Diabetes Mellitus

1. Diabetes Mellitus Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University April 2014 Munir Gharaibeh, MD, PhD, MHPE

2. Diabetes Mellitus A disease characterized by high blood sugar level? A disease characterized by insulin deficiency? A metabolic disorder manifested by abnormalities in CHO, lipid and protein metabolism Munir Gharaibeh, MD, PhD, MHPE

3. Diabetes Mellitus • Diabetes is a major cause of heart disease and stroke • Diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness among adults in the United States • Diabetes is the seventh leading cause of death in the United States Munir Gharaibeh, MD, PhD, MHPE

4. 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 kids less than 6 months. Munir Gharaibeh, MD, PhD, MHPE

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

6. Type I; Juvenile-onset; IDDM • Type I DM in most cases is associated with HLA types (histocompatibility antigens) and presence of β-islet cell antibodies suggesting an autoimmune-mediated destruction of insulin producing cells and hence to a near total loss of endogenous insulin production • Insulin lack could be idiopathic Munir Gharaibeh, MD, PhD, MHPE

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

8. 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) Munir Gharaibeh, MD, PhD, MHPE

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

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

11. Goals of DM Treatment Ensure good patient-clinic relationship. Control symptoms. Prevent acute metabolic crisis of KA & hypoglycemia. Maintain normal growth & BW. Encourage self-reliance & self-care. Eliminate risk factors: Smoking, ↑ BP,↑ lipids… Munir Gharaibeh, MD, PhD, MHPE

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

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

14. Biosynthesis of Insulin RERGolgi Insulin PreproinsulinProinsulin C-peptide Proinsulin has slight insulin-like activity (1/10 the potency of insulin) C-peptide is devoid of any insulin-like activity Munir Gharaibeh, MD, PhD, MHPE

15. Insulin Protein; A (21 aa) & B (30 aa) chains; disulfied bonds Munir Gharaibeh, MD, PhD, MHPE

16. Secretion of Insulin Ca++ dependent [blood glucose] is the major regulator Factors/drugs ↑ release: Glucose; AAs; FAs; GH; glucagon; ACTH; sulfonylureas; β-adrenergics, cholinergic drugs… Factors/drugs ↓ release: α-adrenergics; anticholinergics; phenytoin; alloxan; streptozotocin (streptozocin) Munir Gharaibeh, MD, PhD, MHPE

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

18. Munir Gharaibeh, MD, PhD, MHPE

19. Effects of Insulin ↑ glucose uptake or transport → muscles & adipocytes ↑ glucose oxidation by muscles ↓ hepatic gluconeogenesis ↑ hepatic glycogen synthesis and storage; ↓ glycogenolysis ↑ AA uptake and protein synthesis by muscles and liver ↓ lipolysis ↓ ketogenesis Munir Gharaibeh, MD, PhD, MHPE

20. Insulin Preparations Natural: Bovine Porcine. Human: limited supply, short t1/2 & problems with stability Biosynthetic:rHI Munir Gharaibeh, MD, PhD, MHPE

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

22. 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. Munir Gharaibeh, MD, PhD, MHPE

23. Insulin Preparations ** Ultra-rapid onset; very short acting: O (hr)P (hr)DOA (hr) Insulin Lispro0.25-0.5 0.5-1 3-4 Insulin Aspart Insulin Glulisine ** Rapid onset & short acting: Crystalline zinc 0.3-0.7 2-4 5-8 (Regular; Soluble) Insulin zinc prompt (Semilente) Munir Gharaibeh, MD, PhD, MHPE

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

25. Insulin Preparations PeaklessInsulins: 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 Munir Gharaibeh, MD, PhD, MHPE

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

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

30. 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 Munir Gharaibeh, MD, PhD, MHPE

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33. Side Effects of Insulin Therapy Hypoglycemia; ↑ sympathetic activity Lipodystrophy Allergy Induration Munir Gharaibeh, MD, PhD, MHPE

34. Oral Hypoglycemic Agents Munir Gharaibeh, MD, PhD, MHPE

35. Oral Hypoglycemic AgentsBiguanides Metformin Metformin is only effective in type II DM (effects require insulin) ↓ CHO absorption ↓ hepatic gluconeogenesis; ↑ glycolysis ↓ glucagon release ↑ peripheral utilization of glucose Munir Gharaibeh, MD, PhD, MHPE

36. Biguanides Side effects: N & V, metallic taste Abdominal pain and diarrhea Hypoglycemia is rare. Lactic acidosis. ↓ Vitamin B12 absorption. Munir Gharaibeh, MD, PhD, MHPE

37. Sulfonylureas First Generationt1/2DOA Tolbutamide 7 6-12 Chlorpropamide 34 24-72 Tolazamide 7 12-16 Acetohexamide 5 12-18 Munir Gharaibeh, MD, PhD, MHPE

38. Sulfonylureas Second Generationt1/2DOA Glyburide (Glibenclamide) 4 20-24 Glipizide 3 14-16 Gliclazide 8 10-15 Glimeperide 5 18-22 Munir Gharaibeh, MD, PhD, MHPE

39. Actions of Sulfonylureas ↑ insulin release (major MOA) (Receptor-mediated effect) ↑ no. of β-cells, ↑ no. of insulin receptors ↑ peripheral cells sensitivity to insulin effect ↑ insulin binding to its receptors ↑ insulin affinity to its receptors ↓ hepatic gluconeogenesis ↓ glucagon release, ↑ somatostatin release… Munir Gharaibeh, MD, PhD, MHPE

40. Mechanism of Action of Sulfonylureas • Drug binds 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. Munir Gharaibeh, MD, PhD, MHPE

41. Munir Gharaibeh, MD, PhD, MHPE

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

43. Side Effects of Sulfonylureas Hypoglycemia, like insulin. N & V, dizziness. Allergy. Agranulocytosis. Hepatic dysfunction. Munir Gharaibeh, MD, PhD, MHPE

44. 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. Munir Gharaibeh, MD, PhD, MHPE

45. α-glucosidase inhibitors α-glucosidase inhibitors also ↓ insulin secretion following administration, 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. Munir Gharaibeh, MD, PhD, MHPE

46. Prandial Glucose Regulators Repaglinide Nateglinide Mitiglinide… ↑ insulin release (similar action to sulfonylureas). Taken before meals (every meal). Could be taken with metformin or insulin. Hypoglycemia is infrequent. Munir Gharaibeh, MD, PhD, MHPE

47. Thiazolidinediones (TZD’s) Rosiglitazone(? withdrawn) Pioglitazone (has shorter t1/2) Troglitazone... Used in NIDDM patients who have insulin resistance. PeroxisomeProliferator-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 Munir Gharaibeh, MD, PhD, MHPE

48. 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 believed to be responsible for ↑ B.P,↑ lipids and atherosclerosis in patients with insulin resistance Munir Gharaibeh, MD, PhD, MHPE

49. Munir Gharaibeh, MD, PhD, MHPE

50. 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. ↑ insulin release and ↓ glucagon release following meals. ↓ gastric emptying & leads to induction of satiety. Munir Gharaibeh, MD, PhD, MHPE