for mbbs and md physiology students

1. DIABETES MELLITUS AND HYPOGLYCEMIA

4. Diabetes mellitus
Diabetes mellitus, commonly called just diabetes, refers to a clinical syndrome of
hyperglycaemia occurring due to deficiency of insulin.
Types and stages of diabetes mellitus
Diabetes mellitus can be classified into following types:
1. Primary diabetes mellitus in which the cause is not known. It is of further
two types:
• Insulin-dependent diabetes mellitus (IDDM) or type-I, and
• Noninsulin-dependent diabetes mellitus (NIDDM) or
type-II.
2. Secondary diabetes mellitus. It is associated with certain pathological
conditions such as pancreatitis, cystic fibrosis, acromegaly and Cushing
syndrome.

6. Stages in the development of diabetes mellitus include:
• Prediabetics or potential diabetics. These are the persons with normal blood glucose
level but are potential candidates to develop diabetes due to strong genetic
predispositions, e.g. first-degree relative of diabetics.
• Latent diabetics and chemical diabetics. These persons have normal fasting and
postprandial blood glucose levels and normal glucose tolerance test. But their blood
glucose becomes abnormally high during stress or after administration of
glucocorticoids.
• Clinical diabetics have hyperglycaemia, glycosuria and typical symptoms but without
complications
• Complicated diabetics are patients with longstanding neglected diabetes with multiple
complications.

9. Insulin-dependent diabetes mellitus or type-I
• Insulin-dependent diabetes mellitus (IDDM), or type-I diabetes, is considered an
autoimmune disorder in which antibodies destroy the β cells of islets causing an
absolute deficiency of insulin.
• Genetic susceptibility is a major determinant while environmental
factors act as a trigger.
• The current view regarding type-1 diabetes is that this is a T cellmediated
disease. The main genetic abnormality is in major histocompatibility complex (MHC)
gene located on chromosome 6, though other genes are also involved

13. Characteristic features of IDDM are:
• It manifests before 40 years of age (usually between 12 and 15 years) and is also
called juvenile onset diabetes.
It accounts for 10–20%.
• Patients are usually lean.
• Classical triad of presenting symptoms consisting of polyuria, polydipsia and
polyphagia is associated with weight loss.
• Ketosis and acidosis are common complications of this diabetes mellitus.
• Plasma insulin levels are very low or undetectable.

17. Non-insulin-dependent diabetes mellitus or type-II
Noninsulin-dependent diabetes mellitus (NIDDM) or type-II diabetes is also a genetic
disorder.
Overeating coupled with underactivity leading to obesity acts as a diabetogenic factor in
genetically predisposed individuals.
It is supposed to occur due to decrease in insulin receptors on the insulin-responsive
(target) cells.
In type-II diabetes, the genetic component is stronger compared to type-I.

20. Characteristic features of NIDDM are:
• It manifests after 40 years of age and so is also called as adult onset diabetes or
maturity onset diabetes in young (MODY).
• It is most common and accounts for 80–90% of diabetic population.
• Most of the patients are obese.
• Symptoms begin gradually and may be ignored and many a times diagnosis is made
on urine examination which shows glycosuria.
• Plasma insulin levels are often normal or even elevated.
• Ketoacidosis is not very common

21. Obesity (the metabolic syndrome)
The incidence of obesity is increasing; it relates to the discrepancy between energy
consumption and energy expenditure.
The risk of type-II diabetes increases 10-fold with body mass index (BMI) >30 kg/m2
(normal BMI 18.5–24.9 kg/m2).
The susceptibility to obesity and its adverse consequences vary.
Metabolic syndrome is mainly a glucose metabolism
disorder; therefore, it has special relation with diabetes mellitus.

24. As the body weight increases, there is increase in insulin resistance leading to
decreasing ability of insulin to move glucose into muscle and adipose
tissues, and glucose release from liver. Hence, obesity is associated with
hyperinsulinaemia, dyslipidaemia (increased level of circulating
triglycerides and HDL) and development of atherosclerosis.
The combination of these findings is commonly referred to as metabolic
syndrome or syndrome X.
The patients with this syndrome may present as prediabetic or full-fledged type-II
diabetes

25. Pathophysiology of diabetes mellitus
Pathophysiology of diabetes mellitus revolves around the metabolic alterations
associated with insulin deficiency.
Most important among them are hyperglycaemia, ketoacidosis, hypertriglyceridaemia
and protein catabolism
1. Hyperglycaemia and its consequences
Hyperglycaemia (elevation of blood glucose concentration) is the
characteristic feature of uncontrolled diabetes mellitus. It occurs due to
lack of insulin resulting in:
• Decreased peripheral utilization of glucose.
• Increased hepatic output of glucose (owing to glycogenolysis and gluconeogenesis)
into the circulation.

29. Consequences of hyperglycaemia are:
• Glycosuria and its consequences,
• Impaired phagocytic function,
• Hyperosmolar effects and
• Glycosylation of haemoglobin

31. i. Glycosuria and its consequences
• Glycosuria, i.e. excretion of glucose into the urine, occurs
when the blood glucose level rises above the renal threshold
point, i.e. above 180 mg/100 ml.
• Polyuria, i.e. passage of large amount of urine frequently. It is
the result of osmotic diuresis caused by renal excretion of
osmotically active glucose molecules.

32. • Loss of electrolytes (sodium, potassium and phosphate) in urine also
occurs as a side effect of osmotic diuresis.
• Cellular dehydration. High glucose concentration increases osmotic pressure of
extracellular fluid and osmotic transfer of water from cells to extracellular fluid leading
to dehydration of cells.
In addition to it, osmotic diuresis causes increased loss of water from the body there
by reducing extracellular fluid volume which also causes compensatory
dehydration of cells.
• Polydipsia, i.e. excessive drinking

33. Increased caloric loss is the result of loss of glucose in urine.
• Polyphagia, i.e. excessive eating, occurs due to stimulation of satiety
centre caused by deficient utilization of glucose in the hypothalamic
ventromedial nuclei.
Increased caloric loss also results in compensatory polyphagia.
• Loss of body weight occurs because of loss of calories in the urine and
mobilization of fats and proteins for energy production.
Since loss of body weight occurs in spite of excessive food intake, diabetes
is called a condition of starvation in the midst of plenty.

34. ii. Impaired phagocytic function.
Hyperglycaemia impairs all aspects of leucocytic phagocytic function, i.e.
adherence, diapedesis, phagocytosis and intracellular killing.
Because of impaired phagocytic function, diabetics are more prone to
infections compared with the nondiabetics.

35. iii. Hyperosmolar effects.
Osmolarity of the blood goes on increasing with the increasing blood sugar levels. With
the passage of time, a stage may come when glucose production is increased and
urinary excretion is decreased, and the plasma glucose level may increase up to 1000
mg%.
Under such circumstances the plasma osmolality may be over 375 mOsm/kg.
Such a high hyperosmolality may cause dehydration in central nervous system
leading to impairment of cerebral functions.
Ultimately, a condition called nonketotic hyperosmolar coma may result, which may be
even fatal.

36. Glycosylation of tissue proteins occurs when the blood glucose
levels remain elevated for a prolonged duration (years).
Glycosylation leads to irreversible changes in the chemical
structure of tissue proteins.
These chemical changes have been implicated in producing long-
term complications of diabetes mellitus, such as:
• Diabetic nephropathy,
• Diabetic retinopathy,
• Diabetic neuropathy and so on.

37. 2. Ketosis, hypertriglyceridaemia and their
consequences
Since due to insulin deficiency the utilization of glucose is poor, the body
turns to fats for obtaining energy by lipolysis.
Degree of lipolysis is directly proportional to the deficiency of insulin. As a result of
lipolysis, plasma levels of FFAs are increased. FFAs provide energy to the glucose
starved insulin-sensitive tissues like skeletal muscle.
Excessive FFAs in plasma leads to:
• Hypertriglyceridaemia and
• Ketosis.

38. Hypertriglyceridaemia.
Conversion of FFAs to triglycerides and secretion of VLDL and
chylomicrons is comparatively higher in diabetics.
Further, the activity of enzyme lipoprotein lipase is low in diabetic patients.
Consequently, the plasma levels of VLDL, and chylomicrons and
triglycerides are increased.
Hypercholesterolaemia is also frequently seen in diabetics.

39. Ketosis.
Utilization of fats beyond a certain point in the face of impaired
carbohydrate utilization leads to formation of ketone bodies in
excess.
Ketone bodies act as metabolic fuel in the liver. If production of
ketone bodies is more than their destruction, there occurs ketosis
or ketonaemia.

40. Consequences of ketosis include:
• Cellular dehydration. Ketone bodies being hyperosmolar remove water from the
cells producing cellular dehydration.
• Ketoacidosis. Ketone bodies being strong acids dissociate readily and release
H+ ions. In the blood, these H+ ions are buffered by bicarbonate ions (HCO3 −) to
form carbonic acid.
Fall in bicarbonate level in blood leads to acidosis called ketoacidosis.
Ketoacidosis develops rapidly in IDDM due to an absolute lack of insulin. This
is not commonly seen in NIDDM where there is partial or no loss of insulin (but
there is insulin resistance).

41. Features of ketoacidosis are:
• Rapid, deep respiration (dyspnoea, Kussmaul breathing),
• Acetone smell in patient’s breath and
• Urine becomes highly acidic.
• Electrolyte

42. Electrolyte loss. When capacity of kidney to replace plasma cations, accompanying the
organic anions with H1 and NH41 is exceeded, Na1 and K1 are lost in the urine.
The electrolyte and water loss further adds to cellular dehydration.
• Hypovolaemia and hypotension may ultimately result from water and
electrolytic loss and cellular dehydration.
• Coma and death. Depression of consciousness to the level of coma may eventually
ensure owing to marked acidosis and dehydration which
may finally lead to death.

43. 3. Protein catabolism
Insulin is an anabolic hormone, i.e. it promotes protein synthesis and it also inhibits
proteolysis.
Therefore, in diabetes, due to insulin deficiency, the protein anabolism is suppressed
and catabolism is increased. The amino acids released so are:
• Used in large amounts for energy production and
• Act as substrate for enhanced gluconeogenesis in liver promoted by
insulin deficiency.
.

44. consequences of suppression of protein anabolism and
increased catabolism include:
• Protein depletion in the body,
• Muscle wasting and
• Negative nitrogen balance.

45. Clinical features, complications and diagnosis of diabetes mellitus
After understanding the pathophysiology of diabetes mellitus, the
clinical features, complications and diagnosis of diabetes mellitus can be
understood easily.
Cardinal symptoms include polyuria, polydypsia, polyphagia and
weight loss. Occurrence of these symptoms have been explained in
pathophysiology.
Biochemical signs include hyperglycaemia, glycosuria, ketosis,
ketonuria and ketoacidosis. These have been fully elucidated in
pathophysiology.

47. Diagnosis of diabetes mellitus
In clinically suspected cases, diagnosis is confirmed by the following
investigations:
1. Urine examination for glycosuria.
This is a rapid, simple and easy test for diagnosis of diabetes mellitus.
Amount of glucose excreted in urine depends upon the severity of
disease.
Disadvantage. Glycosuria depends upon the renal threshold level which
itself is variable; hence, both overdiagnosis (false positive) and
underdiagnosis (false negative) of diabetes are possible. For example, a
nondiabetic individual with low renal threshold may pass glucose in
the urine (renal glycosuria), while on the other hand, a diabetic with
raised renal threshold will have a negative urine test for glucose.

48. 2. Urine examination for ketone bodies.
Presence of ketone bodies (acetone) in urine along with
glycosuria is almost diagnostic of diabetes mellitus. Other causes
of ketonuria arestarvation, prolonged fasting, following high fat
diet and after repeated vomiting.
3. Fasting and postprandial blood glucose
Levels. Samples for estimation of fasting blood glucose is taken
after
overnight fast and that for postprandial are taken after 2 h of
normal diet.
Normal values of plasma glucose are:
• Fasting: 70–110 mg% and
• Postprandial (after 2 h of meals): <140 mg%.

49. 4. Glucose tolerance test (GTT).
To perform this test, the patient is advised to have normal (unrestricted)
carbohydrate diet at least 3 days prior to test.
In the early morning, after an overnight fast, the fasting sample of blood
and urine are taken. Then 75.0 g of glucose dissolved in 300 ml (a glass)
of water is given orally, and blood and urine samples are collected every
half an hour for 2½–3 h.
Plasma glucose levels are plotted against the time scale and the graph so
obtained is known as glucose tolerance curve. The results are interpreted
as):

50. (x
• In a normal person, fasting plasma glucose levels range between 70 and 110 mg%,
after glucose intake. The peak value of about 140 mg% is reached in an hour or so
which returns to fasting level within 2–2½ h
. Urine does not show the presence of glucose.
• In diabetes mellitus, glucose tolerance curve is abnormal. Fasting glucose
level is high (≥126 mg%) after glucose intake peak is also high (≥200 mg%), and does
not return to fasting level for a long time (4–6 h).
. This slow fall of glucose level indicates failure to control due to
lack of insulin secretion following sugar ingestion.
• Impaired glucose tolerance. The fasting plasma levels between 110 and 126 mg% and
peak values (after glucose ingestion) between 140 and 200 mg% are classified as
impaired glucose tolerance). Suchpatients are potential candidates to develop diabetes
later on.

51. . Glycosylated haemoglobin: The rate of formation of HbA1C is directly
proportional to ambient blood glucose concentration; a rise of 1% HbA1C
fraction indicates an average increase of 2 mmol/L (36 g%) plasma
glucose.

53. Complications include:
• Predisposition to infections due to impaired
phagocytic function and protein depletion.
• Acute complications include ketotic coma and
nonketotic hyperosmolar coma

54. • Chronic complications include:
• Atherosclerosis, i.e. deposition of lipids underneath the
tunica intima of blood vessels.
The common sites are coronary, cerebral and peripheral
arteries.
It occurs due to longstanding hyperlipidaemia and
hypercholesterolaemia.
.

55. • Microangiopathy, a vascular lesion in which the capillary
basement membrane is thicker, probably due to structural
changes caused in tissue proteins by their glycosylation. It is
responsible for common complications of longstanding diabetes,
which includes:
• Diabetic retinopathy leading to blindness,
• Diabetic nephropathy leading to renal failure and
• Diabetic neuropathy involves autonomic nervous
system and peripheral nerves

66. Management of diabetes mellitus
Goals of therapy.
Goals of therapy of diabetes mellitus, irrespective of the type of diabetes are:
• To maintain blood glucose to normal or near normal,
• To maintain ideal body weight as far as possible,
• To keep the patient symptom free and
• To prevent or retard the onset of complications.
Treatment modalities
1. Dietary management may be required alone or in association with
drug therapy. Total energy intake should be specified to keep ideal body weight:
• Low energy and weight reducing diet is recommended for obese patients with
NIDDM.
• Weight maintenance diet is prescribed to nonobese patients with NIDDM.

67. 2. Oral hypoglycaemic agents (OHA) along with dietary
management is indicated in patients with NIDDM.
• OHA are divided into two groups: sulphonylurea and
biguanides.
More commonly used drugs belong to
second generation of sulphonylurea, e.g. glibenclamide.

68. 3. Insulin along with dietary management. Insulin is delivered by
injections with a very fine and sharp needle.
Indications of insulin use include:
• All patients with IDDM (juvenile onset diabetes),
• Newly detected diabetes with ketoacidosis,
• Emergencies associated with IDDM and NIDDM and
• Patients with NIDDM not controlled by oral
hypoglycaemic agents.

69. Types of insulin: Two types of insulin preparations (short acting and long
acting) are commercially available.
Regimens of insulin therapy include:
• Conventional regimen (single or two injections daily),
• Multiple subcutaneous injection regimen (3–4 injections
daily covering the major meals and snacks) and
• Continuous subcutaneous insulin is delivered by insulin
pump.

71. Gestational diabetes
During pregnancy, maternal glucose metabolism changes to meet
nutritional demand of developing fetus.
In second trimester of pregnancy, insulin resistance decreases and at the
same time renal threshold for glucose lowers.
• Gestational diabetes develops when pancreas is unable to secrete
insulin to compensate insulin resistance.
The risk factors include: obesity, family history of type-II diabetes.
.

72. Treatment include: strict glycaemic control is required by dietary
modification, particularly reducing consumption of refined
carbohydrates.
In patients with established diabetes, during pregnancy:
• Insulin doses must be increased.
• Monitoring is very essential, this includes:
• Frequent estimation of blood glucose including
postprandial measurements,
• HbA1C,
• Checks blood glucose periodically during night.
• Regular monitoring of fetus size and screening of fetal
abnormalities

73. Hypoglycaemia
Hypoglycaemia refers to a clinical condition caused by blood glucose
levels below 45 mg% (2.5 mmol/L). The human body has developed a
well-regulated system for an efficient maintenance of blood glucose
concentration.
However, still hypoglycaemia (though not common) is observed under
some circumstances.
Types and causes of hypoglycaemia
Broadly, hypoglycaemia may be divided into two types:
• Hypoglycaemia in nondiabetics and
• Hypoglycaemia in diabetics (more common).

74. A. Hypoglycaemia in nondiabetics
1. Postprandial hypoglycaemia, also known as reactive hypoglycaemia, occurs
typically after meals within 4 h after ingestion of food.
2. It is caused by transient rise in insulin levels, and symptoms are short lasting. It is
more common in patients who have undergone gastric resection.
In such patients, rapid movement of swallowed food into the intestine leads to
sudden and marked increase in insulin secretion.
The patients are advised to eat frequently rather than the three usual meals.

75. 2. Postabsorption or fasting hypoglycaemia usually does not
occur in normal fasting patients. It is seen in patients with:
• Insulin-secreting tumours (adenomas) of pancreatic islets
causing hyperinsulinism, which is a rare condition. Some
adenomas (15%) may be malignant.
• In some malignant tumours which do not involve pancreatic
islets but hypoglycaemia occurs because of increased secretion of
IGF-II.
• In hepatic failure, degradation of insulin is less which may result
in raised levels of insulin and hypoglycaemia.

76. • Hypoglycaemia also occurs in hyperthyroidism and patients who have
undergone gastrectomy.
Gastrectomy leads to rapid passage of food into the intestine resulting in
rapid absorption of glucose, though the plasma glucose level rises rapidly
but followed by a rapid fall (hypoglycaemia) due to rise in
insulin secretion.

77. 3. Hypoglycaemia due to alcohol intake.
In some individuals who are starved or engaged in prolonged exercise,
alcohol consumption may cause hypoglycaemia due to decreased
gluconeogenesis

78. B. Hypoglycaemia in diabetics.
Hypoglycaemia in diabetics is more common than in nondiabetics.
About 4% deaths of IDDM are said to be due to hypoglycaemia.
Causes of hypoglycaemia in diabetics include:
• Overdose of antidiabetic drugs, especially insulin, is comparatively a common cause
of hypoglycaemia. This occurs due to difficulty in adjusting the requirement of
antidiabetic agents.
This is particularly observed in patients who are on an intensive treatment regimen.
Other factors responsible for hypoglycaemia in patients on regular
antidiabetic treatment are:
• Intake of too little or no food,
• Heavy exercise,
• Mismatch between insulin administration and food
habits,
• Alcohol intake, etc.

79. Symptoms and signs of hypoglycaemia
Symptoms and signs of hypoglycaemia occur due to effects of low levels
of glucose per se (mainly on nervous system especially brain) and
because of sympathetic stimulation (mainly on CVS, GIT and skin).
1. CNS
symptoms are called neuroglycopenic symptoms. Since metabolism of brain
mainly depends on blood glucose level, it is depressed when glucose
level falls below 50–70 mg%.
CNS becomes quite excitable (due to facilitation of neuronal activity by
hypoglycaemia) which results into hallucinations, extreme nervousness, tremors,
confusion, difficulty in concentration, inco-ordination, convulsions, drowsiness and
cognitive dysfunctions.

80. When blood glucose levels fall further (<30 mg%),
hypoglycaemic coma may develop, which needs to
be differentiated from hyperglycaemic coma in
diabetics and needs an emergency treatment by
immediate administration of large quantity of
glucose intravenously

81. Management
Treatment of acute hypoglycaemia depends on its severity and whether
the patient is conscious and able to swallow. The emergency treatment of
hypoglycaemia includes:
• In mild cases: The subject can be self-treated by fast-acting oral
carbohydrate (10–15 g) is taken as glucose drink or tablet followed by
snack containing complex carbohydrates.
• In severe cases: External help is required. If the patient Is
semiconscious/unconscious, parenteral treatment is required as:
• Intravenous 75 ml 20% dextrose or intramuscular
glucagon (1 mg)
• If patient is conscious and able to swallow, give oral refined glucose as
drink or sweets (25 g) or supply glucose gel/jam/honey to buccal
mucosa.

82. Prevention of hypoglycaemia
• Patient’s education regarding potential causes and risk factor inducing
hypoglycaemia, and its treatment (accessible supply of glucose), and regular blood
glucose monitoring is fundamental to prevent potentially diagnosed side effect of
treatment.
• Relatives, friends should also need to be familiar with signs and symptoms of
hypoglycaemia and also instructed as to how a situation is to be managed.
2. CVS symptoms
in hypoglycaemia are palpitation, tachycardia and cardiac arrhythmias.
3. GIT symptoms
include nausea and vomiting.
4. Skin symptoms
are sweating and hypothermia