Munir Gharaibeh, MD, PhD, MHPE Diabetes Mellitus Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University August 2015 August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Diabetes Mellitus Diabetes is a major cause of heart disease and stroke Diabetes is a leading cause of renal failure, lower-limb amputations, and blindness. Diabetes is the seventh leading cause of death in the United States August 18 Munir Gharaibeh, MD, PhD, MHPE

Type I; Juvenile-onset; IDDM 10-20% of diabetics Most commonly occurs in childhood or adolescence but may occur at any age August 18 Munir Gharaibeh, MD, PhD, MHPE

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…) August 18 Munir Gharaibeh, MD, PhD, MHPE

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 history of DM (?genetic background). August 18 Munir Gharaibeh, MD, PhD, MHPE

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) August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Clinical Picture of DM Early manifestations: Polyurea, Polydipsia, Polyphagia, Ketoacidosis (type I). Late manifestations or complications: Atherosclerosis, IHD, Retinopathy, Nephropathy , Neuropathy August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Management of DM -Type I: Diet + Insulin therapy -Type II: Diet + exercise ± Oral hypoglycemic agents ± Insulin August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Secretion of Insulin Ca++ dependent Blood glucoselevel 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; streptozocin. August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE 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. August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Insulin Preparations Natural: Bovine Porcine. Old preparations, no longer available in Jordan. Impure, cause allergy. Biosynthetic: rHI August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Insulin Preparations - Potency: Human > porcine > bovine Allergy: - Bovine > porcine > human(proinsulin is a major contaminant). Insulins are classified according to duration of action (DOA) August 18 Munir Gharaibeh, MD, PhD, MHPE

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. August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Insulin Preparations Ultra-rapid onset; very short acting: 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) Insulin zinc prompt (Semilente) August 18 Munir Gharaibeh, MD, PhD, MHPE

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

Munir Gharaibeh, MD, PhD, MHPE 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 August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Insulin Preparations 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. August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE All insulin preparations are mainly given S.C; except regular insulin, insulin Glulisine & insulin Aspart , which can also be given IV August 18 Munir Gharaibeh, MD, PhD, MHPE

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 August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE August 18 Munir Gharaibeh, MD, PhD, MHPE

Side Effects of Insulin Therapy Hypoglycemia; manifested as symptoms of sympathetic ove ractivity. Lipodystrophy Allergy Induration August 18 Munir Gharaibeh, MD, PhD, MHPE

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. August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Biguanides Side effects: Nausea and vomiting, metallic taste. Abdominal pain and diarrhea. Hypoglycemia is rare. Lactic acidosis. ↓ Vitamin B12 absorption. August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Sulfonylureas First Generation t1/2 DOA Tolbutamide 7 6-12 Chlorpropamide 34 24-72 Tolazamide 7 12-16 Acetohexamide 5 12-18 August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Sulfonylureas Second Generation t1/2 DOA Glyburide (Glibenclamide) 4 20-24 Glipizide 3 14-16 Gliclazide 8 10-15 Glimeperide 5 18-22 August 18 Munir Gharaibeh, MD, PhD, MHPE

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. August 18

Munir Gharaibeh, MD, PhD, MHPE Sulfonylureas Sulfonylureas differ in potency, bioavailability, duration, tolerance, extent of protein binding, and metabolic fate. Sulfonylureas have many interactions: Propranolol, sulfa drugs, oral anticoagulants, aspirin, ↑ effects of sulfonylureas Clinical uses: DM Nocturnal enuresis (Glyburide → ↑ ADH release) August 18 Munir Gharaibeh, MD, PhD, MHPE

Side Effects of Sulfonylureas Hypoglycemia, like insulin. Nausea, vomiting, dizziness. Allergy, due to sulfa moiety. Agranulocytosis. Hepatic dysfunction. August 18 Munir Gharaibeh, MD, PhD, MHPE

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. August 18 Munir Gharaibeh, MD, PhD, MHPE

Prandial Glucose Regulators Repaglinide Nateglinide Mitiglinide… ↑ Insulin release (similar action to sulfonylureas). Taken before meals. Could be taken with metformin or insulin. Hypoglycemia is infrequent. August 18 Munir Gharaibeh, MD, PhD, MHPE

Thiazolidinediones (TZD’s) Rosiglitazone Pioglitazone Troglitazone Peroxisome Proliferator-Activated Receptors (PPAR) agonists. ↑ Sensitivity of peripheral tissues to insulin effect. ↓ Glucose exit or output from the liver. ↓insulin resistance. August 18 Munir Gharaibeh, MD, PhD, MHPE

Incretin Hormones Inhibitors Sitagliptin Gemigliptin Linagliptin Orally effective selective DPP-4 inhibitors ↑ blood levels of GLP-1, GIP, insulin, and C-peptide and ↓ glucagon blood levels. August 18 Munir Gharaibeh, MD, PhD, MHPE

Aldose Reductase (AR) Inhibitors Epalrestat Ranirestat Fidarestat AR AR Glucose Fructose Sorbitol Sorbitol has been implicated in the pathogenesis of retinopathy, neuropathy and nephropathy AR inhibitors proved to improve diabetic polyneuropathy. Orally effective. August 18 Munir Gharaibeh, MD, PhD, MHPE

Munir Gharaibeh, MD, PhD, MHPE Other Drugs Somatostatin In low doses → ↓ glucagon release Drugs Under Evaluation: ACEI’s; ARB’s; Statins. Pancreatic transplantation and gene therapy August 18 Munir Gharaibeh, MD, PhD, MHPE