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Hypoglycemia
Hypoglycemia
Abstract
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].
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Hypoglycemia: Essential Clinical Guidelines
DOI: http://dx.doi.org/10.5772/intechopen.86994
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:
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].
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.
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.
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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Hypoglycemia: Essential Clinical Guidelines
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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.
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:
Table 2.
Etiological factors of hypoglycemia.
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• Transcription errors
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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Hypoglycemia: Essential Clinical Guidelines
DOI: http://dx.doi.org/10.5772/intechopen.86994
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].
Table 3.
Signs and symptoms of hypoglycemia.
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Hypoglycemia: Essential Clinical Guidelines
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Table 4.
Edinburgh hypoglycemia scale.
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.
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.
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.
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
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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].
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Hypoglycemia: Essential Clinical Guidelines
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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.
• History collection
• Physical examination
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• Insulin
• C-peptide
• Beta-hydroxybutyrate
• Proinsulin
• Electrolytes, BUN/Cr, UA
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.
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Figure 1.
Schematic representation of emergency management of hypoglycemia.
• 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
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• 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.
• Do not skip meal and balance the meal plan with insulin or oral hypoglycemic
agent.
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Hypoglycemia: Essential Clinical Guidelines
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• 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.
14. Conclusion
Acknowledgements
The author would like to thank the IntechOpen publishers for offering me an
opportunity to write the chapter on Hypoglycemia.
Conflict of interest
Author details
Thenmozhi Paluchamy
Saveetha College of Nursing, SIMATS, Chennai, Tamil Nadu, India
© 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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