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DIABETIC MELLITUS
Diabetes mellitus is a clinical syndrome characterized by hyperglycemia due to absolute
or relative deficiency of insulin results to general metabolic impairment (metabolic
effect). Which is a 3rd leading causes of death in developing country and associated with
most causes of blindness, amputation, heart attack, renal failure and stroke
Hyperglycemia is the high plasma glucose level above the normal range, diabetic patient
present with chronic hyperglycemia due to insufficient or inefficient insulin activity.
Insulin is anabolic polypeptide hormone which produce by Beta-cells of islets of
Langerhans of pancreas which maintain level of blood glucose by increasing utilization
of glucose, inhibiting production and promote storage of glucose as glycogen.

CLASSIFICATION OF DIABETIC MELLITUS

There are two mainly type of diabetic mellitus
1. TYPE-1 DIABETES MELLITUS: also called
a. Immune mediated type-1 diabetes mellitus.
b. Idiopathic type-1 diabetes mellitus.
It is also called ‘insulin dependent diabetes mellitus’ (IDDM). In this type,
patients have absolute deficiency of insulin due to the destruction of beta cells of islets
of Langerhans of pancreas most due to autoimmune , virus , also drugs and pancreas is
ultimately fail to produce insulin.
This kind of diabetic mellitus is more severe than other types and appear early
in juvenile onset diabetic mellitus 12-15 years and patient with type 1 diabetic
mellitus need INSULIN THERAPY
2. TYPE-2 DIABETES MELLITUS:
It is also called ‘non-insulin dependent diabetes mellitus’ (NIDDM). In this
type, patients have relative deficiency of insulin most present with insulin resistance
which impaire with utilization of insulin in cell results to hyperglycemia with
associated metabolic effects

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THE CAUSES OF DIABETIC MELLITUS
1. GENETICS: involve in most concerning cause of both types of diabetic as follow
TYPE-1 DIABETES MELLITUS:
Genetic factors account for about one-third of the susceptibility to type-1 diabetes
mellitus. The inheritance of human type-1 diabetes mellitus is polygenic. About
50% of heritability is contributed by human leucocyte antigen (HLA) class-II
genes which are the main effector cells of the destructive autoimmune process.
HLA class-II antigens on the surface of cells present foreign and self-antigens to
T-lymphocytes and play a key role in initiating the autoimmune response. Some
polymorphisms of the HLA-genes that result in specific amino acid substitutions
in the b-chains of class-II antigens may affect the ability of the class-II molecule
to accept and present auto antigens derived from pancreatic islet beta-cells and
this determines whether or not autoimmune damage should take place by
autoimmune destruction pancreatic islet beta-cells.
TYPE-2 DIABETES MELLITUS:
Genetic factors are more important in the development type-2 diabetes
mellitus than in type-1 diabetes mellitus, but there is little information about
what is inherited.
Type-2 diabetes mellitus is characteristically associated with disorders such as
obesity, hypertension and hyperlipidemia, these three disorder forms
metabolic syndrome (syndrome-x) with insulin resistance being the primary
defect.
Single gene defects of pancreatic beta-cell function causes Maturity Onset
Diabetes in the Young (MODY) e.g. a single glucokinase gene defect of
pancreatic beta-cell function is inherited as an autosomal dominant gene and
causes mild hyperglycemia from birth.
Genetic defects of insulin action.
Associated with other genetic syndromes:
o Down’s syndrome. o Klinefelter’s syndrome.
o DIDMOAD (Wolfram’s syndrome):
 Diabetes Inspidus.  Diabetes Mellitus.

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  Optic Atrophy.  Deafness (Nerve).
2. PANCREATIC PATHOLOGIES:
Pancreatitis: inflammation of pancreas parenchymal due to
Drugs e.g. Alcohol, Didanosine, Stavudine etc.
Pancreatic trauma.
Viral infections:
Pathogenesis:
 Destruction of pancreatic beta-cells by direct cytolysis may results from
infection with mumps virus, human immunodeficiency virus,
cytomegalovirus, Epstein-Barr virus and Coxsackie-B4 virus.
 Induction of an autoimmune destructive process results from infection
with rubella virus (in utero).
Cystic fibrosis.
Pancreatectomy.
Haemochromatosis.
Fibrocalculous pancreatopathy.
Malignant disease of the pancreas.
Degenerative changes of the pancreas due aging.
3. EXCESS ENDOGENOUS PRODUCTION OF HORMONAL ANTAGONISTIC TO
INSULIN:
Human placental lactogen:
o During pregnancy, insulin sensitivity is reduced through the action of human
placental lactogen and this affects glucose tolerance. The insulin secreting
cells (beta-cells) of the pancreatic islets may be unable to meet this increased
demand in women genetically predisposed to develop diabetes mellitus.
o The term ‘GESTATIONAL DIABETES’ refers to hyperglycaemia occurring
for the first time during pregnancy. Repeated pregnancy may increase the
likelihood of developing irreversible diabetes, particularly in obese women;
80% of women with gestational diabetes ultimately develop permanent
clinical diabetes requiring treatment.
Glucagons (glucagonoma).
Growth hormone (Acromegaly).

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 Glucocorticoids (Cushing’s syndrome).
Catecholamine’s (Phaeochromocytoma; thyroid hormones-hyperthyroidism).
NB:
Severe burns, trauma and stress may elevate blood glucose by stimulating the
secretion of counter-regulatory hormones (stress hormones) and possibly by
modulating immune activity.
4. DRUGS:
Phenytoin.
Thiazide diuretics e.g. Bendrofluazide.
Corticosteroids e.g. Prednisolone, dexamethasone.
5. Dietary factors:
Introduction of cow’s milk before the age of 2-3 months is associated with the
presence of antibodies to bovine serum albumin and an increased risk of
developing type-1 diabetes mellitus. Bovine serum albumin (BSA), a major

Constituent of cow’s milk, has been implicated in triggering type-1 diabetes mellitus
than those who are breastfed. BSA may cross the neonatal gut and raise antibodies
which May cross-react with and cause damage to beta-cell components of the
pancreas.
High nitrosamine content in the diet (found in smoked and cured meats) and
coffee have been proposed as potentially diabetogenic factors.
5. Liver diseases.
6. Immunological factors:
Type-1 diabetes mellitus is a slow T-cell mediated autoimmune disease.
Autoantibodies developed destroy pancreatic beta-cells important for insulin
secretion.
7. Life style:
 Overeating especially when combined with obesity and under-activity
(sedentary life) is associated with the development of type-2 diabetes mellitus.
 Obesity probably acts as a diabetogenic factor through increasing resistance to
the action of insulin in those genetically predisposed to develop type-2 diabetes
mellitus.

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 PATHOPHYSIOLOGY DIABETIC MELLITUS:
The hyperglycemia of diabetes mellitus develops because of:
An absolute insulin deficiency, as in type-1 diabetes mellitus or a relative insulin
deficiency, as in type-2 diabetes mellitus.
Insensitivity of the target tissues to actions of insulin leading into reduction in
peripheral tissues utilization of glucose.
Reduction of insulin secretion by the hyperglycaemia due to the effects of glucose
toxicity on pancreatic beta-cells function.
Lack of insulin causes three effects:
Decreased anabolism.
Increased catabolism.
Increased secretion of counter-regulatory hormones.
1. DECREASED ANABOLISM:
This leads to:
 Fatigue:
It occurs because of the failure of utilization of glucose by the skeletal muscles.
 Glycosuria:
It occurs when the plasma glucose concentration exceeds the renal threshold (the
capacity of renal tubules to reabsorb glucose from the glomerular filtrate) at
approximately 10 mmol/l.
Glycosuria predisposes the patient to: because pathogens favor glucose conditions to grow.
o Vulvitis.
o Pruritic vulvae.
o Urinary tract infection.

o Balanitis (genital candidiasis).

o Osmotic diuresis:
Because of high concentration of glucose in the glomerular filtrate; water
reabsorption is hindered leading to polyuria and polydipsia in response to
dehydration.
 Salt and water depletion:
This occurs as the result of osmotic diuresis and it is responsible for the hypotension and tachycardia

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3. INCREASED CATABOLISM:
Wasting:
This is caused by:
o Increased glycogenolysis i.e. increased breakdown of glycogen into glucose
from the liver.
o Increased gluconeogenesis i.e. increased formation of glucose from the liver.
o Increased breakdown of proteins in the skeletal muscles.
Weight loss:
Due to the lack of insulin, the body switches from the utilization of glucose as the
source of energy to lipids. This leads to:
o Increased lipolysis i.e. increased breakdown of adipose tissues.
o Increased fatty acid oxidation in the liver.
o Increased lipoprotein lipase secretion (degradative enzyme).
Hyperketonaemia and ketonuria:
o Partial oxidation of fatty acids in the liver provides energy to drive
gluconeogenesis and leads to production of ketone bodies (acetone, aceto-
acetic acid and beta-hydroxy-butyric acid).
o Ketone bodies are organic acids which, when formed in small amounts can be
oxidized and utilized as metabolic fuel.
o However, the rate of utilization of ketone bodies by peripheral tissues is
limited and when the rate of production by the liver exceeds their removal,
hyperketonaemia and ketonuria results.
ACIDOSIS:
o It occurs as the result of hyperketonaemia, as ketone bodies are acidic in
nature.
o Acidosis causes peripheral vasodilatation that leads to hypotension and
hypothermia.
DIABETIC KETOACIDOSIS: It develops as the result of acidosis. And this is emergency
condition.

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3. INCREASED SECRETION OF COUNTER-REGULATORY HORMONES:
Cortisol.
Glucagon.
Growth hormone.
Catecholamine’s e.g. adrenaline. Epinephrine
They stimulate lipolysis, enhance hepatic glucose output and impaired peripheral
utilization of glucose. Prolonged cortisol levels also may cause immunosuppression
and cataract.
If hyperglycaemia develops slowly over months or years, as in type-2 diabetes, the
renal threshold for glucose rises and the symptoms of diabetes are mild. This is the

Reason for the large number of undetected cases of thype-2 diabetes mellitus,
many of which are discovered coincidentally or present for the first time with
complications.

CLINICAL FEATURES TO PATIENT WITH DIABETIC MELLITUS:

3Ps and 2Ws:
o Polyuria. o Polyphagia.
o Polydipsia o Weight loss.
o Weakness (tiredness, fatigue, malaise and apathy).
Nausea.  Irritability.
Headache.  Blurring of vision.
Thirst and dry mouth, due to
dehydration.
 Increased susceptibility to infections: skin sepsis (boils), genital candidiasis (
balanitis) and urinary tract infections.
 A few young people have a form of diabetes designated ‘maturity onset diabetes
of the young’ (MODY).
 Some middle aged and elderly people present with typical autoimmune type-1
diabetes mellitus.
 Classical symptoms of polyuria, polyuria and rapid weight loss are prominent in
type- 1 diabetes mellitus while patients with type-2 diabetes mellitus usually presents
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 with complications of diabetes mellitus.

COMPARATIVE CLINICAL FEATURES OF TYPE-1 AND TYPE-2 DIABETES MELLITUS:

Variable Type-1 diabetes mellitus Type-2 diabetes mellitus
Age at onset < 40 years > 50 years
Duration of symptoms Weeks Months-years
Body weight Normal or low Obese
Ketonuria Present Absent
Rapid death without insulin treatment Yes No
Autoimmune antibodies Present Absent
Diabetes complications at diagnosis Absent Present in 25% of cases
Family history of diabetes mellitus Uncommon Common
Other autoimmune diseases Common Uncommon

CLINICAL DIAGNOSIS OF DIABETIC MELLITUS:

WHO diagnostic criteria for diabetes mellitus,:
 Symptoms suggestive of diabetes mellitus.
 Random or fasting blood glucose (confirms the diagnosis).
o Fasting plasma glucose ≥ 7.0 mmol/L (≥ 126 mg/dL). Or
o Random plasma glucose ≥ 11.1 mmol/L (≥ 199.8 mg/dL).
 An abnormal oral glucose tolerance test (OGTT).

ORAL GLUCOSE TOLERANCE TEST (OGTT)

This is test perfumed to a patient suspected to have diabetic mellitus to asses glucose utilization
and patient must be prepared and restricted from using carbohydrates diet prior to OGTT and then
75g of glucose is mixed with 300mls of water and patient take it with 3-5minutes , assessment
continues every 30 minutes with interval of 2hrs
 Indications for oral glucose tolerance test:
o Fasting blood glucose 6.1-6.9 mmol/L.
o Random blood glucose 7.8-11.0 mmol/L.

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  How to do oral glucose tolerance test:
o Patient should be on unrestricted carbohydrate diet for 3 days before test.
o Fast the patient overnight.
o Rest the patient for 30 minutes before the test and no smoking for the duration
seated for the test.
o Take sample of blood to measure fasting plasma glucose.
o Give a patient to drink 75 g of glucose dissolved in 300 mls of water.
o Thereafter, samples of blood are collected at half hourly intervals for at least 2
hours and their glucose content is estimated.

Variable Plasma glucose Whole blood glucose

venous (capillary) (mmol/dL) venous (capillary) (mmol/dL)
Diabetes mellitus
Fasting ≥ 7.0 (≥ 7.0) ≥ 6.1 (6.1)
2 hours after glucose load ≥ 11.1 (≥12.2) ≥ 10.0 (≥ 11.1)
Impaired glucose tolerance
Fasting < 7.0 (< 7.0) < 6.1 (6.1)
2 hours after glucose load 7.8-11.0 (8.9-12.1) 6.7- 9.9 (7.8-11.0)

 Impaired glucose tolerance indicates the need for further evaluation. Many patients
with impaired glucose tolerance progress to frank diabetes mellitus with time.(Pre-
diabates)
 Venous blood glucose concentration is lower than capillary blood. Whole blood
glucose is lower than plasma glucose because red blood cells contain relatively little
glucose.

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STRESS HYPERGLYCAEMIA
 Stress-Hyperglycaemia may develop in patients without diabetes mellitus in
conditions which impose a burden on the pancreatic beta-cells e.g. pregnancy,
infection, myocardial infarction, severe stress or treatment with diabetogenic drugs
e.g. corticosteroids.
 It is because these conditions trigger the release of counter-regulatory hormones in
such conditions. Therefore, whenever you get higher blood sugar levels re-measure
on the next day to exclude stress hyperglycaemia. Stress-hyperglycaemia usually
disappears spontaneously without treatment after the condition has resolved.

COMPLICATIONS OF DIABETIC MELLITUS

1. Acute complications:
 Lactic acidosis:
Coma due to lactic acidosis is likely to occur in diabetic patient taking biguanide.
Clinical features:
o No acetone smell. o Kussmaul’s breathing.
o Mild or absent ketonuria.
o Mild to moderate dehydration.
o Elevation of serum lactic acid (> 5.0 mmol/L).
o Plasma bicarbonate and pH (< 7.2) are markedly reduced.

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 Hypoglycaemia:
Definition: Blood glucose concentration of less than 2.5mmol/L.
Clinical features:
o Symptoms due to acute activation of autonomic nervous system:
 Hunger.  Sweating.
 Anxiety.  Pounding heart.
 Trembling/tremors.
o Symptoms resulting from glucose deprivation of the brain (neuroglycopenia):
 Confusion.  Drowsiness.
 Convulsion.  Inco-ordination.
 Speech difficulty.
 Inability to
concentrate.
o Non-specific:
 Nausea.  Headache  Tiredness
o Symptoms suggestive of nocturnal hypoglycaemia:
 Poor sleep.  Chronic fatigue.
 ‘Hangover’.  Morning headache.
 Vivid dreams or
nightmares.
 Sometimes a relative may observe the following:
a. Restlessness. b. Profuse sweating.
c. Twitching or convulsion.
o Causes:
 Alcohol.  Malabsorption.
 Factitious hypoglycaemia.
 Unexpected or unusual exercise.
 Missed, delayed or inadequate meal.
 Other endocrine disorders e.g. Addison’s disease.
 Gastroparesis diabetocorum due to autonomic neuropathy.
 Poorly designed insulin regime, particularly that predisposing to nocturnal
hypoglycaemia.
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  Defective glucose counter-regulation or unawareness of hypoglycaemia.
 Diabetes ketoacidosis:
The differences in coma due to hypoglycaemia and diabetic ketoacidosis:
Variables Hypoglycaemia coma Coma due to diabetic ketoacidosis
History No food, too much insulin or Too little insulin, an infection or
unaccustomed digestive disturbance.
exercise
Onset In good previous health or related to Ill-health for several days.
last
insulin injection.
Symptoms Hypoglycaemia, occasional vomiting Glycosuria and dehydration,
from abdominal
depot insulin. pain and vomiting.
Signs Moist skin and tongue. Dry skin and tongue.
Full pulse. Weak pulse.
Normal or raised systolic blood pressure Low blood pressure.
Shallow or normal breathing. Air hunger (Kussmaul’s breathing).
Brisk deep tendon reflexes Diminished deep tendon reflexes.
Urine No ketonuria. Hyperglycaemia.
No glycosuria, if bladder recently empted. Reduced plasma bicarbonate.

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  Acute circulatory failure.
 Non-ketotic hyperosmolar diabetic coma.
2. Chronic complications:
A. Macrovascular complications:
i. Cerebral vascular diseases:
 Cerebral vascular accident.
 Transient ischaemic attack.
ii. Coronary artery diseases:
 Angina pectoris.  Myocardial infarction.
iii. Peripheral vascular disease:
 Claudication.
 Ischaemia (including gangrene).
B. Microvascular complications:
i. Diabetes nephropathy: Presents with renal failure.
ii. Diabetes retinopathy and cataract: Presents with impaired vision.
iii. Diabetic foot disease: Presents with either foot ulceration or arthropathy.
iv. Diabetic neuropathy:
 Somatic neuropathy: (Peripheral neuropathy)
o Polyneuropathy.
o Mononeuropathy, including mononeuritis multiplex.
Presentation:
o Motor weakness:
It presents with either muscle weakness or paralysis of limb (s). It
mainly affects proximal parts (including amyotrophic lateral sclerosis).
o Sensory loss:
It presents with paraesthesia, tingling sensation, numbness (pin and
needle sensations), hyperaesthesia and burning pain. It mainly affects
distal parts.
 Visceral neuropathy: (Autonomic neuropathy)
o Cardiovascular system:
 Fixed heart rate.

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  Resting tachycardia.
 Postural hypotension.
o Gastrointestinal tract:
 Gastroparesis diabetocorum:
It causes abdominal fullness, nausea, vomiting and unstable
diabetes mellitus, due to delayed gastric emptying.
 Constipation due to colonic atony.
 Dysphagia due to oesophageal atony.
 Nocturnal diarrhoea ± faecal incontinence.
o Genitourinary system:
 Impotence.
 Retrograde ejaculation.
 Those due to atonic urinary bladder:
a. Urinary retention.
b. Urinary incontinence.

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 c. Recurrent urinary tract infection.
o Sudomotor:
 Gustatory sweating.
 Anhidrosis and fissures in the feet.
 Nocturnal sweating without hypoglycaemia.
o Vasomotor:
 Bullous formation.
 Feet feeling cold due to loss of skin vasomotor responses.
 Dependent oedema due to loss of vasomotor tone and increased
vascular permeability.
o Pupillary:
 Decreased pupil size.
 Resistance to mydriatics.
 Delayed or absent reflexes to light.
o Loss of awareness of hypoglycaemia:
It results from dysfunction of the hypothalamus and altered glycaemic
threshold for autonomic activation.

Investigations:
Baseline investigations:
 Random or fasting blood glucose.
 Chest x-ray: To exclude tuberculosis.
 ECG: To exclude myocardial infarction.
 Serum creatinine: To exclude nephropathy.
 Funduscopy: To exclude diabetic retinopathy.
 Lipid profile: Total cholesterol, LDL, HDL, triglycerides.
 Urinalysis:
o Urinary glucose:
The disadvantage of using urinary glucose as a diagnostic or screening procedure:
1. The individual variation in renal threshold:
Apart from diabetes mellitus, the most common cause of glycosuria is a low

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 renal threshold for glucose, which is common during pregnancy (because
renal threshold for glucose falls due to increase in glomerular filtration rate)
and in young people.
2. In some individuals a rapid but transitory rise of blood glucose follows a meal
and the concentration exceeds the normal renal threshold; during this time
glucose will be present in the urine.
3. It may occur in hyperthyroidism, peptic ulceration, hepatic disease or after
gastric surgery (when it is caused by rapid gastric emptying and more rapid
absorption of glucose into the circulation).
o Urinary protein:
Urinary protein is identified using dipstick method. The test is capable of
detecting urinary albumin greater than 300 mg/L.
The presence of urinary albumin indicates the risk of developing diabetic
nephropathy and/or macrovascular complications.

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 o Urinary ketone bodies:
Ketonuria may be found in normal people who have been:
a. Fasting. b. Vomiting repeatedly.
c. Exercising strenuously for long periods.
d. Eating diet high in fat and low in carbohydrate.
NB: If ketonuria is associated with glycosuria, the diagnosis of diabetes mellitus
is likely.

Treatment:
Four methods of treatment are available for diabetic patients:
 Diet alone.
 Oral hypoglycaemic drugs.
 Insulin.
 Combined oral hypoglycaemic therapy and insulin.

Diet alone:
Aims of dietary management:
 Abolish symptoms of hyperglycaemia.
 Reduce overall blood glucose and minimise fluctuations.
 Achieve weight reduction in obese patients to reduce insulin resistance,
hyperglycaemia and dyslipidaemia.
 Avoid hypoglycaemia associated with therapeutic agents e.g. insulin and
sulphonylureas.
 Avoid weight gain associated with therapeutic agents e.g. insulin, sulphonylureas and
thiazolidinediones.
 Avoid ‘atherogenic’ diets or those which may aggravate diabetic complications e.g.
high protein intake in nephropathy.
NB: Dietary measures are required in the treatment of all diabetic patients to achieve
normal metabolism.
Foods that should not be avoided unless a patient is hypoglycaemic:
 Cake.  S gar.
u  Honey.
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  Cold drinks with  Sweets.  Chocolate.
sugar.  Glucose.  Sugar cane.
Two basic types:  Ice cream.  Tinned fruits.
A. Low-energy, weight reducing diet:
It is necessary in obese people to:
 Use diet low in refined carbohydrate and high in unrefined carbohydrate.
 Omit snacks between meals.
 Use non-nutritive sweeteners such as saccharin, aspartame etc. which provide
means for reducing energy intake without loss of palatability.
B. Weight maintenance diet:
It is necessary in individuals with normal body mass index (BMI) to use diet:
 High in carbohydrate.
 Low in fat:

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 Groundnut and sunflower oil are preferred while animal fat, coconut oil and palm
oil are not recommended because high LDL-cholesterol content.
A ‘plate model’ for meal planning:
The plate is divided into three positions:
 A smallest portion (one fifth of total area) is for meat, fish, eggs or cheese.
 The remainder is divided in roughly equal proportions between the staple food
e.g. Rice, potatoes, bread, ‘ugali’ (stiff-porridge) and vegetables or fruit.
NB: It is better to have multiple small meals than few large meals.
Effects of alcohol:
 Alcohol inhibits gluconeogenesis which may potentiate hypoglycaemic action of
sulphonylureas and insulin.
 The similarity of the features of alcohol intoxication and hypoglycaemia which
may confuse the observers.
 Alcohol predispose towards the development of lactic acidosis in patients taking
metformin.
 Alcohol can induce a ‘disulfiram type’ of reaction in some patients taking
chlorpropamide.
NB: Abstinence from alcohol should be encouraged if obesity, hypertension or
hyperlipidaemia is present.
Salt:
Restriction in dietary salt is important in management of diabetic patients with
hypertension.
Fat:
 Encourage diet low in low-density lipoprotein (LDL) cholesterol and high in
high-density lipoprotein (HDL) cholesterol.
 High density lipoprotein reduces low-density lipoprotein from the circulation to
the liver. Low-density lipoprotein cholesterol is associated with macrovascular
complications of diabetes mellitus.
Artificial sweeteners:
 Low-caloric and sugar free drinks are useful for patients with diabetes. These
dinks usually contain non-nutritive sweeteners and provide a means for reducing
energy intake without loss of palatability.
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  Examples of these non-nutritive sweeteners are saccharin, aspartame, sucramate
and acesulphame-K.

Oral hypoglycaemic drugs:

1. Drugs that increase insulin secretions:
 Sulphonylureas.
 Meglitinides and amino acid derivatives.
2. Drugs that improve insulin actions:
 Biguanides.  Thiazolidinediones.
NB: They do not increase plasma concentration of insulin and therefore, do not cause
hypoglycaemia.
3. Drugs that improve intestinal absorption of food:
 Alpha-glycosidase inhibitors.

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 These drugs are effective in reducing hyperglycaemia in patients with type-2 diabetes
mellitus.

1. Drugs that increase insulin secretions:

A. Sulphonylureas:
Examples:
 First generation sulphonylureas:
o Tolbutamide. o Chlorpropamide.
 Second generation sulphonylureas:
o Glipizide. o Glimepiride.
o Gliclazide. o Glibenclamide.
NB: Gliclazide and Glipizide have fewer side effects but Glibenclamide can
induce severe hypoglycaemia and should be avoided in elderly patients.
Mechanism of action:
 Suppression of glucagon.
 It also reduces the hepatic release of glucose.
 Stimulates insulin release from the pancreatic beta cells.
 Insulin sensitivity is increased at peripheral target sites.
Indications:
Non-obese patients with type-2 diabetes mellitus who fails to respond to dietary
measures alone.
Contraindications:
o Pregnancy.
o Treatment of type-1 diabetes.
o Hypersensitivity to tolbutamide.
o Diabetes complicated by ketoacidosis.
o Sulphonamide or any component of the formulation.
o Severe renal, hepatic, thyroid or other endocrine disease.
Uses:
 It may be used alone (non-obese patients). Or
 In combination with other drugs in patients who are > 40 years old, e.g.

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 o Sulphonylureas + Metformin (obese patients).
o Sulphonylureas + thiazolidinedione, -glucosidase inhibitor, prandial
glucose regulator or bedtime isophane/lente/insulatard insulin (non-obese
patients).
Dose:
 Chlorpropamide:
o Initial dose:
 250 mg/day in mild to moderate diabetes in middle-aged and stable
diabetic.
 100-125 mg/day in older patients.
o Dose adjustment:
Subsequent dosages may be increased or decreased by 50-125 mg/day at
3- to 5-day intervals.
o Maintenance dose:
 100-250 mg/day.

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  Severe patients with diabetes may require 500 mg/day (avoid doses
>750 mg/day).
NB: It has half life of 36 hours. It may cause severe and prolonged
hypoglycaemia.
 Glibenclamide:
o Initial dose:
2.5-5 mg/day, administered with breakfast or the first main meal of the
day. In patients who are more sensitive to hypoglycemic drugs, start at
1.25 mg/day.
o Dose adjustment:
Increase in increments of no more than 2.5 mg/day at weekly intervals
based on the patient's blood glucose response.
o Maintenance dose:
1.25-20 mg/day given as single or divided doses; maximum: 20 mg/day.
B. Meglitinides and amino acid derivatives:
Examples:
 Nateglinide.  Repaglinide.
Mechanism of action:
It stimulates insulin release from the pancreatic beta cells to reduce postprandial
hyperglycaemia.
Contraindications:
 Type-1 diabetes mellitus (insulin dependent, IDDM).
 Diabetic ketoacidosis, with or without coma (treat with insulin).
 Hypersensitivity to nateglinide/rapaglinide or any component of the
formulation.
Dose:
Nateglinide:
Initial and maintenance dose: 120 mg three times/day, 1-30 minutes before meals.
Patients close to Hb A1c goal may be started at 60 mg three times/day.
Rapaglinide:
Dose range: 0.5-4 mg taken with meals. Maximum recommended daily dose is
16 mg.
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 Note:
 Doses should be taken within 15 minutes of the meal, but time may vary
from immediately preceding the meal to as long as 30 minutes before the
meal.
 It may be given alone or in combination with metformin or a
thiazolidinedione.

2. Drugs that improve insulin actions:

A. Biguanides:
Example: Metformin.
Mechanism of action:
 Decreasing intestinal absorption of glucose.
 Decreases hepatic glucose production i.e. gluconeogenesis.

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  It improves insulin sensitivity by increasing peripheral glucose uptake and
utilization.

NB:
 It has no hypoglycaemic effect in non-diabetic individuals.
 It does not increase insulin secretion or cause hypoglycaemia.
Indications:
 Obese patients, as its administration does not associate with increase in body
weight.
 Combination with sulphonylureas drugs, as the hypoglycaemic effect of
metformin is synergistic with that of the sulphonylureas drugs.
Contraindications:
 Hypersensitivity to metformin or any component of the formulation.
 Renal disease or renal dysfunction (serum creatinine ≥ 1.5 mg/dL in males or
≥ 1.4 mg/dL in females).
 Congestive heart failure requiring pharmacological management.
 Acute or chronic metabolic acidosis with or without coma (including diabetic
ketoacidosis).
 In those who take alcohol in excess, because of the increased risk of lactic
acidosis.
NB: Temporarily discontinue in patients undergoing radiological studies in
which intravascular iodinated contrast materials are utilized.
Dose:
Metformin 500 mg 8-12 hourly given with food to maximum dose of 1 g 8 hourly.
Allow 1-2 weeks between dose titrations.
B. Thiazolidinediones:
Examples:
 Pioglitazone.  Rosiglitazone.
Mechanisms of action:
They work through enhancing the actions of endogenous insulin without
increasing pancreatic insulin secretion by improving the insulin sensitivity
(mainly in adipose tissue) in patients with insulin resistance.
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Contraindications:
 Hypersensitivity to Rosiglitazone/Pioglitazone or any component of the
formulation.
 Active liver disease (transaminases > 2.5 times the upper limit of normal at
baseline).
 Patients who previously experienced jaundice during troglitazone therapy.
Dose:
Rosiglitazone:
 Monotherapy:
4 mg daily as a single daily dose or in divided doses twice daily. If response is
inadequate after 12 weeks of treatment, the dosage may be increased to 8 mg
daily as a single daily dose or in divided doses twice daily.
 Combination therapy with:

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 o Sulphonylureas:
4 mg daily as a single daily dose or in divided doses twice daily; dose of
Sulphonylurea should be reduced if the patient reports hypoglycaemia.
Doses of rosiglitazone > 4 mg/day are not indicated in combination with
Sulphonylureas.
o Metformin:
4 mg daily as a single daily dose or in divided doses twice daily. If
response is inadequate after 12 weeks of treatment, the dosage may be
increased to 8 mg daily as a single daily dose or in divided doses twice
daily. It is unlikely that the dose of metformin will need to be reduced
due to hypoglycaemia.
o Insulin:
4 mg daily as a single daily dose or in divided doses twice daily. Dose of
insulin should be reduced by 10-25% if the patient reports
hypoglycaemia or if the plasma glucose falls to < 100 mg/dL.
Doses of rosiglitazone > 4 mg/day are not indicated in combination with
insulin.
Pioglitazone:
 Monotherapy:
15-30 mg once daily; if response is inadequate, the dosage may be increased
in increments up to 45 mg once daily; maximum recommended dose: 45 mg
once daily.
 Combination therapy with: (Maximum: 45 mg/day)
o Sulphonylureas:
15-30 mg once daily; dose of sulfonylurea should be reduced if the
patient reports hypoglycemia.
o Metformin:
15-30 mg once daily; it is unlikely that the dose of metformin will need
to be reduced due to hypoglycemia.
o Insulin:
15-30 mg once daily; dose of insulin should be reduced by 10-25% if the
patient reports hypoglycemia or if the plasma glucose falls to below 100
28
 mg/dL.

3. Drugs that improve intestinal absorption of food:

A. -glycosidase inhibitors:
Examples:
 Miglitol.  Acarbose.
Mechanism of action:
 It inhibits the metabolism of sucrose to glucose and fructose.
 Competitive inhibitor of pancreatic alpha-amylase and intestinal brush
border alpha-glucosidases, resulting in delayed hydrolysis of ingested
complex carbohydrates and disaccharides and absorption of glucose.
Contraindications:
 Patients with diabetic ketoacidosis or cirrhosis.
 Hypersensitivity to Acarbose/miglitol or any component of the formulation.

29
  Patients who have conditions that may deteriorate as a result of increased gas
formation in the intestine.
 Patients with inflammatory bowel disease, colonic ulceration, partial
intestinal obstruction or in patients predisposed to intestinal obstruction.
 Patients who have chronic intestinal diseases associated with marked
disorders of digestion or absorption.
Use: They can be combined with sulphonylureas.
 Acarbose:
o Initial dose: 25 mg three times/day.
o Dose adjustment:
o It should be adjusted at 4- to 8-week intervals based on 1-hour
postprandial glucose levels and tolerance until maintenance dose is
reached;
o Maintenance dose: 50-100 mg three times/day.
Maximum:
 ≤ 60 kg: 50 mg three times/day.
 > 60 kg: 100 mg three times/day.
Acarbose when given in combination with sulphonylurea has synergistic
effect in lower blood glucose.
 Miglitol:
o 25 mg three times/day with the first bite of food at each meal.
 Titration: The dose may be increased to 50 mg three times/day after 4-
8 weeks.
 Maximum: 100 mg three times/day
Insulin preparations:

Type of insulin Onset of action Peak Duration of action

(hours) (hours) (hours)
Fast-acting (Insulin analogue) < 0.5 0.5-2.5 3-4.5
Short-acting (Soluble, regular insulin or actrapid) 0.5-1 1-4 4-8
Intermediate-acting (Isophane or Lente/Insulatard insulin) 1-3 3-8 7-14
Long-acting (bovine ultralente) 2-4 6-12 12-30
30
Long-acting (insulin analogue-glargine) 1-2 None 24

Metabolic actions of insulin:

Insulin has mainly two types of effects, anabolic and anticatabolic effects.
Anabolic effects:
 Carbohydrate metabolism:
o Glycolysis. o Glycogenesis.
o Glucose phosphorylation.
o Glucose transport (in muscles and adipose tissues).
 Lipid metabolism:
o Triglyceride synthesis. o Fatty acid synthesis (in liver).
o Activates lipoprotein lipase activity (in adipose tissues).
 Protein metabolism:
o Protein synthesis. o Amino acid transport.

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Anticatabolic effects:
 Carbohydrate metabolism:
o Gluconeogenesis (glucose synthesis from liver).
o Glycogenolysis (glycogen breakdown into glucose).
 Lipid metabolism: Insulin prevents
o Lipolysis. o Ketogenesis.
o Fatty acid oxidation (in liver).
o Lipoprotein lipase activity (in muscles).
 Protein metabolism: Insulin prevents protein degradation.

Sites of insulin injection

Insulin is injected subcutaneously into
the:  Outer thighs.
 Buttocks.  Anterior abdominal wall.
 Upper arms.
NB: Soluble insulin may be given intravenously but never with lente/insulatard.
Dose: 0.5-1 i.u/kg/day.
Side effects of insulin therapy:
 Weight gain.  Local allergy (rare).
 Hypoglycaemia.  Lipodystrophy at the injection sites.
 Insulin antibodies formation (animal insulin).
 Peripheral oedema (insulin treatment causes salt and water retention in the short
term).
Insulin regimens:
 Short acting insulin has to be injected at least 30 minutes before meal to allow
adequate time for absorption. However, fast acting insulin analogues can be
administered immediately before food or even after meal and their peak action
coincides more closely with the post-prandial rise in blood glucose.

32
 It is cleared from the body by the liver and kidneys; therefore, plasma insulin
concentrations are elevated in patients with liver disease or renal failure.
A. Once daily injection:
 Rarely achieve satisfactory glycaemic control.
 It is reserved either for some elderly patients or for those who retain significant
endogenous insulin secretion and have a low insulin requirement.
B. Twice daily administration regimen:
 Twice daily administration of a short acting and intermediate acting insulin
(usually soluble insulin and isophane/lente/insulatard insulin), given in
combination before breakfast and before evening meal, is the simplest and most
commonly used regimen.
 Two thirds of the total daily requirement of insulin is given in the morning in a
ratio of 1:2, short acting insulin:intermediate acting insulin. The remaining one
third is given in the evening at the same ratio (to avoid nocturnal hypoglycaemia).

33
C. Multiple injection regimens:
 With short acting insulin being taken before each meal and intermediate acting
insulin being injected at bedtime.
 This type of regimen allows greater freedom of timing of meals and of value to
individuals with variable day to day activities, but snacks have to be taken
between the meals to prevent hypoglycaemia.

Combined oral hypoglycaemic therapy and insulin:

 In diabetic patients who are requiring increasing doses of a sulphonylureas or
biguanide, either alone or in combination with each other or with a
thiazolidinediones, the introduction of a single dose of an intermediate acting insulin
(usually isophane insulin, or Lente/Insulatard insulin ), administered at bedtime, may
improve glycaemic control and delay the development of pancreatic b-cell failure.
 The exogenous insulin suppresses hepatic glucose output during the night and lowers
fasting blood glucose.

Treatment of peripheral sensorimotor and autonomic neuropathies:

 Pain and paraesthesiae from peripheral somatic neuropathies:
o Strict glycaemic control and either of the following:
o Topical agents e.g. Capsaicin.
o Tricyclic antidepressants e.g. Amitriptyline or imipramine.
o Anticonvulsants e.g. Carbamazepine, Phenytoin, Gabapentin.
 Postural hypotension:
o Support stocking and either of the following:
o Fludrocortisone.
o -adrenoceptor agonist e.g. Midodrine.
o Non-steroid anti-inflammatory drugs (NSAIDs).
 Gastroparesis diabetocorum:
 Erythromycin.
 Magnesium trisilicate. Or
 Dopamine agonists e.g. Metoclopramide or Domperidone.

34
 Diarrhoea:
o Broad-spectrum antibiotics. And either of the following:
o Clonidine. o Octreotide. o Loperamide.
 Incontinence (faecal or urinary)
Anticholinergic drugs e.g. Probanthine (Propantheline) 15 mg BD for two weeks.
 Constipation:
Stimulant laxative e.g. Senna, Magnesium trisilicate or Bisacodyl.
 Atonic bladder: Intermittent self-catheterization.
 Excessive sweating without hypoglycaemia:
o Clonidine. Or
o Topical antimuscarinic agent e.g. Glycopyrrolate. Or
o Anticholinergic drugs e.g. Probanthine (Propantheline), Poldine.

35
 Erectile dysfunction (impotence)
o Psychological counselling.
o Vacuum tumescence devices.
o Phosphodiesterase inhibitors e.g. Sildenafil (Viagra).
o Implantation of semi-rigid silicone penile prosthesis into the corpus cavernosa.
o Papaverine or prostaglandin-E1 e.g. Alprostadil injection into corpus cavernosum
before intercourse.

Prognosis:
Factors associated with increased mortality and morbidity:
 Obesity.  Raised blood pressure.
 Hyperlipidaemia.  Early age at onset of disease.
 Duration of diabetes.  Proteinuria; microalbuminuria.
 High glycated haemoglobin (HbA1C).

Preventions:
Primary:
 Strict glycaemic control with intensive insulin therapy is the primary prevention of
diabetic retinopathy, neuropathy and nephropathy.
 Avoid obesity by increasing physical activities, avoiding diet rich in LDL-cholesterol
and avoiding overeating.
 Avoid using coffee and diet rich in nitrosamine.
 Do not smoke during pregnancy.
 Do not introduce cow’s milk to children before the age of 2-3 months.
 The induction of diabetes by mumps and Coxsackie-B4 viruses can be prevented by
administration of MMR (Measles, Mumps and Rubella) vaccine and live attenuated
vaccine against Coxsackie-B4 viruses respectively.
Secondary:
Diabetic education:
 Patient should understand the nature of the disease, complications and the importance
of glycaemic control.

36
 Feet care:
o Patients should inspect their feet daily before going to bed.
o Diabetic patients should not use tight, loose or high-heeled shoes.
 They should have knowledge on diabetic diet on what to eat, how much and how
often.
 Every patient who is capable of learning must be taught how to perform capillary
blood glucose estimations and tests of urinary ketones, to keep the records of the
results and understand their significance.
 Those requiring insulin need to learn how to measure their dose of insulin accurately
with an insulin syringe, to give their own injections and to adjust the dose themselves
on the basis of blood glucose estimations and other factors such as illness, unusual
exercise and hypoglycaemic episodes.
 Patients must be familiar with symptoms of hypoglycaemia and what they should do
when it happens.

37
 Diabetic patients on medications e.g. insulin or oral hypoglycaemic drugs should
carry a diabetic card and a packet of glucose with them at all times. The diabetic card
should have the following:
o Name of the patient.
o Address.
o The fact that they are diabetic patient.
o The nature and dose of any insulin or other drugs they may be taking.
o The name, address and telephone number of their family doctor and any specialist
diabetic clinic they may be attending.

References:
1. McCulloch D.K. Drugs that modify intestinal absorption of food: Alpha-glucosidase
inhibitors and lipase inhibitors. www.UpToDate.com version: 13.1. Last uptodated:
September 01, 2004.
2. McCulloch D.K. Drugs that improve insulin action: Biguanides (Metformin) and
Thiazolidinediones. www.UpToDate.com version: 13.1. Last uptodated: November
17, 2004.
3. McCulloch D.K. Drugs that increase insulin secretion: Sulphonylureas and
Meglinitides. www.UpToDate.com version: 13.1. Last uptodated: June 25, 2004.
4. Edwards C.R.W, Baird J.D, Frier B.M, Shepherd J. and Toft A.D. Endocrine and
metabolic diseases, including diabetes mellitus. 17 th edition, chapter: 12, page: 724-
764.
5. Frier B.M. and Fisher B.M. Endocrine and metabolic diseases, including diabetes
mellitus. 19th edition, chapter: 12, page: 641-682.

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