Hypoglycemia

When the blood glucose concentration falls to less than 45 mg/dl, the symptoms
of hypoglycemia appear. The manifestations include headache, anxiety,
confusion, sweating, slurred speech, seizures and coma, and, if not corrected,
death. All these symptoms are directly and indirectly related to the deprivation
of glucose supply to the central nervous system (particularly the brain) due to a
fall in blood glucose level.
The mammalian body has developed a well regulated system for an efficient
maintenance of blood glucose concentration (details already described).
Hypoglycemia, therefore, is not commonly observed. The following three types
of hypoglycemia are encountered by physicians.
1. Post-prandial hypoglycemia : This is also called reactive hypoglycemia and
is observed in subjects with an elevated insulin secretion following a meal.
This causes transient hypoglycemia and is associated with mild symptoms.
The patient is advised to eat frequently rather than the 3 usual meals.
2. Fasting hypoglycemia : Low blood glucose concentration in fasting is not
very common. However, fasting hypoglycemia is observed in patients with
pancreatic β-cell tumor and hepatocellular damage.
3. Hypoglycemia due to alcohol intake : In some individuals who are starved
or engaged in prolonged exercise, alcohol consumption may cause
hypoglycemia. This is due to the accumulation of NADH (during the course
of alcohol metabolism by alcohol dehydrogenase) which diverts the pyruvate
and oxaloacetate (substrates of gluconeogenesis) to form, respectively, lactate
and malate. The net effect is that gluconeogenesis is reduced due to alcohol
consumption.
4. Hypoglycemia due to insulin overdose : The most common complication of
insulin therapy in diabetic patients is hypoglycemia. This is particularly
observed in patients who are on intensive treatment regime.
5. Hypoglycemia in premature infants : Premature and underweight infants
have smaller stores of liver glycogen, and are susceptible to hypoglycemia.

Classification of diabetes mellitus

Diabetes mellitus is a metabolic disease, more appropriately a disorder of fuel
metabolism. It is mainly characterized by hyperglycemia that leads to several
long term complications.
 Diabetes mellitus is broadly divided into 2 groups, namely insulin-dependent
diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus
(NIDDM). This classification is mainly based on the requirement of insulin for
treatment.

Insulin-dependent diabetes mellitus (IDDM)

IDDM, also known as type I diabetes or (less frequently) juvenile onset
diabetes, mainly occurs in childhood (particularly between 12–15 yrs age).
IDDM accounts for about 10 to 20% of the known diabetics. This disease is
characterized by almost total deficiency of insulin due to destruction of β-cells of
pancreas. The β-cell destruction may be caused by drugs, viruses or
autoimmunity. Due to certain genetic variation, the β-cells are recognized as
non-self and they are destroyed by immune mediated injury. Usually, the
symptoms of diabetes appear when 80–90% of the β-cells have been destroyed.
The pancreas ultimately fails to secrete insulin in response to glucose ingestion.
The patients of IDDM require insulin therapy.

Non-insulin dependent diabetes mellitus (NIDDM)

NIDDM, also called type II diabetes or (less frequently) adult-onset diabetes, is
the most common, accounting for 80 to 90% of the diabetic population. NIDDM
occurs in adults (usually above 35 years) and is less severe than IDDM. The
causative factors of NIDDM include genetic and environmental. NIDDM more
commonly occurs in obese individuals. Over-eating coupled with underactivity
leading to obesity is associated with the development of NIDDM. Obesity acts
as a diabetogenic factor and leads to a decrease in insulin receptors on the insulin
responsive (target) cells. The patients of NIDDM may have either normal or
even increased insulin levels. Many a times weight reduction by diet control
alone is often sufficient to correct NIDDM.
Recent research findings on NIDDM suggest that increased levels of tumor
necrosis factor-α (TNF-α) and resistin, and reduced seretion of adiponectin by
adipocytes of obese people cause insulin resistance (by impairing insulin
receptor function).
The comparison between IDDM and NIDDM is given in Table 36.2. (For
metabolic syndrome refer p-326)

Table 36.2
Comparison of two types of diabetes mellitus

Glucose Tolerance Test (GTT)

The diagnosis of diabetes can be made on the basis of individual's response to
oral glucose load, the oral glucose tolerance test (OGTT).

Preparation of the subject for GTT

The person should have been taking carbohydrate-rich diet for at least 3 days
prior to the test. All drugs known to influence carbohydrate metabolism should
be discontinued (for at least 2 days). The subject should avoid strenuous exercise
on the previous day of the test. He/she should be in an overnight (at least 10 hr)
fasting state. During the course of GTT, the person should be comfortably
seated and should refrain from smoking and exercise.

Procedure for GTT

Glucose tolerance test should be conducted preferably in the morning (ideal 9 to
11 AM). A fasting blood sample is drawn and urine collected. The subject is
given 75 g glucose orally, dissolved in about 300 ml of water, to be drunk in
about 5 minutes. Blood and urine samples are collected at 30 minute intervals for
at least 2 hours. All blood samples are subjected to glucose estimation while
urine samples are qualitatively tested for glucose.
Interpretation of GTT
The graphic representation of the GTT results is depicted in Fig.36.8. The
fasting plasma glucose level is 75–110 mg/dl in normal persons. On oral glucose
load, the concentration increases and the peak value (140 mg/dl) is reached in
less than an hour which returns to normal by 2 hours. Glucose is not detected in
any of the urine samples.

FIG. 36.8 Oral glucose tolerance test.

In individuals with impaired glucose tolerance, the fasting (110–126 mg/dl)

as well as 2 hour (140–200 mg/dl) plasma glucose levels are elevated. These
subjects slowly develop frank diabetes at an estimated rate of 2% per year.
Dietary restriction and exercise are advocated for the treatment of impaired
glucose tolerance.
The WHO criteria for the diagnosis of diabetes by OGTT is presented in
Table 36.3. A person is said to be suffering from diabetes mellitus if his/her
fasting plasma glucose exceeds 7.0 mmol/l (126 mg/dl) and, at 2 hrs. 11.1
mmol/l (200 mg/dl).

Table 36.3
Diagnostic criteria for oral glucose tolerance test (WHO 1999)

Other relevant aspects of GTT

1. For conducting GTT in children, oral glucose is given on the basis of weight
(1.5 to 1.75 g/kg).
2. In case of pregnant women, 100 g oral glucose is recommended. Further, the
diagnostic criteria for diabetes in pregnancy should be more stringent than
WHO recommendations.
3. In the mini GTT carried out in some laboratories, fasting and 2 hrs. sample
(instead of 1/2 hr. intervals) of blood and urine are collected.
4. The GTT is rather unphysiological. To evaluate the glucose handling of the
body under physiological conditions, fasting blood sample is drawn, the
subject is allowed to take heavy breakfast, blood samples are collected at 1
hour and 2 hrs (post-prandial—meaning after food). Urine samples are also
collected. This type of test is commonly employed in established diabetic
patients for monitoring the control.
5. For individuals with suspected malabsorption, intravenous GTT is carried
out.
6. Corticosteroid stressed GTT is employed to detect latent diabetes.

Glycosuria
The commonest cause of glucose excretion in urine (glycosuria) is diabetes
mellitus. Therefore, glycosuria is the first line screening test for diabetes.
Normally, glucose does not appear in urine until the plasma glucose
concentration exceeds renal threshold (180 mg/dl). As age advances, renal
threshold for glucose increases marginally.

Renal glycosuria
Renal glycosuria is a benign condition due to a reduced renal threshold for
glucose. It is unrelated to diabetes and, therefore, should not be mistaken as
diabetes. Further, it is not accompanied by the classical symptoms of diabetes.

Alimentary glycosuria
In certain individuals, blood glucose level rises rapidly after meals resulting in
its spill over into urine. This condition is referred to as alimentary (lag storage)
glycosuria. It is observed in some normal people, and in patients of hepatic
diseases, hyperthyroidism and peptic ulcer.

Metabolic changes in diabetes

Diabetes mellitus is associated with several metabolic alterations. Most
important among them are hyperglycemia, ketoacidosis and
hypertriglyceridemia (Fig.36.9).

FIG. 36.9 Major metabolic alterations in diabetes mellitus.

1. Hyperglycemia : Elevation of blood glucose concentration is the hallmark of

uncontrolled diabetes. Hyperglycemia is primarily due to reduced glucose
uptake by tissues and its increased production via gluconeogenesis and
glycogenolysis. When the blood glucose level goes beyond the renal
threshold, glucose is excreted into urine (glycosuria).
Glucose toxicity
High concentrations of glucose can be harmful causing osmotic effects/
hypertonic effects (water drawn from cells into extracellular fluid and excreted
into urine, resulting in dehydration), β-cell damage by free radicals (due to
enhanced oxidative phosphorylation, oxidative stress, and increased free
radicals) and glycation of proteins (associated with diabetic complications-
neuropathy, nephropathy, retinopathy etc.).
2. Ketoacidosis : Increased mobilization of fatty acids results in overproduction
of ketone bodies which often leads to ketoacidosis.
3. Hypertriglyceridemia : Conversion of fatty acids to triacylglycerols and the
secretion of VLDL and chylomicrons is comparatively higher in diabetics.
Further, the activity of the enzyme lipoprotein lipase is low in diabetic
patients. Consequently, the plasma levels of VLDL, chylomicrons and
triacylglycerols are increased. Hypercholesterolemia is also frequently seen
in diabetics.

Long term effects of diabetes

Hyperglycemia is directly or indirectly associated with several complications.
These include atherosclerosis, retinopathy, nephropathy and neuropathy. The
biochemical basis of these complications is not clearly understood. It is believed
that at least some of them are related to microvascular changes caused by
glycation of proteins.

Management of diabetes
Diet, exercise, drug and, finally, insulin are the management options in diabetics.
Approximately, 50% of the new cases of diabetes can be adequately controlled
by diet alone, 20–30% need oral hypoglycemic drugs while the remaining 20–
30% require insulin.

Dietary management
A diabetic patient is advised to consume low calories (i.e. low carbohydrate and
fat), high protein and fiber rich diet. Carbohydrates should be taken in the form
of starches and complex sugars. As far as possible, refined sugars (sucrose,
glucose) should be avoided. Fat intake should be drastically reduced so as to
meet the nutritional requirements of unsaturated fatty acids. Diet control and
exercise will help to a large extent obese NIDDM patients.
Hypoglycemic drugs
The oral hypoglycemic drugs are broadly of two categories-sulfonylureas and
biguanides. The latter are less commonly used these days due to side effects.
Sulfonylureas such as acetohexamide, tolbutamide and glibenclamide are
frequently used. They promote the secretion of endogenous insulin and thus help
in reducing blood glucose level.

Management with insulin

Two types of insulin preparations are commercially available—short acting and
long acting. The short acting insulins are unmodified and their action lasts for
about 6 hours. The long acting insulins are modified ones (such as adsorption to
protamine) and act for several hours, which depends on the type of preparation.
The advent of genetic engineering is a boon to diabetic patients since bulk
quantities of insulin can be produced in the laboratory.

Biochemical indices of diabetic control

For a diabetic patient who is on treatment (drug or insulin therapy), periodical
assessment of the efficacy of the treatment is essential. Urine glucose detection
and blood glucose estimations are traditionally followed in several laboratories.
In recent years, more reliable and long-term biochemical indices of diabetic
control are in use.

Glycated hemoglobin
Glycated or glycosylated hemoglobin refers to the glucose derived products of
normal adult hemoglobin (HbA). Glycation is a post-translational, nonenzymatic
addition of sugar residue to amino acids of proteins. Among the glycated
hemoglobins, the most abundant form is HbA1c.
HbA1c is produced by the condensation of glucose with N-terminal valine of
each β-chain of HbA.

Diagnostic importance of HbA1c

The rate of synthesis of HbA1c is directly related to the exposure of RBC to
glucose. Thus, the concentration of HbA1c serves as an indication of the blood
glucose concentration over a period, approximating to the half-life of RBC
(hemoglobin) i.e. 6–8 weeks. A close correlation between blood glucose and
HbA1c concentrations has been observed when simultaneously monitored for
several months.
Normally, HbA1c concentration is about 3–5% of the total hemoglobin. In
diabetic patients, HbA1c is elevated (to as high as 15%). Determination of HbA1c
is used for monitoring of diabetes control. HbA1c reflects the mean blood
glucose level over 2 months period prior to its measurement.
In the routine clinical practice, if the HbA1c concentration is less than 7%, the
diabetic patient is considered to be in good control.

Estimated average glucose(eAG)

eAG is a new term (introduced by American Diabetic Association) used in
diabetic management. It is a laboratory tool to understand the approximate
relationship between HbA1c and glucose concentrations, and is given by the
following formula

(e.g. for HBA1c values of 6%, 8% and 10%, the eAG values
respectively are 126 mg/dl, 183 mg/ dl and 240 mg/dl)

Biomedical/clinical concepts
Diabetes affects about 2–3% of the population and is a major
cause of blindness, renal failure, heart attack and stroke.
The hormone insulin has been implicated in the development of
diabetes.
Diabetic ketoacidosis is frequently encountered in severe
uncontrolled diabetics. The management includes administration
of insulin, fluids and potassium.
The hypoglycemic drugs commonly used in diabetic patients
include tolbutamide, glibenclamide and acetohexamide.
Measurement of glycated hemoglobin (HbA1c) serves as a marker
for diabetic control.