norepinephrine and epinephrine) from the adrenal medullae
and acetylcholine from postsynaptic sympathetic nerve endings. Elevated epi-
nephrine levels leads the symptoms and signs of shakiness, palpitations, sweating,
nervousness, anxiety, pupil dilation, dry mouth, pallor. The cholinergic-mediated
symptoms are hunger, diaphoresis and paresthesia. However, only 20% of the total
neurogenic symptom was found during hypoglycemia among epinephrine infusion
in intensively and conventionally treated euglycemic type 1 diabetic individuals
which indicates that the symptoms of hypoglycemic is multifocal and is mainly
araised from efferent pathways of central nervous system [43].
Neuroglycopenic symptoms occur as a result of deprivation of glucose in the
brain cells during hypoglycemia. Neuroglycopenic symptoms are very difficult
to perceive by an individual rather it is most often recognized by family mem-
bers, friends and bystanders. These symptoms include irritability, confusion,
aphasia, paresthesias, ataxia, headache and the most severe symptoms are
seizures stupor, coma, and even death. It can also include transient focal neuro-
logical deficits such as diplopia, hemiparesis.

Autonomic symptoms Neuroglycopenic symptoms

Sweating Blurred vision

Tingling Difficulty speaking
Trembling Feeling faint
Feeling shaky Difficulty thinking
Feeling hungry Confusion
Palpitations Dizziness
Anxiety Feeling drowsy
Irritability

Autonomic signs Neuroglycopenic signs

Tachycardia Transient Focal Neurological Deficit occasionally

Increased systolic blood pressure
Pallor
Diaphoresis
Mydriasis

Table 3.
Signs and symptoms of hypoglycemia.

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Autonomic Neuroglycopenic General malaise

Sweating Confusion Headache

Palpitations Drowsiness Nausea
Shaking Odd behavior
Hunger Speech difficulty
Incoordination

Table 4.
Edinburgh hypoglycemia scale.

Neurogenic and neuroglycopenic symptoms are manifested by the activation of

the sympatho-adrenal system and brain’s glucose deprivation. The brain is continu-
ously depends on a circulating glucose for energy and for cognitive function. If
blood glucose levels fall causes cognitive dysfunction [44]. The 11 most commonly
reported symptoms were used to form the Edinburgh Hypoglycemia Scale [45] and
are reproduced in Table 4.

8. Levels of hypoglycemia

According to the blood glucose level and manifestation of signs and symptoms
in response to low blood glucose level, hypoglycemia can be categorized into Level I,
Level II and Level III or mild, moderate and severe hypoglycemia.

8.1 Level I (mild) hypoglycemia

The range of blood glucose level is 54–70 mg/dl. Symptoms include tremor,
palpitations, tachycardia, nervousness, sweating and hunger due to sympathetic
nervous system is stimulation.

8.2 Level II (moderate) hypoglycemia

The range of blood glucose level is 40–54 mg/dl. It may produce confusion,
irritation, inability to concentrate, headache, lightheadedness, memory loss,
numbness of the lips and tongue, slurred speech, lack of coordination, emotional
changes, drowsiness, and double vision, or any combination of these symptoms due
to impaired function of central nervous system.

8.3 Level III (severe hypoglycemia)

In severe hypoglycemia, the blood glucose level is less than 40 mg/dl. Central
nervous system function is impaired further. Symptoms may include disoriented
behavior, seizures, stupor, or loss of consciousness. During this stage they need help
from another as they unable to function because of physical and mental changes.

9. M
 echanisms of counter-regulatory responses to hypoglycemia in type
1 diabetes

Type 1 diabetes mellitus is otherwise called insulin dependent diabetes mellitus

which occur due to little production of insulin or no insulin from pancreatic beta-
cells characterized by hyperglycemia and its associated symptoms. The treatment
include for the management of diabetes mellitus is insulin, diet and exercise and

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lifestyle modification. Insulin helps to convert the glucose into glycogen and store
in the liver and muscles. If there is an imbalance between the insulin administration
and food intake leads to hypoglycemia. Physiologically glucagon will be secreted
by the pancreatic alpha-cells to convert the stored glycogen into glucose or from
non-carbohydrate substances. However in patients with type 1 diabetes for more
than years epinephrine is main physiological defense in response to hypoglycemia
because glucagon secretory response to hypoglycemia is irreversibly lost. In later,
epinephrine response to hypoglycemia also impaired unfortunately among patients
with type 1 diabetes undergoing intensive treatment of insulin and at greater risk
for recurrent hypoglycemia [46, 47]. There is more than 50% reduction in counter-
regulatory responses toward the future hypoglycemia due to repeated attack of
hypoglycemia which results in vicious cycle of iatrogenic hypoglycemia-associated
autonomic failure and also subsequent hypoglycemia may also leads to anteced-
ent hypoglycemia. Even short durations 20 minutes of antecedent hypoglycemia
can produce significant impairment in counter-regulatory responses and also two
episodes of hypoglycemia of 70 mg/dl can also blunt subsequent counter-regulatory
responses by ∼30% in men [48]. Patient may experience severe and significant
clinical consequences due to reduced adrenergic sensitivity of poor tissue respon-
sive to circulating epinephrine and deficient responses of glucagon with reduction
in ANS counter-regulatory responses. These patients also had reduced β-adrenergic
sensitivity compared to patients with normal counter-regulatory responses to
hypoglycemia and healthy control subjects [49] and had reduced whole-body tissue
sensitivity to epinephrine, which was exacerbated by intensive glycemic control.
This reduced tissue responsiveness to epinephrine is an additional contributor to
the syndrome of hypoglycemia-associated autonomic failure and reduced tissue
sensitivity to epinephrine resulted in decrease endogenous glucose production and
less inhibition of insulin-stimulated glucose uptake. Despite with persistent blunted
epinephrine response to hypoglycemia, hypoglycemic symptom and β-adrenergic
sensitivity responses increase [50] to restore the endocrine and autonomic function.
Although controversial, other studies have also stated that with strict avoidance of
antecedent hypoglycemia some or all of the features of hypoglycemia-associated
autonomic failure can be reversed [51–53].

9.1 Mechanisms of counter-regulatory responses to hypoglycemia in type 2

diabetes

Type 2 diabetes mellitus is a heterogeneous group of disease caused by inadequate

secretion of insulin or improper utilization of secreted insulin or both. It may the
affect all groups of people from children to older adults. Children are more com-
monly affected nowadays due to rise in childhood obesity. Treatment regime includes
diet, exercise, oral hypoglycemic agents, glucagon like peptide-1 analogs, insulin,
or combination of these and varies depending on the response to treatment and
progressive β-cell failure [54]. The symptoms of hypoglycemia associated autonomic
failure among type 2 diabetes depends on age, treatment modality (diet versus oral
hypoglycemic agents versus insulin), comorbidity, body fat composition, metabolic
control, and the presence of diabetic neuropathies [54, 55]. However, neuroendo-
crine contributes in glycemic responses to hypoglycemia in advanced type 2 diabetes.
The glucagon response to low blood glucose level was also absent in advanced
insulin-treated type 2 diabetes. Autonomic and symptomatic responses by glycemic
threshold to hypoglycemia were also altered to lower plasma glucose concentrations
by recent antecedent hypoglycemia. Hence, the risk for hypoglycemia-associated
autonomic failure was high in advanced type 2 diabetes as like those with type 1
diabetes and leads to harmful cycle of recurrent iatrogenic hypoglycemia [46, 55].

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10. Inborn errors of metabolism causing hypoglycemia

Non-diabetic hypoglycemia also results from inborn errors of metabolism.

Such hypoglycemia most commonly occurs in infancy but can also occur in adult-
hood. Cases in adults can be classified into those resulting in fasting hypoglycemia,
postprandial hypoglycemia, and exercise-induced hypoglycemia.

10.1 Fasting (postabsorptive) hypoglycemia

It is rare; disorders of glycogenolysis can result in fasting hypoglycemia. These

disorders include glycogen storage disease (GSD) of types 0, 1, 3, and 4 and
Fanconi-Bickel syndrome.

10.2 Patients with GSD

Type 1 and 3 characteristically have high blood lactate levels before and after
meals, respectively. Both groups have hypertriglyceridemia, but ketones are high
in GSD type 3. Defects in fatty acid oxidation also result in fasting hypoglyce-
mia. These defects can include (1) defects in the carnitine cycle; (2) fatty-acid
β-oxidation disorders; (3) electron transfer disturbances; and (4) ketogenesis
disorders. Finally, defects in gluconeogenesis (fructose-1, 6-biphosphatase) have
been reported to result in recurrent hypoglycemia and lactic acidosis.

10.3 Postprandial (reactive) hypoglycemia

Inborn errors of metabolism resulting in postprandial hypoglycemia are also

rare. These errors include (1) glucokinase, SUR1, and Kir6.2 potassium channel
mutations; (2) congenital disorders of glycosylation; and (3) inherited fructose
intolerance.

10.4 Exercise-induced hypoglycemia

Exercise-induced hypoglycemia, by definition, follows exercise. It results in

hyperinsulinemia caused by increased activity of monocarboxylate transporter 1 in
β cells.

11. Accidental, surreptitious, or malicious hypoglycemia

Hypoglycemia caused by endogenous hyperinsulinism due to functional β-cell

disorders, insulinoma, or the insulin autoimmune syndrome is called as accidental,
surreptitious, or malicious hypoglycemia. It may also occur by accidental admin-
istration of insulin, or accidental ingestion of an insulin secretagogue such as
sulfonylurea because ingestion of an insulin secretagogue causes hypoglycemia with
increased C-peptide levels and hypoglycemia caused by exogenous insulin with
decrease C-peptide levels reflecting suppression of insulin secretion.

12. Assessment and diagnostic methods

• History collection

• Physical examination

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• Diagnostic investigation: It includes

• Glucose—fasting and postprandial blood glucose

• Complete blood count

• Insulin

• C-peptide

• Beta-hydroxybutyrate

• Proinsulin

• Antibodies for insulin and its receptors

• Sulfonylurea and meglitinide screen

• Electrolytes, BUN/Cr, UA

• liver function tests,

• cortisol and thyroid levels, growth hormone level

• Other tests: CT and MRI

Whipple triad is the clinical presentation of pancreatic insulinoma and consists

of: fasting hypoglycemia (<50 mg/dl), symptoms of hypoglycemia, immediate
relief of symptoms after the administration of IV glucose.

13. Management of hypoglycemia

The aim of the treatment includes correction of glucose deficiency, prevent the
complication associated with hypoglycemia and treat the underlying the cause.
Treat the patient in the emergency department as shown in the Figure 1.

• History collection and physical examination

• Check the blood glucose—capillary blood glucose

• Assess the mental status of the client

• Access intravenous line if needed

• Monitor blood glucose level

• Administer 15 g of fast acting glucose in the form of glucose tablets or glucose

containing fluids, candy or food. For, e.g., three or four commercially prepared
glucose tablets; 4–6 oz. of fruit juice or regular soda, 6–10 hard candies, 2–3
tsp. of sugar or honey is appropriate if the patient is able to take orally

• Check for blood glucose 15 min later.

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Figure 1.
Schematic representation of emergency management of hypoglycemia.

• Instruct the patient to eat protein and carbohydrate containing snack to

maintain their blood glucose after 60 min if the blood glucose is higher than
70 mg/dl

• Treatment is repeated with 15 g of carbohydrates if glucose level is remains

less than 70 mg/dl after the initial intake of 15 g of glucose. It may be probably
repeated up to 1–3 times

• Instruct the patient to avoid adding more table sugar to juice, even “unsweet-
ened” juice, which may cause a sudden increase in glucose, resulting in hyper-
glycemia in later hours.

• Administer parenteral therapy with 25% dextrose if unable to take oral foods

• Administer inj. glucagon 1.0 mg subcutaneous/intramuscular can be used

especially in type 1 diabetes mellitus.

• The somatostatin analog octreotide can be used to suppress insulin secretion in

sulfonylurea-induced hypoglycemia.

• Identify and treat the underlying cause

13.1 Management of hypoglycemia in the unconscious patient

• Assessment of glasgow coma scale

• Monitor airway, breathing, circulation

• Constant monitoring of blood glucose level

• Administer 1 g of glucagon subcutaneously or intravenously

• Administer 50% dextrose in 25–50 mL of water intravenously

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Blood Glucose Levels

• Check the patient for regaining from the state of unconsciousness. If hypogly-
cemic state extends for more than 5 h results in profound hypoglycemia which
may cause permanent brain damage.

• Administer IV Mannitol and dexamethasone, IV glucose with constant glucose

monitoring to necessary until regain from the state of unconsciousness to
conscious and restore normal brain function

13.2 Management of non-diabetic hypoglycemia

Depend on the underlying etiology

• Discontinue the offending drugs or reduce their doses

• Treat the underlying critical illnesses

• Replace the cortisol and growth hormone if levels are deficient.

• Surgical, radiotherapeutic, or chemotherapeutic reduction of a non–islet cell

tumor.

• Surgical resection of an insulinoma is curative

• Medical therapy with diazoxide or octreotide can be used if resection is not

possible and in patient with a non-tumor beta cell tumor

13.3 Health education

• Consult with a dietitian to develop or adjust meal plan to maintain consistency

in carbohydrates at meals by calculating grams of carbohydrates so that plan
for medication and/or insulin.

• Self-monitoring of blood glucose to detect the episodes of hypoglycemia at

the earliest. Self-monitoring of blood glucose level should give an idea of what
makes the blood glucose level drop.

• Do not skip meal and balance the meal plan with insulin or oral hypoglycemic
agent.

• Quit alcohol and smoking.

• Maintain the body weight.

• Follow medication dose regularly.

• Avoidance of exercise while having the symptoms of hypoglycemia.

• Ingestion of carbohydrate especially rapidly absorbed glucose during the

symptoms of hypoglycemia.

• Remember and follow rule of 15 which means 15 g of glucose raise 50 mg/dl in

15 min during hypoglycemia state.

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• Intravenous glucose is the preferable treatment of severe hypoglycemia, par-

ticularly that caused by a sulfonylurea.

• Keeping the hypo box hypoglycemic kit which contains glucose, glucagon, juice,
etc.

• Instructing the family members and care givers about usage this kit, check for
expiry date and replacing the used content in the kit.

• Always carry the sweetener which contains easily absorbable simple sugar and
identity card.

• Regular check-up and follow-up care.

14. Conclusion

Hypoglycemia is a common, potentially avoidable consequence of diabetes

treatment. This chapter emphasis on causes and risk factors of hypoglycemia,
recognition of symptoms of hypoglycemia, glucose regulatory and counter regula-
tory mechanism, management and prevention of hypoglycemia thereby prevent the
potential complications of hypoglycemia. Health care professionals have a major
role in educating clients with diabetes mellitus about hypoglycemia and to follow
their hypoglycemia management plan while caring the clients.

Acknowledgements

The author would like to thank the IntechOpen publishers for offering me an
opportunity to write the chapter on Hypoglycemia.

Conflict of interest

The author declares no conflict of interest.

Author details

Thenmozhi Paluchamy
Saveetha College of Nursing, SIMATS, Chennai, Tamil Nadu, India

*Address all correspondence to: [email protected]

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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Blood Glucose Levels

References

[1] Workgroup on Hypoglycemia, et al. Prevalence and incidence of

American Diabetes Association. hypoglycaemia in 532,542 people with
Defining and reporting hypoglycemia type 2 diabetes on oral therapies and
in diabetes: A report from the American insulin: A systematic review and meta-
Diabetes Association Workgroup analysis of population based studies.
on hypoglycemia. Diabetes Care. PLoS One. 2015;10(6):e0126427. DOI:
2005;28:1245-1249 10.1371/journal.pone.0126427

[2] Hinkle JL. Brunner and Siddarth’s [10] Donnelly LA, Morris AD, Frier
Textbook of Medical-Surgical Nursing. BM, et al. Frequency and predictors of
13th ed. Philadelphia, PA: Wolters Kluwer hypoglycaemia in type 1 and insulin-
Health Publication; 2014. pp. 862-865 treated type 2 diabetes: A population-
based study. Diabetic Medicine.
[3] Metchich LN, Petit WA, Inzucchi 2005;22(6):749-755
SE. The most common type of
hypoglycemia is insulin-induced [11] Laing SP, Swerdlow AJ, Slater SD,
hypoglycemia in diabetes. The American Botha JL, Burden AC, Waugh NR, et al.
Journal of Medicine. 2002;113:317-323 The British Diabetic Association Cohort
Study. II. Cause-specific mortality
[4] American Diabetes Association. in patients with insulin-treated
Hospital admission guidelines for diabetes mellitus. Diabetic Medicine.
diabetes (position statement). Diabetes 1999;16:466-471
Care. 2004;27(Suppl. 1):S103
[12] The U.K. Prospective Diabetes Study
[5] Briscoe VJ, Davis SN. Hypoglycemia Group. Intensive blood-glucose control
in type 1 and type 2 diabetes: with sulfonylureas or insulin compared
Physiology, pathophysiology, and with conventional treatment and risk
management. Clinical Diabetes. of complication in patients with type 2
2006;24(3):115-121 diabetes. Lancet. 1998;352:837-853

[6] Dajkovich G, Barkley TW Jr. [13] Cryer PE. Glucose homeostasis

Understanding insulin pump therapy. and hypoglycemia. In: Larsen RP,
Journal of Community Health Nursing. Kronenberg HM, Melmed S, Polonsky
2015;32(3):131-140 KS, editors. Williams Textbook of
Endocrinology. 10th ed. Vol. 88. St.
[7] Cryer PE. Hypoglycemia: Louis, MO: WB Saunders; 2003.
Pathophysiology, Diagnosis, and pp. 1589-1590
Treatment. New York, NY, USA: Oxford
University Press; 1997 [14] Adler E, Paauw D. Medical myths
involving diabetes. Primary Care.
[8] The Writing Team for the Diabetes 2003;30:607-618
Control and Complications Trial/
Epidemiology of Diabetes Interventions [15] Malouf R, Brust JC. Hypoglycemia:
and Complications Research Group. Causes, neurological manifestations,
Effect of intensive therapy on the and outcome. Annals of Neurology.
microvascular complications of 1985;17:421-430
type 1 diabetes mellitus. JAMA.
2002;287(19):2563-2569 [16] Stahl M, Berger W. Higher incidence
of severe hypoglycaemia leading to
[9] Edridge CL, Dunkley AJ, Bodicoat hospital admission in type 2 diabetic
DH, Rose TC, Gray LJ, Davies MJ, patients treated with long-acting versus

16
Hypoglycemia: Essential Clinical Guidelines
DOI: http://dx.doi.org/10.5772/intechopen.86994

short-acting sulphonylureas. Diabetic [25] Ter Braak E, Appelman A, Erkelens

Medicine. 1999;16:586-590 D, van Haeften T. Glibenclamide
decreases glucagon release during
[17] Moradi M, Mousavi S. Drug mild hypoglycaemia. Diabetologia.
use evaluation of diabetes mellitus 1998;41(suppl 1):A68
in non-hospitalized patients.
International Journal of Pharmacy [26] Banarer S, McGregor VP, Cryer
and Pharmaceutical Sciences. PE. Intraislet hyperinsulinemia prevents
2016;8:337-341 the glucagon response to hypoglycemia
despite an intact autonomic response.
[18] Kalsi A, Singh S, Taneja N, Kukal Diabetes. 2002;51:958-965
S, Mani S. Current treatments for
type 2 diabetes, their side effects and [27] Boyle PJ, Schwartz NS, Shah
possible complementary treatments. SD, Clutter WE, Cryer PE. Plasma
International Journal of Pharmacy and glucose concentrations at the onset
Pharmaceutical Sciences. 2015;7:13-18 of hypoglycemic symptoms in
patients with poorly controlled
[19] Holstein A, Egberts EH. Risk diabetes and in non-diabetics. The
of hypoglycaemia with oral New England Journal of Medicine.
antidiabetic agents in patients with 1988;318:1487-1492
type 2 diabetes. Experimental and
Clinical Endocrinology & Diabetes. [28] Heller SR, Cryer PE. Reduced
2003;111:405-414 neuroendocrine and symptomatic
responses to subsequent hypoglycemia
[20] Diedrich L, Sandoval D, Davis SN. after 1 episode of hypoglycemia
Hypoglycemia associated autonomic in nondiabetic humans. Diabetes.
failure. Clinical Autonomic Research. 1991;40:223-226
2002;12:358-365
[29] Davis MR, Shamoon H.
[21] The DCCT Research Group. Counterregulatory adaptation to
Epidemiology of severe hypoglycemia in recurrent hypoglycemia in normal
the diabetes control and complications humans. The Journal of Clinical
trial. The American Journal of Medicine. Endocrinology and Metabolism.
1991;90:450-459 1991;73:995-1001

[22] Schwartz NS, Clutter WE, Shah [30] Davis SN, Fowler S, Costa F.
SD, Cryer PE. Glycemic thresholds for Hypoglycemic counterregulatory
activation of glucose counterregulatory responses differ between men and
systems are higher than the threshold women with type 1 diabetes. Diabetes.
for symptoms. The Journal of Clinical 2000;49:65-72
Investigation. 1987;79:777-781
[31] Zammitt NN, Frier BM.
[23] Mitrakou A, Ryan C, Veneman T, Hypoglycemia in type 2 diabetes.
et al. Hierarchy of glycemic thresholds Diabetes Care. 2005;28:2948-2961
for counterregulatory hormone
secretion, symptoms, and cerebral [32] McAuley V, Deary IJ, Freier BM.
dysfunction. The American Journal of Symptoms of hypoglycemia in people
Physiology. 1991;260:E67-E74 with diabetes. Diabetic Medicine.
2001;18:690-705
[24] Unger RH. The Berson memorial
lecture. Insulin-glucagon relationships [33] Amiel SA, Sherwin RS, Simonson
in the defense against hypoglycemia. DC, Tamborlane WV. Effect of intensive
Diabetes. 1983;32:575-583 insulin therapy on glycemic thresholds

17
Blood Glucose Levels

for counterregulatory hormone release. [42] Spyer G, Hattersley AT,

Diabetes. 1988;37:901-907 MacDonald IA, Amiel S, MacLeod KM.
Hypoglycaemic counterregulation at
[34] Korzon-Burakowska A, Hopkins normal blood glucose concentrations
D, Matyka K, Lomas J, Pernet A, in patients with well controlled type 2
Macdonald I, et al. Effects of glycemic diabetes. Lancet. 2000;356:1970-1974
control on protective responses against
hypoglycemia in type 2 diabetes. [43] Aftab-Guy D, Sandoval D,
Diabetes Care. 1998;21:283-290 Richardson MA, Tate D, Davis SN.
Effects of glycemic control on target
[35] Cryer PE, Davis SN, Shamoon H. organ responses to epinephrine in
Hypoglycemia in diabetes. Diabetes type 1 diabetes. American Journal
Care. 2003;26:1902-1912 of Physiology. Endocrinology and
Metabolism. 2005;289:E258-E265
[36] The DCCT Research Group. The
effect of intensive treatment of diabetes [44] Inkster B, Frier BM. The effects
on the development and progression of acute hypoglycaemia on cognitive
of long term complication in insulin- function in type 1 diabetes. The British
dependent diabetes mellitus. The Journal of Diabetes and Vascular
New England Journal of Medicine. Disease. 2012;12:221-226
1993;329:977-986
[45] Deary IJ, Hepburn DA, MacLeod
[37] Cryer PE. Hypoglycemia KM, Frier BM. Partitioning the
risk reduction in type 1 diabetes. symptoms of hypoglycaemia using
Experimental and Clinical multi-sample confirmatory factor
Endocrinology & Diabetes. analysis. Diabetologia. 1993;36:771-777
2001;109:S412-S423
[46] Cryer PE. Mechanisms of
[38] Cryer PE. Current concepts: Diverse hypoglycemia-associated autonomic
causes of hypoglycemia-associated failure and its component syndromes in
autonomic failure in diabetes. The diabetes. Diabetes. 2005;54:3592-3598
New England Journal of Medicine.
2004;350:2272-2279 [47] White NH, Skor A, Cryer PE,
Levandoski L, Dier DM, Santiago JV.
[39] Davis SN, Tate D. Effects Identification of type 1 diabetic patients
of morning hypoglycemia on at increased risk for hypoglycemia
neuroendocrine and metabolic during intensive therapy. The
responses to subsequent afternoon New England Journal of Medicine.
hypoglycemia in normal man. The 1993;308:485-491
Journal of Clinical Endocrinology and
Metabolism. 2001;86:2043-2050 [48] Davis SN, Shavers C, Mosqueda-
Garcia R, Costa F. Effects of differing
[40] Dagogo-Jack SE, Craft S, Cryer PE. antecedent hypoglycemia on subsequent
Hypoglycemia-associated autonomic counterregulation in normal humans.
failure in insulin-dependent diabetes Diabetes. 1997;46:328-1335
mellitus. The Journal of Clinical
Investigation. 1993;91:819-828 [49] Korytkowski MT, Mokan M,
Veneman TE, Mitrakou A, Cryer PE,
[41] Segel SA, Paramore DS, Cryer PE. Gerich JE. Reduced betaadrenergic
Defective glucose counterregulation in sensitivity in patients with type 1
type 2 diabetes (Abstract). Diabetes. diabetes and hypoglycemia unawareness.
2000;49:A131 Diabetes Care. 1998;21:1939-1943

18
Hypoglycemia: Essential Clinical Guidelines
DOI: http://dx.doi.org/10.5772/intechopen.86994

[50] Fritsche A, Stefan N, Haring H,

Gerich J, Stumvoll M. Avoidance of
hypoglycemia restores hypoglycemia
awareness by increasing betaadrenergic
sensitivity in type 1 diabetes. Annals of
Internal Medicine. 2001;134:729-736

[51] Cranston I, Lomas J, Maran A,

Macdonald I, Amiel SA. Restoration
of hypoglycemia awareness in patients
with long-duration insulin-dependent
diabetes. Lancet. 1994;344:283-287

[52] Fanelli C, Pampanelli S, Epifano L,

Rambotti AM, Ciofetta M, Modarelli
F, et al. Relative roles of insulin
and hypoglycemia on induction of
neuroendocrine responses to, symptoms
of, and deterioration of cognitive
function in hypoglycemia in male
and female humans. Diabetologia.
1994;37:797-807

[53] Dagogo-Jack S, Rattarasarn C,

Cryer PE. Reversal of hypoglycemia
unawareness, but not defective glucose
counterregulation, in IDDM. Diabetes.
1994;43:1426-1434

[54] de Galan BE, Hoekstra JBL. Glucose

counterregulation in type 2 diabetes
mellitus. Diabetic Medicine.
2001;18:519-527

[55] Segel SA, Paramore DS, Cryer PE.

Hypoglycemia-associated autonomic
failure in advanced type 2 diabetes.
Diabetes. 2002;51:724-732

19