2. Introduction
• Type 1 diabetes – where insulin deficiency can lead to ketoacidosis
• Type 2 diabetes – where insulin resistance and a relative lack of
insulin lead to hyperglycaemia –
• Glucose intolerance and diabetes mellitus are increasingly prevalent
in affluent and developing countries.
• Addressing risk factors distinct from blood glucose, especially
hypertension.
• In this topic focus mainly on the types of insulin and oral
hypoglycaemic agents.
3. PATHOPHYSIOLOGY
• Insulin is secreted by β-cells of the islets of Langerhans.
• It lowers blood glucose, but also modulates the metabolic disposition
of fats and amino acids, as well as carbohydrate.
• It is secreted together with inactive C-peptide.
• its plasma concentration is low or absent in patients with type 1
diabetes.
• Diabetes mellitus fasting blood glucose concentration of
7mmol/L is caused by an absolute or relative lack of insulin.
• In type 1 diabetes there is an absolute deficiency of insulin
4. • Type 1 - patients are usually young and non-obese at presentation.
• There is an inherited predisposition.
• In type 2 diabetes there is a relative lack of insulin secretion, coupled with
marked resistance to its action.
• Type 2 diabetes is rarely associated with diabetic ketoacidosis.
• high of blood glucose levels gives rise to these effects:
• 1. diuresis (polyuria) with consequent decreased volume reduction
• 2. blurred vision.
• 3. Glycosuria predisposes to Candida infection, especially in women.
• 4. Weight loss.
• 5. retinopathy
5. PRINCIPLES OF MANAGEMENT
• In young type 1 patients there is good evidence that improved
diabetic control reduces complications.
• To minimize the metabolic derangement associated with diabetes
mellitus in order to reduce the development of such complications.
• Education and support are essential to motivate the patient to learn
how to adjust their insulin dose to optimize glycaemic control.
• In older type 2 patients, hypoglycaemic treatment aims to minimize
symptoms of polyuria, polydipsia or recurrent Candida infection.
6. DIET IN DIABETES MELLITUS
• It is important to achieve and maintain ideal body weight on a non-atherogenic
diet.
• Caloric intake must be matched with insulin injections.
• Simple sugars should be restricted because they are rapidly absorbed.
• should be replaced by foods that give rise to delayed and reduced glucose
absorption.
• Artificial sweeteners are useful for those with a ‘sweet tooth’.)
• A fibre-rich diet reduces peak glucose levels after meals and reduces the insulin
requirement.
• Saturated fat and cholesterol intake should be minimized.
• There is no place for commercially promoted ‘special diabetic foods’, which are
expensive.
7. DRUGS USED TO TREAT DIABETES MELLITUS
• INSULINS
• Insulin is a polypeptide.
• Insulin is available in several formulations
• e.g. with protamine and or with zinc) which differ in pharmacokinetic
properties, especially their rates of absorption and durations of action.
• ‘designer’ insulins are synthetic polypeptides closely related to insulin
• but with Small changes in amino acid composition which change their
properties.
• For example, a lysine and a proline residue are switched in insulin lispro,
which consequently has a very rapid absorption and onset.
• whereas insulin glargine is very slow acting and is used to provide a low
level of insulin activity during the 24-hour period.
8. Use
• Insulin is indicated in type 1 diabetes mellitus and in about one-third
of patients with type 2 disease.
• Insulin is administered by subcutaneous injection.
• The effective dose of human insulin less than that of animal insulins.
• Soluble insulin is the only preparation suitable for intravenous use.
• It is administered intravenously in diabetic emergencies
• Subcutaneously before meals in chronic management.
• Formulations of human insulins are available in various ratios of
short-acting and longer-lasting forms e.g. 30:70 commonly used twice
daily.
9. Mechanism of action
• Insulin acts by binding to transmembrane glycoprotein receptors.
Receptor occupancy results in:
• 1. activation of insulin-dependent glucose transport processes.
• 2. inhibition of adenylyl cyclase-dependent metabolism (lipolysis,
proteolysis, glycogenolysis).
• 3. intracellular accumulation of potassium and phosphate which is
linked to glucose transport in some tissues.
10. Adverse reactions
• 1. Hypoglycaemia
• 2. Insulin-induced post-hypoglycaemic hyperglycaemia (Somogyi
effect)
• 3. Local or systemic allergic reactions to insulin, with itching, redness
and swelling at the injection site.
• 4. Lipodystrophy: the disappearance of subcutaneous fat at or near
• 5. Insulin resistance, defined arbitrarily as a daily requirement of
more than 200 units.
11. ORAL HYPOGLYCAEMIC DRUGS AND TYPE 2
DIABETES
• Oral hypoglycaemic drugs are useful in type 2 diabetes as adjuncts to
dietary restraint.
• They fall into four groups:
• 1. biguanides (metformin);
• 2. sulphonylureas and related drugs
• 3. thiazolidinediones (glitazones);
• 4. α-glucosidase inhibitors (acarbose).
• type 2 diabetic patients initially achieve satisfactory control with diet
either alone or combined with one of these agents.
12. BIGUANIDES: METFORMIN
• Metformin is the only biguanide available.
• It is used in type 2 diabetic patients inadequately controlled by diet.
• Its aids weight reduction so it is a first choice drug for obese type 2
patient
• It must not be used in patients at risk of lactic acidosis
• Contraindicated in: renal failure ,alcoholics,cirrhosis, chronic lung
disease ,cardiac failure , congenital mitochondria, acute myocardial
infarction.
13. Mechanism of action
• This remains uncertain.
• Biguanides do not produce hypoglycaemia and
• They are effective in animals with removed pancreas. animal
• Effects of metformin include:
• reduced glucose absorption from the gut.
• inhibition of gluconeogenesis in the liver.
14. Adverse effects
• nausea
• metallic taste,
• anorexia, vomiting and diarrhoea.
• The symptoms are worst when treatment is initiated and a few
patients cannot tolerate even small doses.
• Lactic acidosis.
• Absorption of vitamin B12 is reduced by metformin.
15. SULPHONYLUREAS AND RELATED DRUGS
• Tolbutamide, glibenclamide, gliclazide
• Used for type 2 diabetics who have not responded adequately to diet
alone or diet and metformin with which they are additive.
• They improve symptoms of polyuria and polydipsia,
• In contrast to metformin stimulate appetite.
• Chlorpropamide, the longest-acting agent in this group has a higher
incidence of adverse effects especially hypoglycaemia.
• Tolbutamide and gliclazide are shorter acting than glibenclamide.
16. RELATED DRUGS
• Repaglinide, Nateglinide are chemically distinct, but act at the same
receptor.
• They are shorter acting even than Tolbutamide.
• but more expensive.
• They are given before meals.
17. Mechanism of action
• The hypoglycaemic effect of these drugs depends on the presence of
functioning B cells.
• Sulphonylureas like glucose, depolarize B cells and release insulin.
18. Adverse effects
• hypoglycaemia.
• Allergic reactions such rashes, drug fever,
• gastrointestinal upsets.
• transient jaundice (usually cholestatic) and
• haematopoietic changes, including thrombocytopenia, neutropenia
and pancytopenia.
19. THIAZOLIDINEDIONES (GLITAZONES
• Piolitazone, Rosiglitazone were developed from the chance finding
that a fibrate drug increased insulin sensitivity.
• Glitazones lower blood glucose and haemoglobin A1c (HbA1c) in type
2 diabetes mellitus.
• Their effect on mortality or diabetic complications not fully
established.
• but they have rapidly become very widely used.
20. Mechanism of action
• Glitazones bind to the peroxisome-proliferating activator receptor γ
(PPARγ),
• A nuclear receptor found mainly in adipocytes and also in
hepatocytes and myocytes.
• They works slowly increasing the sensitivity to insulin.
21. Adverse effects
• The first glitazones caused severe hepatotoxicity and are not used.
• Hepatotoxicity has not proved problematic with rosiglitazone or
pioglitazone,
• The most common adverse effects are weight gain
• They can also exacerbate cardiac dysfunction and are therefore
contraindicated in heart failure.
• Increased bone fractures and osteoporosis has been noted.
• They are contraindicated during pregnancy.
22. ACARBOSE
• Acarbose is used in type 2 diabetes mellitus in patients who are
inadequately controlled on diet alone or diet and other oral hypoglycaemic
agents.
• Acarbose is a reversible competitive inhibitor of intestinal α-glucoside
hydrolases and
• It delays the absorption of starch and sucrose, but has no affect the
absorption of ingested glucose.
• The postprandial glycaemic rise after a meal containing complex
carbohydrates is reduced and its peak is delayed.
• It causes increased gas formation which results in flatulence, abdominal
distension and occasionally diarrhoea.
