1. 1 Diabetes Mellitus  Is a clinical syndrome characterized by an elevated of blood glucose due to relative or absolute deficiency of insulin.  (insulin is produced by β -cells in the islets of Langerhans).

2. 2 Aetiology and Classification 1.Primary ( the majority) A.IDDM (Insulin dependent diabetes mellitus), type I, juvenile onset). B.NIDDM ( non-insulin dependent diabetes mellitus) type II, maturity onset).

3. 3 2.Secondary due to : A. Pancreatic diseases viruses, autoimmune viruses, autoimmune diseases, chemical toxins). diseases, chemical toxins). B. Insulin antagonists *Growth hormone *Growth hormone *Adrenocortical hormones (increase *Adrenocortical hormones (increase gluconogenesis and decrease gluconogenesis and decrease utilization of glucose by utilization of glucose by peripheral tissues), peripheral tissues),

4. 4 * Adrenaline ( increases * Adrenaline ( increases glycogen breakdown and glycogen breakdown and suppresses of insulin suppresses of insulin secretion). secretion). * Thiazides diuretics * Thiazides diuretics * Thyroid * Thyroid *Gestational. *Gestational. C. Liver cirrhosis and hepatitis. hepatitis.

5. 5 IDDM  Usually affecting a young age group or at any age.  Characterized by absolute def. of insulin and massive β -cell necrosis.  Associated with viruses, auto-immune diseases.  Require exogenous insulin.  May associated with Islet cell antibodies.  No genetic predisposition.

6. 6 NIDDM  The majority of patients.  Genetic factors is strong.  Obesity.  Age over 40.  Inactivity, diet and pregnancy.  No autoimmune diseases or viruses.

7. 7  Clinically usually milder than IDDM.  Some beta β- cell function, but insulin secretion is variable- normal, high or low.  Resistance to insulin by target tissues, decrease in insulin receptors, or an abnormal insulin molecule.

8. 8 Clinical presentation of DM 1.Hyperglycemia Due to reduced rate of removal of glucose from the blood by periph. Tissues, or an increase rate of release of glucose from the liver into Due to reduced rate of removal of glucose from the blood by periph. Tissues, or an increase rate of release of glucose from the liver into circulation. circulation.

9. 9 2. Glycosuria When BS more than 180mg/dl When BS more than 180mg/dl ( 10 mmol). ( 10 mmol). 3.Polyuria, polydepsia, polyphagia, thirst and nocturia.

10. 10 4.Loss of weight and tiredness, pruritus. 5.Impotence. 6.Kitoacidosis. 7.Neuropathy, nephropathy and retinopathy

11. 11 Diagnosis  Glycosuria.  Random blood sugar (more than 14 mmol/L, or 250 mg/dL).  Glucose tolerance test.

12. 12 Treatment 1.Diet. 2.Diet and oral hypoglycemic agents. 3.Diet and insulin.

13. 13 INSULIN * Is a polypeptide hormone ( two peptide chain connected by disulfide bonds). * Synthesized as a pro-insulin which undergoes proteolytic cleavage to form insulin and peptide C (give better index of insulin level).

14. 14  Secretion is stimulated by high glucose level, some amino acids and GIT hormones.  Blood Glucose is taken up by glucose transporter into β -cell of the pancreas, where its phosphorylated by GLUCOKINASE (glucose sensor).

15. 15  Glucose products enter the mitochondrial respiratory chain and generate ATP, which causes a block of K channels, leading to influx of Ca resulting in pulsatile insulin exocytosis ( sulfonylureas and meglitinides acts by inhibition of K channels).

16. 16 PHARMACOKINETICS * Insulin secreted from β -cells enters the portal vein and passes to the liver. * 50% of it stay in the liver and the rest passes into systemic circulation (concentration is 15% of that entering (concentration is 15% of that entering the liver).

17. 17 * When insulin is injected the concentration in systemic circulation and peripheral organs is the same. * It is given by injection, digested if swallowed.

18. 18  * About 10% appears in the urine. the urine.  * Inactivated by the liver and kidneys (extensive and kidneys (extensive first pass metabolism). first pass metabolism).

19. 19 * The half-life is 5 min. * It is available in needles and syringes, insulin pens, external infusions and implantable pumps.

20. 20 ACTIONS OF INSULIN 1.Reduction of blood glucose level by: A. Stimulations of glucose uptake by peripheral tissues( which convert it into glycogen and fat).

21. 21 B. Stimulation of glycogen synthesis. synthesis. C. Reduction of hepatic output of glucose [ diminished glucose [ diminished breakdown of glycogen, and breakdown of glycogen, and diminished gluconeogenesis diminished gluconeogenesis (glucose from proteins)]. (glucose from proteins)].

22. 22 2- Fat: Inhibits the breakdown of fat (lipolysis). of fat (lipolysis). 3- Enhances protein synthesis. synthesis. 4- Enhances K+ entry into cells. cells.

23. 23 5- Enhances amino acids entry across cell membrane. across cell membrane. 6- It stimulate appetite (if falls below normal level). below normal level). 7- Causes osmotic diuresis if glucose level above renal glucose level above renal threshold. threshold.

24. 24 SOURCES OF INSULIN 1- Animal: beef or pork. 2-Human : Less immunogenic than animal insulins. Less immunogenic than animal insulins. * Absorbed more rapidly if given S/C. * Absorbed more rapidly if given S/C. * Requirement is less than animal ones. * Requirement is less than animal ones.

25. 25 * Produced by recombinant DNA technology using special strain of E.COLI or yeast.  Modification of amino acids sequence of human insulin produced insulins with different pharmacokinetic property.

26. 26 ADMINISTRATION *Is not given orally (polypeptide is degraded in the GIT). degraded in the GIT). Is given subcutaneously. Is given subcutaneously. In acute emergency its given IV. In acute emergency its given IV. *Given by continuous subcutaneous Infusion to reduce multiple injections.

27. 27  Aerosol preparations inhaled and absorbed through the lungs. absorbed through the lungs. Oral spray that is absorbed by buccal mucosa. Oral spray that is absorbed by buccal mucosa. Orally Orally  Inactivated by INSULINASE enzyme, that is found in the liver and kidney.

28. 28 INSULIN PREPARATIONS * They differ in their onset and duration of action, which is due to the size and of action, which is due to the size and composition of insulin crystals and the amino acid sequence of the polypeptide ( the less soluble the longer duration). composition of insulin crystals and the amino acid sequence of the polypeptide ( the less soluble the longer duration). * Dose, site of injection, blood supply, temperature, and physical activity can temperature, and physical activity can alter the duration of action. alter the duration of action.

29. 29 PREPARATIONS 1- Rapid-onset and ultrashort insulins. A. Regular insulin (soluble, crystalline zinc insulin).

30. 30 The only preparation which can be given IV in emergency. Usually it is given S/C. Clear solution. The only preparation which can be given IV in emergency. Usually it is given S/C. Clear solution. Effect start in 15 min, peak 50- 120 min and last for 5-7 hours. Effect start in 15 min, peak 50- 120 min and last for 5-7 hours. It is safe to be given in pregnancy. It is safe to be given in pregnancy.

31. 31 B. LISPRO,ASPART, GLULISINE insulins. GLULISINE insulins.  Ultrashort preparations ( rapid onset and short duration).  LISPRO insulin is rapidly absorbed than regular insulin after S/C administration.

32. 32  Peak action in 30-90 min.  Given 15 min before meal.  Can be given IV (insulin pump).  ASPART and GLULISINE insulins are similar to lispro.

33. 33 2. Intermediate-acting A.Lente insulin Slow onset of action with Slow onset of action with longer duration than longer duration than Soluble insulin. Soluble insulin.

34. 34  B. Isophane insulin (12h) NPH insulin (12h) NPH insulin suspension (neutral suspension (neutral protamine hagedorn). protamine hagedorn). * Suspension of crystalline zinc insulin combined with protamine. * Suspension of crystalline zinc insulin combined with protamine.

35. 35 3. Long acting insulins A.Ultralente insulin. Insulin zinc suspension. zinc suspension. B. Insulin glargine. It is slow in action than NPH and has prolonged hypoglycemic effect. It is slow in action than NPH and has prolonged hypoglycemic effect.

36. 36 ADVERSE EFFECTS TO INSULIN 1. Hypoglycemia The most common, could be due to delay food intake, large doses of insulin and physical exertion. The most common, could be due to delay food intake, large doses of insulin and physical exertion.  Confusion, coma, sweating, tachycardia, palpitation, tremor, nausea and hunger.  Give glucose orally or IV, glucagons IM,SC,IV.

37. 37 2.Lipodystrophy at the injection sites( rare with human insulin). 3.Allergic reactions may occur to any insulin including human (commonly due to zinc content).

38. 38 Insulin resistance and hormones that increase blood glucose. Due to decline in number and affinity of receptors (required more than 200 unit/day). Due to decline in number and affinity of receptors (required more than 200 unit/day).

39. 39  1.Glucagon Polypeptide secreted from α- islet cells of the pancreas, released in response to hypoglycemia, releases liver glycogen as glucose. Polypeptide secreted from α- islet cells of the pancreas, released in response to hypoglycemia, releases liver glycogen as glucose.

40. 40  2. Adrenaline Raises blood sugar Raises blood sugar by mobilizing liver by mobilizing liver and muscle and muscle glycogen. glycogen.

41. 41  3. Adrenal steroids Antagonize the action of insulin, increases gluconeogenesis and reduce glucose uptake and utilization by the tissues. Antagonize the action of insulin, increases gluconeogenesis and reduce glucose uptake and utilization by the tissues.

42. 42  4. Oral contraceptives. Impair carbohydrate Impair carbohydrate tolerance. tolerance.  5. Growth hormone antagonizes the effects of antagonizes the effects of insulin insulin 6. Thyroid hormones. Increases the requirement for insulin. the requirement for insulin.

43. 43 ORAL HYPOGLYCEMIC AGENTS

44. 44 ORAL HYPOGLYCEMIC AGENTS  They have a place in 20-30% of the patients. * Their action is dependent on the presence of insulin- sulphanylureas (at least 30% of normal β- cell function is present).

45. 45 1.SULPHANYLUREAS Mode of action A. Stimulation of Insulin release from the pancreas by blocking the ATP- sensitive K+ channels resulting in depolarization and Ca+ influx. They do not increase insulin formation. They do not increase insulin formation.

46. 46 B. Increasing the binding of insulin to target tissues and receptors and increasing the receptor number. C. Decreasing hepatic glucose output and increase glucose uptake by the muscles. D.Reduction in serum glucagon level.

47. 47 Preparations 1.Tolbutamide *Shortest duration of action *Half-life 8 h (6-12) *Rapidly metabolized by oxidation in the liver. in the liver. *Can be given in renal failure.

48. 48 Causes:  Hypoglycemia, GIT upset, rashes, alcohol intolerance, blood disorders( rare)  Contraindicated in pregnancy (should be treated with insulin).

49. 49 2.Chloropropamide Has long duration of action-36h. with many adverse reactions, its use is declining. 3. Glibenclamide (daonil) (t1/2 10h ) (t1/2 10h )

50. 50 Second generation Commonly used in clinical practice. 4. Glyburide (18h) 5. Glipizide (20h) 6. Glimperide They should not be used in liver and renal failure

51. 51 2. THE BIGUANIDES Mechanism of action: Mechanism of action: 1.Slowing glucose absorption from GIT. from GIT. 2. Stimulation of glycolysis in periph. tissues. (stimulate glucose uptake by the muscles) muscles).

52. 52 3. Reduced hepatic gluconeogenesis. (reduce glucose release from the liver). liver). 4. Reduced plasma glucagon level. level. 5.Increase insulin binding to insulin receptors.

53. 53 6. Inhibits LDL and cholesterol with rise in HDL. cholesterol with rise in HDL. 7. Rarely can cause hypoglycemia. hypoglycemia. 8. Proven to decrease CV mortality.

54. 54 Metformin Well absorbed orally Well absorbed orally Not metabolized Not metabolized Excreted by the kidneys Excreted by the kidneys T1/2 2 hours T1/2 2 hours Contraindicated in: renal and liver failure, pregnancy, Contraindicated in: renal and liver failure, pregnancy,

55. 55 severe infections, cardio- respiratory failure and alcohol abuse. severe infections, cardio- respiratory failure and alcohol abuse. Adverse effects 1. GIT upset. 2. Interfere with vit B12 absorption absorption 3. Rarely lactic acidosis.

56. 56 C - α glucosidase inhibitor ACARBOSE, MIGLITOL Delays the digestion of carbohydrates,so reduces carbohydrate absorption in the intestine. Delays the digestion of carbohydrates,so reduces carbohydrate absorption in the intestine.

57. 57  They reversibly inhibiting membrane bound membrane bound α -glucosidase in the α -glucosidase in the intestinal brush borders intestinal brush borders (enzyme responsible for (enzyme responsible for hydrolysis of hydrolysis of oligosaccharides to oligosaccharides to glucose ). glucose ).

58. 58  They do not increase insulin release nor action on the target tissues. Does not cause hypoglycemia Does not cause hypoglycemia Acarbose is Poorly absorbed Acarbose is Poorly absorbed and metabolized by intestinal bacteria. and metabolized by intestinal bacteria.

59. 59 Miglitol is well absorbed, excreted unchanged in the urine. Miglitol is well absorbed, excreted unchanged in the urine. They can cause flatulence, diarrhea and abdominal cramping. They can cause flatulence, diarrhea and abdominal cramping. Can be used with other drugs. Can be used with other drugs.

60. 60 D- Thiazolidinediones or glitazones Pioglitazone Rosiglitazone They reduce tissue resistance to insulin. They reduce tissue resistance to insulin. Used in combination with metformin or sulphanylureas. Used in combination with metformin or sulphanylureas. Onset of action is slow. Onset of action is slow.

61. 61 Both drugs are absorbed well  Extensively bound to albumin.  Metabolized by CYP450.  Excretion by the urine (unchanged drug by bile).  Can be given in renal failure

62. 62 *Not recommended in pregnancy. *Pioglitazone can be used with insulin. *Rosiglutazone is not used with insulin( causing edema). It can be used with metformin and glyburide to improve sugar control. It can be used with metformin and glyburide to improve sugar control.

63. 63 Causes : Liver toxicity Weight gain Raises LDL level (rosiglitazone). LDL is not affected with the use of pioglutazone. Both may raise HDL. Headache, anemia.