1. Insulin & Antidiabetic Drugs Peng Qing

2. Objectives  Be able to describe the insulin preparations, the effects of insulin, clinical uses and adverse reactions of insulin.  Be able to list the major oral drug classes used and give example.

3. Background  Diabetes mellitus classification: 1. Type I. insulin-dependent diabetes mellitus (IDDM): pancreatic B cell destruction (immune-mediated in most cases) 2. Type II. non-insulin-dependent diabetes mellitus (NIDDM): ＞ 90%, defects of insulin secretion and action, insulin resistance. 3. Type 3, other; 4. Type 4, gestational diabetes mellitus

4. Insulin  Small protein containing 51 amino acids arranged in two chains (A and B) linked by disulfide bridges.  Insulin and C-peptide are released from pancreatic B cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose.

5. Insulin

6. Effects of Insulin on Its Targets  Insulin promotes synthesis and storage of glycogen, triglycerides, and protein in its major target tissues: liver, fat, and muscle.  The release of insulin from the pancreas is stimulated by increased blood glucose, incretins, vagal nerve stimulation, and other factors.

8. Principal types and duration of action of insulin preparations  Four principal types of injected insulins are available: (1) rapid-acting, with very fast onset and short duration ;(insulin aspart, insulin lispro) (2) short-acting, with rapid onset of action; (Regular insulin ) (3) intermediate-acting; (protamine zinc insulin) (4) long-acting, with slow onset of action (Insulin glargine )

9. Pharmacokinetics  Insulin is a protein, which can be destructed by digestive enzyme. Oral adminstration is invalid.  Absorption is rapid when subcutaneous injection (i.h.)  Inactivation in liver and kidney.

11. Mechanism of Action  Insulin receptor on the membranes consists of two heterodimers( 异二聚 体 ), each containing An α subunit, entirely extracellular and constitutes the recognition site. An β subunit, spans the membrane and contains a tyrosine kinase( 激酶 ).

12. Phosphorylations results in multiple effects, including -translocation of glucose transporters to the cell membrane with a resultant increase in glucose uptake; - increased glycogen synthase activity and increased glycogen formation; -multiple effects on protein synthesis, lipolysis, and lipogenesis; and enhance DNA synthesis and cell growth and division.

13. Clinical Uses  Therapy of all insulin deficient diabetes. 1. IDDM (type 1) 2. NIDDM (type 2) which cannot be controled by diet therapy or oral hypoglycemic agents. 3. Diabetes with acute or severe complication (Diabetic ketoacidosis, hyperosmolar hyperglycemic syndrome). 4. Diabetes accompanied severe infection, wasting disease( 消耗性疾病 ), high fever, pregnance, trauma and operation. 5. Hyperkalemia.

14. Adverse Reactions 1.Hypoglycemia: most common complication of insulin therapy. relieved by glucose administration 2.Insulin allergy: local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti- insulin IgE antibodies.

15. 3.Insulin resistance:  Acute resistance: induced by stress ( 应激 ). ① insulin antagonist (eg, GC, adrenaline) ↑ ; ② pH ↓→ insulin-R ↓ ; ③ free fatty acid and ketone body in blood ↑→ inhibit glucose utilization.  Chronic resistance: ① pro-receptor abnormality: anti-insulin antibodies; ② receptor level change: number ↓, or affinity ↓ ③ post-receptor abnormality: abnormal glucose transport system or enzyme system in target cell. 4. Lipoatrophia at injection site ( 脂肪萎缩 )

16. Oral Hypoglycemic Agents Insulin sensitizer a-glucosidase inhibitors Biguanides Insulin secretagogues

17. Insulin secretagogues :sulfonylureas  First-generation: tolbutamide( 甲苯磺丁脲 ; 甲 糖宁 ; D 860 ), chlorpropamide( 氯磺丙脲 )  Second-generation: glyburide( 格列本脲 ; 优降 糖 ; 降糖灵, glibenclamide), glipizide( 格列吡嗪, 吡磺环己脲 ), glimepiride( 格列美脲 ); gliclazide( 格列齐特, 达美康 )

18. Sulfonylureas Mechanism of Action - increase insulin release from the pancreas. -a reduction of serum glucagon levels

19. sulfonylureas+ B cell inward rectifier-type ATP-sensitive potassium channel close receptor depolarization Voltage-gated Ca 2+ channelopen efflux of K + ↓ Ca 2+ influx preformed insulin Release of

20. Pharmacological Effects 1. Reduce blood glucose levels: 2. Stimulation of ADH secretion and potentiation of its action at the renal tubule → therapy of diabetes insipidus( 尿崩症 ). 3. Effects on blood coagulation: platelet adhesiveness ↓, plasminogen( 纤溶酶原 ) synthesis ↑

21. Clinical Uses 1. Type 2 diabetes with a functioning pancreas islet but invalid to diet therapy. 2. Diabetes insipidus( 尿崩症 ): chlorpropamide( 氯磺丙脲 )

22. Adverse Reactions  Cutaneous anaphylaxis( 皮肤过敏 ), gastrointestinal disorder, liver damage  Hematologic toxicity: leukopenia, blood platelet ↓, hemolytic anemia  Persistent hypoglycemia  Contraindicated in patients with hepatic or renal insufficiency.

23. Insulin secretagogues: meglitinides  Repaglinide, the first member of the group, was approved for clinical use in 1998  modulate B-cell insulin release by regulating potassium efflux through the potassium channels.  has a very fast onset of action  use in controlling postprandial glucose excursions for type 2 diabetics.

24. Insulin Sensitizer  Insulin resistance Acquired: type 1 diabetes —— control blood glucose Hereditary: type 2 diabetes —— insulin sensitizer  Thiazolidinediones ( Tzds, 噻唑烷酮类化合 物 ) : rosiglitazone ( 罗格列酮 ), pioglitazone ( 吡 格列酮 )

25. Pharmacological Effects 1. Tzds reduce insulin resistance 2. Ameliorate lipid metabolism disturbance 3. Prevent vascular complications in type 2 diabetics 4. Improve the function of pancreatic B cell

26. Mechanism of Action Competitively activate peroxisome( 过氧化物酶 ) proliferator-activated receptor-γ(PPAR γ, nuclear receptor ) → modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation.

27. Precautions and adverse effects  fluid retention, especially when used in combination with insulin or insulin secretagogues.  increased risk of heart failure  Anovulatory women may resume ovulation and should be counseled on the increased risk of pregnancy.  hepatotoxicity  increased bone fracture in women.

28. Biguanides ( 双胍类 )  Metformin( 甲福明, 二甲双胍 ), phenformin( 苯乙 福明 ; 苯乙双胍 ; 降糖灵 )  Phenformin was discontinued in the USA because of its association with lactic acidosis and because there was no documentation of any long-term benefit from its use.  Not bound to plasma proteins, not metabolized, excreted by the kidneys as the active compound.

29.  Mechanism of action remain elusive maybe includes: ① direct stimulation of glycolysis in tissues, with increased glucose removal from blood; ② reduced hepatic gluconeogenesis; ③ slowing of glucose absorption from the gastrointestinal tract ④ reduction of plasma glucagon levels.

30.  Clinical Uses: 1. for patients whose hyperglycemia is due to ineffective insulin action. Biguanides does not increase weight or provoke hypoglycemia.  Adverse Reaction: lactic acidosis gastrointestinal reaction(anorexia 食欲减退, nausea, vomiting, abdominal discomfort, diarrhea),

31. Acarbose ( 阿卡波糖 )  α-glucosidase ( 葡萄糖苷酶 ) inhibitors  Mechanism: competed glycoside-hydrolase with carbohydrate on the small intestine epithelium brush border → hydrolysis of carbohydrate ↓→ delay the absorption of glucose.  Pharmacological Effect: lower the postprandial( 餐后 ) blood glucose levels.  Adverse Reactions: gastrointestinal discomfort.