1. Diabetes Mellitus Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University August 2015 November 15 1 Munir Gharaibeh, MD, PhD, MHPE

2. Diabetes Mellitus Diabetes is a major cause of heart disease and stroke Diabetes is a major cause of heart disease and stroke Diabetes is a leading cause of renal failure, nontraumatic lower-limb amputations, and blindness. Diabetes is a leading cause of renal failure, nontraumatic lower-limb amputations, and blindness. Diabetes is the seventh leading cause of death in the United States Diabetes is the seventh leading cause of death in the United States November 15 2 Munir Gharaibeh, MD, PhD, MHPE

3. Type I; Juvenile-onset; IDDM - 10-20% of diabetics - Most commonly occurs in childhood or adolescence but may occur at any age - Mainly affects children at an age 10-14, not reported in children less than 6 months of age. November 15 3 Munir Gharaibeh, MD, PhD, MHPE

4. Type I; Juvenile-onset; IDDM - Patients have little or no pancreatic function - Often present with ketoacidosis - Characterized by downhill course-severe type of DM with high mortality. - Easy to diagnose ( severe weight loss; easy fatigability; polyuria; polydipsia; polyphagia etc … ) November 15 4 Munir Gharaibeh, MD, PhD, MHPE

5. Type I; Juvenile-onset; IDDM - Usually associated with HLA types histocompatibility antigens and presence of β-islet cell antibodies suggesting an autoimmune-mediated destruction of insulin producing cells leading to a near total loss of endogenous insulin production. - Insulin lack could be idiopathic November 15 5 Munir Gharaibeh, MD, PhD, MHPE

6. Type II; Maturity or Adult-onset; IIDM - Represents 80-90% of diabetics - Usually discovered accidentally after age 30-40 yrs 30-40 yrs - Most patients are obese. - More common in females as compared to males. - Patients have strong family history of DM (?genetic background). November 15 6 Munir Gharaibeh, MD, PhD, MHPE

7. Type II; Maturity or Adult-onset; IIDM - Most cases have mild polyuria and fatigue. - Ketoacidosis is rare, unless in certain circumstances of unusual stress. - Insulin blood levels could be low, normal or high. - Insulin resistance is common (pre- receptor; receptor; post-receptor mechanisms) November 15 7 Munir Gharaibeh, MD, PhD, MHPE

8. Clinical Picture of DM Early manifestations: Early manifestations: Polyurea, Polydipsia, Polyphagia, Ketoacidosis (type I). Late manifestations or complications: Late manifestations or complications: Atherosclerosis, IHD, Retinopathy, Nephropathy, Neuropathy November 15 8 Munir Gharaibeh, MD, PhD, MHPE

9. Diagnosis of DM - Clinical manifestations - Laboratory Tests: - Random blood sugar (RBS) - Fasting blood sugar - Glycosylated hemoglobin - Glucose tolerance test November 15 9 Munir Gharaibeh, MD, PhD, MHPE

10. Goals of DM Treatment Ensure good patient-clinic relationship. Ensure good patient-clinic relationship. Control symptoms. Control symptoms. Prevent acute metabolic crisis of ketoacidosis and hypoglycemia. Prevent acute metabolic crisis of ketoacidosis and hypoglycemia. Maintain normal growth and body weight. Maintain normal growth and body weight. Encourage self-reliance and self-care. Encourage self-reliance and self-care. Eliminate risk factors: Smoking, BP, lipids. Eliminate risk factors: Smoking, BP, lipids. November 15 10 Munir Gharaibeh, MD, PhD, MHPE

11. Goals of DM Treatment Prevent psychological complications: Prevent psychological complications: Accept restrictions on life style. Accept restrictions on life style. Diet control Diet control Monitoring blood glucose and insulin adjustment Monitoring blood glucose and insulin adjustment Know manifestations of hypoglycemia & how to avoid them. Know manifestations of hypoglycemia & how to avoid them. Early treatment of complications: Photocoagulation, foot care advices... Early treatment of complications: Photocoagulation, foot care advices... November 15 11 Munir Gharaibeh, MD, PhD, MHPE

12. Management of DM - Type I: Diet + Insulin therapy - Type II: Diet + exercise ± Oral hypoglycemic agents ± Insulin November 15 12 Munir Gharaibeh, MD, PhD, MHPE

13. Biosynthesis of Insulin RER Golgi Insulin RER Golgi Insulin Preproinsulin Proinsulin C-peptide C-peptide Proinsulin has slight insulin-like activity (1/10 the potency of insulin) C-peptide is devoid of any insulin-like activity November 15 13 Munir Gharaibeh, MD, PhD, MHPE

14. Insulin is a protein composed of two chains. A (21 a.a) and B (30 a.a); combined through disulfied bonds November 15 14 Munir Gharaibeh, MD, PhD, MHPE

15. Secretion of Insulin Ca ++ dependent Blood glucoselevel is the major regulator. Factors/drugs ↑ release: Factors/drugs ↑ release: Glucose; AAs; FAs; GH; glucagon; ACTH; sulfonylureas; β-adrenergics, cholinergic drugs … Factors/drugs ↓ release: Factors/drugs ↓ release: α-adrenergics; anticholinergics; phenytoin; alloxan; streptozocin. November 15 15 Munir Gharaibeh, MD, PhD, MHPE

16. Mechanism of Action of Insulin Insulin binds to its receptor leading to phosphorylation of insulin-receptor complex which in turn starts many protein -kinase activation cascades. These include: translocation of Glu transporter-4 to the plasma membrane and influx of glucose, glycogen synthesis, glycolysis and fatty acid synthesis. November 15 16 Munir Gharaibeh, MD, PhD, MHPE

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18. Effects of Insulin - ↑ Glucose uptake or transport into muscles and adipocytes. - ↑ Glucose oxidation by muscles. - ↓ Hepatic gluconeogenesis. - ↑ Hepatic glycogen synthesis and storage. - ↓ Glycogenolysis. - ↑ AA uptake and protein synthesis by muscles and liver. - ↓ Lipolysis. - ↓ Ketogenesis. November 15 18 Munir Gharaibeh, MD, PhD, MHPE

19. Insulin Preparations Natural:BovinePorcine.Human: limited supply, short t 1/2 and has problems of poor stability. Biosynthetic: rHI November 15 19 Munir Gharaibeh, MD, PhD, MHPE

20. Insulin Preparations - Potency: Human > porcine > bovine Allergy: - Bovine > porcine > human(proinsulin is a major contaminant). Insulins are classified according to duration of action (DOA) November 15 20 Munir Gharaibeh, MD, PhD, MHPE

21. Factors Affecting Insulin Absorption - Site of injection: abdomen > arm > buttocks > thigh. - Exercise increases blood flow at site. - Depth of injection. - Concentration and dose of insulin. - Addition of protamine or isophane to insulin preparations delays absorption and hence duration of action. November 15 21 Munir Gharaibeh, MD, PhD, MHPE

22. Insulin Preparations Ultra-rapid onset; very short acting: O (hr) P (hr) DOA (hr) O (hr) P (hr) DOA (hr) - Insulin Lispro 0.25-0.5 0.5-1 3-4 - Insulin Aspart - - Insulin Glulisine Rapid onset and short acting: - Crystalline zinc 0.3-0.7 2-4 5-8 (Regular; Soluble) (Regular; Soluble) - Insulin zinc prompt (Semilente) (Semilente) November 15 22 Munir Gharaibeh, MD, PhD, MHPE

23. Insulin Preparations Intermediate onset and action: - Insulin zinc suspension 1-2 6-12 18-24 (Lente) (Lente) - Isophane insulin suspension (NPH; Humulin) (NPH; Humulin) Slow onset and action: - Protamine zinc suspension 4-6 14-20 24-36 - Extended insulin zinc suspension (Ultralente) (Ultralente) November 15 23 Munir Gharaibeh, MD, PhD, MHPE

24. Insulin Preparations Peakless Insulins: Insulin Glargine 1-2 - 24-36 Insulin Detemir Mixed insulins: Int. + short 0.5-1 3-8 20-24 Int. + long 2-4 4-16 22-24 November 15 24 Munir Gharaibeh, MD, PhD, MHPE

25. Insulin Preparations Advantages of peakless insulins over intermediate-acting insulins: Advantages of peakless insulins over intermediate-acting insulins: - Constant circulating insulin over 24hr with no pronounced peak. - Reduced risk of hypoglycemia (especially nocturnal hypoglycemia). - Clear solution that does not require resuspension before administration. November 15 25 Munir Gharaibeh, MD, PhD, MHPE

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28. All insulin preparations are mainly given S.C; except regular insulin,, which can also be given IV All insulin preparations are mainly given S.C; except regular insulin, insulin Glulisine & insulin Aspart, which can also be given IV November 15 28 Munir Gharaibeh, MD, PhD, MHPE

29. Methods of insulin administration - Insulin Syringes - Pre-filled insulin pens - Insulin Jet injectors - External insulin pump Methods under clinical trials: - Oral tablets - Inhaled aerosol - Intranasal, - Transdermal - Buccal spray November 15 29 Munir Gharaibeh, MD, PhD, MHPE

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32. Side Effects of Insulin Therapy - Hypoglycemia; manifested as symptoms of sympathetic ove ractivity. - Lipodystrophy - Allergy - Induration November 15 32 Munir Gharaibeh, MD, PhD, MHPE

33. November 15 33 Munir Gharaibeh, MD, PhD, MHPE Oral Hypoglycemic Agents

34. Oral Hypoglycemic Agents Biguanides Metformin Only effective in type II DM (effects require insulin). - ↓ CHO absorption. - ↓ Hepatic gluconeogenesis; ↑ glycolysis. - ↓ Glucagon release. - ↑ Peripheral utilization of glucose. November 15 34 Munir Gharaibeh, MD, PhD, MHPE

35. Biguanides Side effects: - Nausea and vomiting, metallic taste. - Abdominal pain and diarrhea. - Hypoglycemia is rare. - Lactic acidosis. - ↓ Vitamin B 12 absorption. November 15 35 Munir Gharaibeh, MD, PhD, MHPE

36. Sulfonylureas First Generation t 1/2 DOA First Generation t 1/2 DOA Tolbutamide 7 6-12 Chlorpropamide 34 24-72 Tolazamide 7 12-16 Acetohexamide 5 12-18 November 15 36 Munir Gharaibeh, MD, PhD, MHPE

37. Sulfonylureas Second Generation t 1/2 DOA Glyburide (Glibenclamide) 4 20-24 Glipizide 3 14-16 Gliclazide 8 10-15 Glimeperide 5 18-22 November 15 37 Munir Gharaibeh, MD, PhD, MHPE

38. Actions of Sulfonylureas - ↑ Insulin release (major MOA) (Receptor- mediated effect) - ↑ Number of β-cells and insulin receptors. - ↑ Peripheral cells sensitivity to insulin effect. - ↑ Insulin binding to its receptors. - ↑ Insulin affinity to its receptors. - ↓ Hepatic gluconeogenesis. - ↓ Glucagon release. - ↑ Somatostatin release. November 15 38

39. Mechanism of Action of Sulfonylureas - - Bind to receptors linked to ATP-ase sensitive K + ion channel; causing depolarization and opening of voltage dependent Ca ++ channels and influx of Ca ++. - - Ca ++ binds to Calmodulin which activates kinases that cause exocytosis of insulin from the secretory granules. - - Beta cells sense glucose more efficiently, producing more insulin. November 15 39 Munir Gharaibeh, MD, PhD, MHPE

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41. Sulfonylureas Sulfonylureas differ in potency, bioavailability, duration, tolerance, extent of protein binding, and metabolic fate. Sulfonylureas differ in potency, bioavailability, duration, tolerance, extent of protein binding, and metabolic fate. Sulfonylureas have many interactions: Sulfonylureas have many interactions: Propranolol, sulfa drugs, oral anticoagulants, aspirin, ↑ effects of sulfonylureas Clinical uses: Clinical uses: - DM - Nocturnal enuresis (Glyburide → ↑ ADH release) November 15 41 Munir Gharaibeh, MD, PhD, MHPE

42. Side Effects of Sulfonylureas - Hypoglycemia, like insulin. - Nausea, vomiting, dizziness. - Allergy, due to sulfa moiety. - Agranulocytosis. - Hepatic dysfunction. November 15 42 Munir Gharaibeh, MD, PhD, MHPE

43. α-Glucosidase Inhibitors Acarbose Miglitol (more potent) Effective in type II DM ↓ CHO absorption Inhibit α-glucosidase, an enzyme in the brush border of intestine responsible for breakdown of CHO, and hence ↓ glucose absorption. ↓ Fasting and postprandial hyperglycemia. November 15 43 Munir Gharaibeh, MD, PhD, MHPE

44. α-Glucosidase Inhibitors ↓ Insulin secretion, thus sparing β-cells. Reduce incidence and risk of atherosclerosis in diabetics Taken before or with meals. Could be given with insulin and sulfonylureas. Cause abdominal pain and diarrhea. November 15 44 Munir Gharaibeh, MD, PhD, MHPE

45. Prandial Glucose Regulators RepaglinideNateglinideMitiglinide… ↑ Insulin release (similar action to sulfonylureas). Taken before meals. Could be taken with metformin or insulin. Hypoglycemia is infrequent. November 15 45 Munir Gharaibeh, MD, PhD, MHPE

46. Thiazolidinediones (TZD ’ s) Rosiglitazone (withdrawn) Pioglitazone (has shorter t 1/2 ) Troglitazone Used in NIDDM patients who have insulin resistance. Peroxisome Proliferator-Activated Receptors (PPAR) agonists. PPAR ’ s are members of the superfamily of ligand- activated transcription factors located in adipose tissue, skeletal muscle and large intestine. November 15 46 Munir Gharaibeh, MD, PhD, MHPE

47. Thiazolidinediones (TZD ’ s) ↑ Sensitivity of peripheral tissues to insulin effect. ↓ Glucose exit or output from the liver. ↓insulin resistance. Good for patients with ↑ insulin levels, which are also believed to be responsible for ↑ B.P,↑ lipids and atherosclerosis in patients with insulin resistance. November 15 47 Munir Gharaibeh, MD, PhD, MHPE

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49. Incretin Hormones 2 polypeptides which ↑ glucose absorption by gut. 1. Glucagon-like peptide-1 (GLP-1). Produced by the L cells in ileum and colon: A.↑ Insulin release and ↓ glucagon release following meals. A.↑ Insulin release and ↓ glucagon release following meals. B. ↓ Gastric emptying and induction of satiety. B. ↓ Gastric emptying and induction of satiety. November 15 49 Munir Gharaibeh, MD, PhD, MHPE

50. Glucagon-like peptide-1 (GLP-1) November 15 50 Munir Gharaibeh, MD, PhD, MHPE

51. Incretin Hormones 2. Glucose-dependent insulinotropic polypeptide (GIP) Produced by the K cells in the proximal gut (duodenum & proximal jejunum) Produced by the K cells in the proximal gut (duodenum & proximal jejunum) Stimulates glucose-dependent insulin release from β-cells. Both GLP & GIP are metabolized by the enzyme dipeptidyl peptidase-4 (DPP-4) which is present in gut, liver, kidneys, lymphocytes and endothelial cells. November 15 51 Munir Gharaibeh, MD, PhD, MHPE

52. Incretin Hormones Normal people Type 2 D.M patients Normal people Type 2 D.M patients Incretin effect Incretin effect Oral Oral Insulin glucose Blood I.V Level Time (min) Time (min) Time (min) Time (min) November 15 52 Munir Gharaibeh, MD, PhD, MHPE

53. Incretin Hormones Inhibitors Sitagliptin Sitagliptin Gemigliptin Gemigliptin Linagliptin Linagliptin Orally effective selective DPP-4 inhibitors ↑ blood levels of GLP-1, GIP, insulin, and C-peptide and ↓ glucagon blood levels. A daily oral dose reduces high blood glucose and HbA1c levels. Could be taken with metformin or sulfonylureas Hypoglycemia is not common. November 15 53 Munir Gharaibeh, MD, PhD, MHPE

54. Incretin Hormones Agonists Exenatide Exenatide Liraglutide Liraglutide Synthetic analogs to GLP-1 ↑ insulin and ↓ glucagon blood levels Considered as an adjunct therapy to metformin or sulfonylureas in patients with type 2 DM who still have suboptimal glycemic control. Given S.C, 60 min before meal. Hypoglycemia is infrequent November 15 54 Munir Gharaibeh, MD, PhD, MHPE

55. Aldose Reductase (AR) Inhibitors EpalrestatRanirestatFidarestat AR AR AR AR Glucose Fructose Sorbitol Glucose Fructose Sorbitol Sorbitol has been implicated in the pathogenesis of retinopathy, neuropathy and nephropathy AR inhibitors proved to improve diabetic polyneuropathy. Orally effective. November 15 55 Munir Gharaibeh, MD, PhD, MHPE

56. Other Drugs - Somatostatin - In low doses → ↓ glucagon release Drugs Under Evaluation: ACEI’s; ARB’s; Statins. ACEI’s; ARB’s; Statins. Pancreatic transplantation and gene therapy November 15 56 Munir Gharaibeh, MD, PhD, MHPE

57. Drugs ↓ Glucose Levels β-blockers Salicylates, indomethacin, naproxin Alcohol.SulfonamidesClofibrate Anabolic steroids. Lithium Ca ++ Ampicillin Bromocriptine. November 15 57 Munir Gharaibeh, MD, PhD, MHPE

58. Drugs ↑ Glucose Levels β-agonists. Thiazides and loop diuretics. Glucocorticoids Oral contraceptive drugs Ca ++ channel blockers Phenytoin.MorphineHeparinNicotineClonidineDiazoxide H 2 -receptor blockers November 15 58 Munir Gharaibeh, MD, PhD, MHPE