Insulin and oral hypoglycemic drugs

Endogenous insulin is secreted from  cells in the pancreas

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

Insulin promotes glucose utilization

正常人糖尿病尿崩症

Different forms of diabetes mellitus

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

Antidiabetic drug classification

A. Insulin and related agents

Structure of insulin

A. Insulin and related agents 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) Mechanism of insulin actions Interacting with insulin receptor Interacting with insulin receptor

Structure of insulin

Interaction between insulin and its receptor IRS: insulin receptor substrate Tyr: tyrosine P: phosphate

Insulin promotes the translocation of glucose transporters into the membrane

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 A. Insulin and related drugs

3. Preparations Properties Properties Preparations PreparationsOnsetPaekDuration Fast-acting Regular insulin h 2-3 h 6-8 h Intermmediate- acting Neutral protamine hagedorn 2-4 h 6-10 h h Long-acting Protamine zinc insulin suspension 3-6 h 6-10 h h A. Insulin and related drugs

Actions of different insulin preparations

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) Insulin resistance: acute, chronic (4) Lipoatrophy: localized in injection sites A. Insulin and related drugs

B. Oral hypoglycemic drugs Insulin secretagogues 促胰岛素分泌药 sulfonylureas （磺酰脲类） tolbutamide (D860, 甲磺丁脲 ) ， glipizide 格列吡嗪 sulfonylureas （磺酰脲类） tolbutamide (D860, 甲磺丁脲 ) ， glipizide 格列吡嗪 non-sulfonylurea insulin secretagogues ( 非磺酰脲类促胰岛素分泌 剂 ) repaglinide 瑞格列奈 non-sulfonylurea insulin secretagogues ( 非磺酰脲类促胰岛素分泌 剂 ) repaglinide 瑞格列奈 GLP-1 agonists & DPP-4 inhibitors GLP-1 agonists & DPP-4 inhibitors Insulin enhancers 胰岛素增敏剂 Thiazolidinediones (TZD, 噻唑烷二酮类化合物 ） rosiglitazone 罗格列酮 Thiazolidinediones (TZD, 噻唑烷二酮类化合物 ） rosiglitazone 罗格列酮 Biguanides ( 双胍类 ) metformine 二甲双胍 Biguanides ( 双胍类 ) metformine 二甲双胍  -Glucosidase inhibitors  葡萄糖苷酶抑制药 : acarbose 阿卡波糖 Others: pramlintide acetate ( 醋酸普兰林肽 ), aldose reductase inhibitors ( 醛糖还原酶抑制剂 )

B. 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 )

B. Oral hypoglycemic drugs 1. Pharmacological effects Blocking K + channel: Ca 2+ inflow , insulin release , Stimulating insulin secretion Increasing insulin sensitivity (long-term use)

Action of sulfonylureas

B. Oral hypoglycemic drugs 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) 

B. Oral hypoglycemic drugs 3. Adverse effects (1) GI reactions (2) CNS reactions (3) Hypoglycemia: especially in elderly, hepatic or renal insufficiencies (4) Others: leukopenia, cholestatic jaundice, hepatic damage

B. Oral hypoglycemic drugs 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.

B. Oral hypoglycemic drugs Non-sulfonylurea insulin secretagogues Repaglinide 瑞格列奈 Repaglinide 瑞格列奈 Nateglinide 那格列奈 Nateglinide 那格列奈 Blocking K ATP channel Blocking K ATP channel Oral insulin secretagogue

Thiazolidinediones (TZD) 噻唑烷二酮类化合物 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 B. Oral hypoglycemic drugs

Rosiglitazone罗格列酮 Pioglitazone Pioglitazone吡格列酮 B. Oral hypoglycemic drugs

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  ), increasing glucose transport into muscle and adipose tissue. Selective agonists for nuclear peroxisome proliferator-activated receptor-  ( PPAR , 过氧化物酶增殖体 激活受体  ), increasing glucose transport into muscle and adipose tissue. (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid  (3) Antihypertensive effects (4) Effect on vascular complications in type 2 patients B. Oral hypoglycemic drugs

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) B. 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）

B. Oral hypoglycemic drugs 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

B. 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