1. Insulin and oral hypoglycemic drugs

2. Endogenous insulin is secreted from  cells in the pancreas Islet of Langerhans Alpha cell: 20%, glucagon Beta cell: 75%, insulin Delta cell: 5%, somatostatin D1 cell: VIP PP cell: pancreatic polypeptide

3. Glucose metabolism and the regulation by insulin and glucogan Diabetes mellitus: Insulin  or its responses   blood glucose   Acute or chronic symptoms

4. §A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both §100 million people worldwide §85-90% cases are Type II Diabetes Mellitus

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

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

7. Natural History of Type 2 Diabetes 0 50 100 150 200 250 -10-5051015202530 Years of Diabetes Glucose (mg/dL) Relative Function (%) Insulin Resistance Insulin Level “Beta-cell failure” *IGT = impaired glucose tolerance 50 100 150 200 250 300 350 Fasting Glucose Post-meal Glucose Adapted from International Diabetes Center (IDC) Minneapolis, Minnesota Obesity IGT Diabetes Uncontrolled hyperglycemia

8. CLASSIFICATION §SECONDARY CAUSES l Exocrine pancreas disease: pancreatitis l Genetic syndromes: Downs, Turners l Infections: CMV, Congenital rubella l Drugs: Glucocorticoids, Dilantin, beta agonists l Endocrinopathies: Cushing's, Acromegaly

9. Classification §Gestational l Presents only during pregnancy l 135,000 cases annually l Increased risk of developing diabetes post partum l Tight glycemic control required to prevent macrosomia, fetal cardiac and CNS abnormalities

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

11. 正常人糖尿病尿崩症

12. Complications of diabetes mellitus §Acute complications § Diabetic ketoacidosis § Hyperosmotic nonketotic coma §Chronic complications § Cardiovascular diseases § Renal damage § Retinal damage § Nerve degeneration § Myopathy § Infection § Rhinocerebral Mucormycosis

13. Therapy of Diabetes Mellitus §Diet §Exercise §Insulin and its enhancers §Oral hypoglycemic drugs

14. Insulin and its enhancers

15. Structure of insulin

16. Insulin and its enhancers Insulin 1. Pharmacological effects (1)Carbohydrate metabolism: reducing blood glucose levels by glycogenolysis , glycogen synthesis , gluconeogenesis  (ketone badies  ) (2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids  (3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism  (4)HR ,myocardial contractility, renal blood flow  (4)HR , myocardial contractility, renal blood flow  Mechanism of insulin actions Interacting with insulin receptor Interacting with insulin receptor

17. Insulin promotes glucose utilization

18. Insulin and its enhancers Insulin 1. Pharmacological effects (1)Carbohydrate metabolism: reducing blood glucose levels by glycogenolysis , glycogen synthesis , gluconeogenesis  (ketone badies  ) (2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids  (3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism  (4)HR ,myocardial contractility, renal blood flow  (4)HR , myocardial contractility, renal blood flow  Mechanism of insulin actions Interacting with insulin receptor Interacting with insulin receptor

20. Insulin and its enhancers Insulin 1. Pharmacological effects (1)Carbohydrate metabolism: reducing blood glucose levels by glycogenolysis , glycogen synthesis , gluconeogenesis  (ketone badies  ) (2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids  (3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism  (4)HR ,myocardial contractility, renal blood flow  (4)HR , myocardial contractility, renal blood flow  Mechanism of insulin actions Interacting with insulin receptor Interacting with insulin receptor

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

22. Insulin promotes the translocation of glucose transporters into the membrane

23. 2. Clinical uses (1)Insulin-dependent patients with diabetes mellitus (type 1 diabetes mellitus) (2) Insulin-independent patients: failure to other drugs (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: promotion of K + uptake into the cells, pshychiatric disorders Insulin and its enhancers

24. 3. Preparations Properties Properties Preparations PreparationsOnsetPeakDuration Fast-acting Regular insulin 0.5-1 h 2-3 h 6-8 h Intermmediate- acting Neutral protamine hagedorn 2-4 h 6-10 h 12-18 h Long-acting Protamine zinc insulin suspension 3-6 h 6-10 h 24-36 h

25. Hirsch IB NEJM 352:174, 2005

26. Rapid Acting Insulin Analogues §Current agents include lispro, aspart, and glulisine. §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 60-90 minutes and duration of ~3-5 hours. §Advantages include: l increased convenience- can take just prior to meal. l better postprandial glycemic control. §Disadvantages include: l short duration of action- can be problematic in Type 1 diabetic without basal insulinization, as with bedtime NPH. l more expensive than regular insulin (~double the cost). Holleman and Hoekstra, NEJM, 337:176-83, 1997 Hirsch, NEJM, 352:174-83, 2005

27. Actions of different insulin preparations

28. 4. Adverse effects (1) Hypersensitivity: treated with H 1 receptor antagonist, glucocorticoids (2) Hypoglycemia: adrenaline secretion (sweating, hunger, weakenss, tachycardia, blurred vision, headache, etc.), treated with 50% glucose (3) Lipoatrophy: localized in injection sites (4) Insulin resistance: Acute: stress induced, need large dose of insulin Chronic: need >200U/d and no complication Insulin and its enhancers

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

30. Rosiglitazone罗格列酮 Pioglitazone Pioglitazone吡格列酮

31. 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  ). Selective agonists for nuclear peroxisome proliferator-activated receptor-  ( PPAR , 过氧化物酶增殖体激活受 体  ). (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid  (3) Antihypertensive effects (4) Effect on vascular complications in type 2 patients Insulin and its enhancers

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

33. Oral hypoglycemic drugs Sulfonylureas （磺酰脲类） Biguanides （双胍类）  -Glucosidase inhibitors （  葡萄糖苷酶抑制药） Others

34. 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 )

36. Sulfonylureas 1. Pharmacological effects (1)Hypoglycemic effect: blocking ATP-sensitive K + channel: Ca 2+ inflow , insulin release , stimulating insulin secretion blocking ATP-sensitive K + channel: Ca 2+ inflow , insulin release , stimulating insulin secretion increasing insulin sensitivity (long-term use) increasing insulin sensitivity (long-term use) inhibit glucagon release inhibit glucagon release (2) Antidiuretic effect (3) Effect on coagulation function

37. Action of sulfonylureas

38. Sulfonylureas 1. Pharmacological effects (1)Hypoglycemic effect: blocking K + channel: Ca 2+ inflow , insulin release , stimulating insulin secretion blocking K + channel: Ca 2+ inflow , insulin release , stimulating insulin secretion increasing insulin sensitivity (long-term use) increasing insulin sensitivity (long-term use) inhibit glucagon release inhibit glucagon release (2) Antidiuretic effect (3) Effect on coagulation function (Gliclazide)

39. 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 ): antiuretic hormone (ADH)  Sulfonylureas

40. 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. (4) Others: cholestatic jaundice, hepatic damage (Chlorpropamide), leukopenia. Sulfonylureas

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

42. Oral hypoglycemic drugs Biguanides （双胍类） Metformin 二甲双胍（甲福明） Metformin 二甲双胍（甲福明） Phenformin 苯乙双胍（苯乙福明） Phenformin 苯乙双胍（苯乙福明）

43. Biguanides 1. Pharmacilogical effects increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut and glucagon release decreasing glucose absorption in gut and glucagon release 2. Clinical uses 2. Clinical uses mild insulin-independent patients with obesity mild insulin-independent patients with obesity 3. Adverse effects severe lactic acidosis (less for metformin), malabsorption of vitamin B 12 and folic acid severe lactic acidosis (less for metformin), malabsorption of vitamin B 12 and folic acid

44. Oral hypoglycemic drugs  -Glucosidase inhibitors （  葡萄糖苷酶抑制药） Acarbose 阿卡波糖 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

45. Oral hypoglycemic drugs Others Repaglinide 瑞格列奈 Oral insulin secretagogue Oral insulin secretagogue

46.  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 §Clinical uses § Type2 DM, diabetic nephropathy, elder DM patient Repaglinide ( 餐时血糖调节剂 )

47. Incretin Mimetics §Mechanism of Action: l Act as an incretin  enhance insulin secretion in response to an oral glucose load. l Suppress post-prandial glucagon secretion in a glucose- dependent manner l Delay gastric emptying l Centrally suppress appetite l 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.

48. Incretin Mimetics §Exenatide (Byetta) is first incretin mimetic on market. 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 l To be used as add on therapy with SU, metformin, or TZD’s l 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%. Keating, Drugs 2005 65(12):1681-92 Site of DPP-IV Inactivation Exenatide A SYLGQAKE R VK A HGFVEATTSDSSYLEG Q AAKEFIAWLVK G R-NH2H2 GLP-1 Human

49. Dipeptidylpeptidase IV (DPP-IV) Inhibitors §Mechanism of Action: l Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal GLP-1 levels l Acts as an incretin  enhances insulin secretion in response to an oral glucose load. l Suppresses post-prandial glucagon secretion in a glucose-dependent manner l Preserves beta cell mass by reducing apoptosis and increased neogenesis (animal models). §Sitagliptin (Januvia) is first DPP-IV inhibitor on market. §Effective as monotherapy or when used in conjunction with metformin or a thiazolidinedione. §Appears to maintain efficacy (?preserved beta cell fxn). §Efficacy: decreases A1C ~0.8%. Riddle and Drucker. Diabetes Care 2006; 29:435-49.

50. Case 1 §50y/o, Chinese Male, §CC: Hyperglycemia found ×2 m §PE: BMI 29 Kg/m 2 WC: 102cm §Lab Findings: FBG 155mg/dl, 2hPG: 276mg/dl, HbA1c: 7.5% §Which DRUG or DRUGS will we order?

51. Treatment Strategies Beyond Lifestyle §In general, try to initiate pharmacotherapy with an oral agent in newly diagnosed type 2 diabetics unless: l Fasting plasma glucose is >300 mg/dl with ketonemia or ketonuria l Markedly symptomatic §In patients who need insulin initially, often can be switched to oral agents after 6-8 weeks when glucose toxicity resolves

52. Answer to Case 1 ( A newly diagnosed type 2 DM patient with obesity) §Lifestyle intervention §Metformin 500mg q.d.-t.i.d

53. “Failure” of a Single Oral Agent §Type 2 diabetes is a progressive disease, with  ’d loss of beta cell function over time. §Need to progress to multi-drug therapy or add insulin in order to maintain a similar level of glycemic control. §If glycemic goals are not met with agent in one class, we must add second agent with different mechanism of action or add insulin 2 Nathan et al. Diabetes Care. 29:1963-1972, 2006. ADA consensus algorithm recommends addition of a SU, thiazolidinedione, or insulin if metformin therapy is not effective in getting patients to goal A1C. 2 ADA consensus algorithm recommends addition of a SU, thiazolidinedione, or insulin if metformin therapy is not effective in getting patients to goal A1C. 2 1 Kahn et al. N Engl J Med, 355:2427, 2006

54. Algorithm for the management of T2DM From: China Guideline for Type 2 Diabetes (CDS,2007) From: China Guideline for Type 2 Diabetes (CDS,2007) Add insulin Add one or several agents below: Sulfonylurea or Meglitinide (one of the two), Glitazones, Alpha-Glucosidase Inhibitor Diet,exercise, weight loss + Metformin 3 month later HbA 1c ﹥ 6.5% 3 month later HbA 1c > 6.5% Overweight or obese patients (BMI >=24Kg/m2)

55. Algorithm for the management of T2DM (Cont’) Non-obese Patients (BMI ﹤ 24kg/m 2 ) Diet, exercise, weight loss + One or several agents below: Metformin, Sulfonylurea or Meglitinide (one of the two), Thiazolidinedione, Alpha-Glucosidase Inhibitor Add insulin 3 month later HbA 1c > 6.5% From: China Guideline for Type 2 Diabetes (CDS,2007)

56. Use of Oral Agents to Optimize Glycemic Control: Conclusions §Choice of oral agents needs to be matched with patient characteristics (thin vs. obese) as well as concurrent medical issues (renal, hepatic, cardiopulmonary status). §Diabetes is a progressive disease, and will require an increasing number of agents and/ or addition of insulin as the duration of diabetes increases. §Each oral agent can only improve A1C a maximum of 2%, so if poor control persists on multiple agents, insulin is needed.

57. Use Of Insulin In Type 2 Diabetes §Indications l When glycemic control deteriorates despite combination oral agents. l Surgery in patients with type 2 DM (transient) l Pregnancy §Method: l Start with bedtime intermediate (NPH) or long acting (glargine, detemir) insulin in addition to oral agents. l If doesn’t work, switch to basal-bolus therapy as used in conventional type 1 DM treatment Can continue metformin.Can continue metformin. Stop insulin secretagogues.Stop insulin secretagogues.

58. 4:00 25 50 75 16:0020:0024:004:00 BreakfastLunchDinner Plasma Insulin µ U/ml) Basal/Bolus Insulin Absorption Pattern w/ Standard Insulin Preparations 8:00 12:008:00 Time REG NPH

59. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine Basal-Bolus Treatment with Rapid and Long Acting Analogues Plasma Insulin Lispro Lispro Lispro or or or Aspart Aspart Aspart or Glulisine Glulisine Glulisine

60. Insulin Pump and Glucose Monitoring Insulin Pump – “Open Loop” Patient sets basal infusion rate and w/ superimposed boluses Continuous Glucose Monitor “Closed Loop” insulin pump system is ultimate goal… infusion rate adjusted based on input from continuous glucose monitor.

61. Case 2 §64y/o, Chinese Male. §CC:polydipsia,polyuria,polyphagia × 12y lower limb edema × 3 m §Metformin 500mg bid + Glipizide 80mg tid §PE: BMI 22kg/m2, WC 78cm, decreased sensation and medium pitting edema in both lower limbs §Lab Findings: UA: PRO 3+,GLU 2+ ; FBG 188mg/dl, 2hPG 266 mg/dl HbA1c 8.3%;

62. Case2 (Cont’) §Liver function tests: nl transaminase, Alb 28g/l SCr:1.5mg/dl, CCr: 52ml/min §Which DRUG or DRUGS should we Prescribe?

63. Answer to case 2 (long diabetes history with diabetic Nephropathy and Chronic renal insufficiency ) §Should start with insulin treatment §Regimen: 1. Regular insulin or rapid acting insulin analogs tid pre- meal + NPH or long acting insulin analog at bedtime 2. Insulin Pump