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Insulin and oral hypoglycemic drugs

Insulin and oral hypoglycemic drugs. Diabetes Mellitus. A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both 194 million people worldwide 90% cases are Type 2. CLASSIFICATION. TYPE 1 (IDDM,10%)

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Insulin and oral hypoglycemic drugs

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  1. Insulin and oral hypoglycemic drugs

  2. Diabetes Mellitus • A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both • 194 million people worldwide • 90% cases are Type 2

  3. CLASSIFICATION • TYPE 1 (IDDM,10%) • Deficiency of insulin secretion • Genetic predisposition and possible links to viral infections and environmental factors • Possible autoimmune process with destruction of beta pancreatic cells • Require insulin supplementation, prone to develop DKA (酮症酸中毒）

  4. CLASSIFICATION • TYPE 2 (NIDDM,90%) • Resistance to action of insulin on target organs • Decrease in insulin production • Increased risk with obesity high fat, high caloric diets • Stronger genetic predisposition • Variety of initial presentations: HHNKS (高血糖高渗性非酮症综合征), nephropathy, retinopathy, neuropathies • Disease can be delayed or prevented with life style changes

  5. CLINICAL FEATURES • Polyuria • Polydipsia • Polyphagia • Weight loss TYPE 1 DM-- acute, severe TYPE 2 DM-- chronic, less severe

  6. Therapy of Diabetes Mellitus • Diet • Exercise • Insulin and its enhancers • Oral hypoglycemic drugs

  7. Insulin and its action enhancers

  8. Structure of insulin

  9. Insulin • 1. Pharmacological effects • Carbohydrate metabolism:reducing blood glucose levels by glucose oxidation and glycolysis ,glycogenolysis, glycogen synthesis , gluconeogenesis  • (2) Lipid metabolism:fat synthesis , lipolysis , plasma free fatty acids , ketone bodies  • (3) Protein metabolism:active transport of amino acids , incorporation of amino acids into protein , protein catabolism  • HR ,myocardial contractility , renal blood flow • Mechanism of insulin actions • Interacting with insulin receptor

  10. Insulin • 1. Pharmacological effects • Carbohydrate metabolism:reducing blood glucose levels by glycose oxidation and glycolysis ,glycogenolysis , glycogen synthesis , gluconeogenesis  • (2) Lipid metabolism:fat synthesis , lipolysis , plasma free fatty acids , ketone bodies  • (3) Protein metabolism:active transport of amino acids , incorporation of amino acids into protein , protein catabolism  • HR , myocardial contractility , renal blood flow • Mechanism of insulin actions • Interacting with insulin receptor

  11. Interaction between insulin and its receptor IRS: insulin receptor substrate tyr: tyrosine P: phosphate

  12. Insulin • 2. Clinical uses • Type 1 diabetes mellitus • (2) Type 2 diabetes mellitus:failure to other drugs or diet control • (3) Diabetic complications:diabetic ketoacidosis (酮症酸中毒), hyperosmotic nonketotic coma（高渗性非酮症性昏迷） • (4) Critical situations of diabetic patients:fever, severe infection, pregnancy, trauma, operation • (5) Others:intracellular lack of K+

  13. 3. Preparations

  14. Rapid Acting Insulin Analogues Current agents include lispro (赖脯胰岛素), aspart (门冬胰岛素), and glulisine (赖谷胰岛素). （人胰岛素类似物） Remain monomeric after injection, resulting in rapid absorption, and relatively rapid onset and offset. Onset of action is 5-15 minutes, with peak action at 30-60 minutes and duration of ~2-5 hours. Advantages include: increased convenience- can take just prior to meal. better postprandial glycemic control. Disadvantages include: short duration of action- can be problematic in Type 1 diabetic without basal insulinization, as with bedtime NPH. more expensive than regular insulin (~double the cost).

  15. 3. Preparations

  16. Regular Insulin Referred to as clear or unmodified insulin. Onset of action 30-60 minutes, Peak action 2-4 hours, Duration of action: 5-7 hours. Advantages: Inexpensive Long track record of safety. Disadvantages: Need to take doses 30-45 minutes prior to eating a meal. Effect is not truly rapid… it is delayed which can result in postprandial hyperglycemia, late hypoglycemia.

  17. 3. Preparations

  18. Glargine (Lantus 甘精胰岛素) Long acting insulin analogue. Onset is ~90 minutes, and it is virtually peakless. Duration is 20-24 hours. Provides ~flat basal insulinization. More expensive Cannot be mixed with other insulins. • The Medical Letter, Vol 43, August 6, 2001

  19. Mixed insulin • 70-30: human monocomponent insulin (单组份人胰岛素) 30% , Human Insulin Isophane Suspension (精蛋白锌人胰岛素）70%. • 50-50: human monocomponent insulin (单组份人胰岛素) 50% , Human Insulin Isophane Suspension (精蛋白锌人胰岛素）50%. • Onset:0.5h, peak 2-12h, duration:16-24h. 30min before breakfast.

  20. Insulin 4. Adverse effects (1) Hypersensitivity: treated with H1 receptor antagonist, glucocorticoids, replaced by human or high purity insulin (2) Hypoglycemia:(sweating, hunger, weakenss, tachycardia, blurred vision, headache, coma, shock, etc.), drink glucose contained water, or treated with 50% glucose (3) Lipoatrophy: localized in injection sites (4) Insulin resistance: Acute: stress etc. induced, need large dose of insulin Chronic: need >200U/d and no complication

  21. Insulin 4. Adverse effects (5) Increase body weight (6) Ametropic eye 屈光不正 (7) Edema

  22. Insulin action enhancers (oral hypoglycemic drugs) Thiazolidinediones (TDs) 噻唑烷酮类化合物 Biguanides (双胍类)

  23. Insulin action enhancers Thiazolidinediones (TDs) 噻唑烷酮类化合物 Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮 Troglitazone 曲格列酮

  24. Insulin action enhancers Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮

  25. Insulin action enhancers 1. Pharmacological effects Selective agonists for nuclear peroxisome proliferator-activated receptor- (PPAR, 过氧化物酶增殖体激活受体). (1) Fat cells differentiate to a lot of small fat cells, and increase GLUT-4 expression (2) Increase signal transmission of insulin (Rosiglitazone increase insulin receptors) (3) Decrease leptin, IL-6 and TNF-alpha expression in fat cells (4) increase GLUT1,4 transcription and expression (5) Inhibit VEGF mediated angiogenesis, to prevent the complications. (6) Increase adiponectin level, recover the function of B cells

  26. Insulin action enhancers 1. Pharmacological effects (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fat acid, LDL  (3) Antihypertensive effects (4) Effect on vascular complications in type 2 patients (5) Recover the function of B cells

  27. Insulin action enhancers 2. Clinical uses Used for treatment of insulin-resistant diabetic patients or type 2 patients 3. Adverse effects Edema, headache, myalgia, GI reactions, hepatic damage (troglitazone)

  28. Insulin action enhancers Biguanides（双胍类） Metformin 二甲双胍（甲福明） Phenformin 苯乙双胍（苯乙福明）

  29. Biguanides 1.Pharmacilogical effects increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut, gluconeogenesis, and glucagon release. 2. Clinical uses mild insulin-independent patients with obesity 3. Adverse effects severe lactic acidosis (less for metformin), malabsorption of vitamin B12 and folic acid

  30. Other oral hypoglycemic drugs Oral insulin secretagogues Sulfonylureas (磺酰脲类) Repaglinide Incretin (GLP-1) Mimetics Dipeptidylpeptidase IV (DPP-IV) Inhibitors

  31. Oral hypoglycemic drugs Sulfonylureas（磺酰脲类） Tolbutamide (D860)甲磺丁脲 Chlorpropamide 氯磺丙脲 Glibenclamide 格列本脲 (优降糖) Glipizide 格列吡嗪 Gliclazide 格列齐特 (达美康)

  32. Sulfonylureas • 1. Pharmacological effects • Hypoglycemic effect: • blocking ATP-sensitive K+ channel: Ca2+ inflow , insulin release , stimulating insulin secretion • increase the binding of insulin and its receptors (still effective after long-term use to recover insulin level) • glucose utilization, glycogen and fat synthesis, insulin receptor number and affinity , insulin metabolism↓ • (2) Antidiuretic effect • (3) Effect on coagulation function

  33. Action of sulfonylureas

  34. Sulfonylureas 1. Pharmacological effects Hypoglycemic effect: blocking ATP-sensitive K+ channel: Ca2+ inflow , insulin release , stimulating insulin secretion, increase the binding of insulin and its receptors (still effective after long-term use to recover insulin level) glucose utilization, glycogen and fat synthesis, insulin receptor number and affinity , insulin metabolism↓ (2) Antidiuretic effect (chlorpropamide): effect of antiuretic hormone (ADH) (3) Effect on coagulation function (gliclazide)

  35. Sulfonylureas 2. Clinical uses (1) Insulin-indenpedent diabetic patients (type 2): alone or combined with insulin (2) Diabetes insipidus (尿崩症): Chlorpropamide (氯磺丙脲)

  36. Sulfonylureas 3. Adverse effects (1) GI reactions (2) CNS reactions (3) Hypoglycemia:especially in elderly, hepatic or renal insufficiencies (4) Others:cholestatic jaundice, hepatic damage (Chlorpropamide),leukopenia.

  37. Sulfonylureas 4. Drug interactions (1) Potentiation of hypoglycemic effects replacement in plasma protein binding:salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc. inhibition of hepatic microsomal enzymes: chloramphenicol, warfarin (2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics:glucocorticoids, thiazides, etc.

  38. Repaglinide (餐时血糖调节剂) • Pharmacological effects • Repaglinide lowers blood glucose by stimulating the release of insulin from the pancreas. • It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion • Protect beta cell • Clinical uses • Type2 DM, diabetic nephropathy, elder DM patient • less hypoglycemia

  39. Incretin (GLP-1) Mimetics Mechanism of Action: Act as an incretin enhance insulin secretion in response to an oral glucose load. Suppress post-prandial glucagon secretion Increase insulin secretion in a glucose-dependent manner Increase somatostatin secretion which inhibit glucagon release Delay gastric emptying Centrally suppress appetite Preserve beta cell mass by reducing apoptosis and increased neogenesis (animal models). • Keating, Drugs. 65(12):1681-92, 2005. Riddle and Drucker. Diabetes Care 2006; 29:435-49.

  40. Incretin (GLP-1) Mimetics Exenatide (Byetta) is first incretin mimetic on market. Synthetic version of salivary protein found in the Gila monster53% overlap with human GLP-1. Must be taken as a BID injection w/in 60 mins prior to meal Major side effects: nausea, vomiting, diarrhea. Increases the risk of Acute pancreatitis. Use not recommended in severe renal impairment. Not recommended as monotherapy To be used as add on therapy with SU, metformin, or TZD’s Increases the risk of Hypoglycemia when added to SU treatment. Major advantage is weight loss (~5 kg) as well as maintained effect (?preserved beta cell function). Efficacy: decreases A1C ~1.0%. Exenatide GLP-1Human Q G H A E G T F T S D V S S Y L E G A A K E F I A W L V K R -N H2 A A VK R SYL GQ AKE Site of DPP-IV Inactivation • Keating, Drugs 2005 65(12):1681-92

  41. Dipeptidylpeptidase IV (DPP-IV) Inhibitors Mechanism of Action: Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal GLP-1 levels Sitagliptin(Januvia) is first DPP-IV inhibitor on market. Effective as monotherapy or when used in conjunction with metformin or a thiazolidinedione. Efficacy: decreases A1C ~0.8%. Riddle and Drucker. Diabetes Care 2006; 29:435-49.

  42. Oral hypoglycemic drugs -Glucosidase inhibitors（葡萄糖苷酶抑制药） Acarbose阿卡波糖 Reducing intestinal absorption of starch (淀粉), dextrin (糊精), and disaccharides (二糖) by inhibiting the action of intestinal brush border -glucosidase

  43. Oral hypoglycemic drugs • Pramlintide acetate (醋酸普兰林肽) • an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal. • delay glucose absorption, inhibit secretion of glucagon • Symlin has been approved by the FDA, for use by Type 1 and Type 2 Diabetics who use insulin. Symlin allows patients to use less insulin, lowers average blood sugar levels, and blood sugar after eating. • Apart from insulin analogs, symlin is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s

  44. Oral hypoglycemic drugs Aldose reductase inhibitor Epalrestat (依帕司他) Treatment of Diabetic Neuropathy

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