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Pancreatic hormones & antidiabetic drugs Shi-Hong Zhang 张世红 [email protected] 胰高血糖素 胰岛素 生长抑素 Overview of Glucose Regulation by Insulin Glucose absorption Lipolysis↓ Insulin secretion Lipogenesis↑ Persistent hepatic glucose output ↓ Glucose disposal ↑ Glycogenesis ↑ Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24. Different types of diabetes mellitus prediabetic metabolic syndrome “Beta-cell failure” Symptoms of diabetes Complications of diabetes mellitus • Acute complications – Diabetic ketoacidosis (酮症酸中毒) – Hyperosmotic nonketotic coma (高渗性非酮症性昏迷) • Chronic complications – – – – – – – Cardiovascular diseases Renal damage Retinal damage Nerve degeneration Infection Myopathy etc. Pharmacological therapy Insulin Oral hypoglycemic drugs Insulin sensitizers 胰岛素增敏剂: Biguanides 双胍类 Thiazolidinediones (TDs,噻唑烷二酮类) Insulin secretagogues (促胰岛素分泌药): Sulfonylureas 磺酰脲类 Meglitinides (Non-SU) 格列奈类 GLP-1 agonists and DPP-4 inhibitors α-glucosidase inhibitors α-葡萄糖苷酶抑制剂 Amylin analogue 胰淀粉样多肽类似物 Aldose reductase inhibitor 醛糖还原酶抑制剂 A. Insulin Frederick Sanger (1918- 2013) A. Insulin 1. Pharmacological effects (1) Carbohydrate metabolism: reduces blood glucose levels by glycogenolysis , glycogen synthesis , gluconeogenesis , glucose transport . (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 (4) Cardiac stimulation (5) Promote cellular K+ uptake Mechanism of insulin actions: Interact with insulin receptors A. Insulin 2. Clinical uses (1) Type I diabetic mellitus (2) Type II diabetic mellitus : extreme high blood glucose or after 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) Promotion of K+ uptake into the cells A. Insulin 3. Preparations Fast-acting insulin Regular insulin 正规胰岛素 Monocomponent insulin 单组分胰岛素 • High solubility • Can be given intravenously • Start working 0.5-1h after injection, reach peak 2-4h, and last 5-7h. A. Insulin 3. Preparations Fast-acting insulin analogs Insulin aspart 门冬胰岛素 (B28 脯氨酸变为门冬氨酸) Insulin lispro 赖脯胰岛素(颠倒B28、29脯赖顺序) •Start working 5-15 minutes after injection, reach peak at 1h, and last ~4 hours. • Used for IDDM and NIDDM with high postmeal glucose. A. Insulin 3. Preparations Intermediate-acting insulin (lente) Neutral protamine hagedorn (NPH, isophane insulin ) 中性(低)精蛋白锌胰岛素 Globin zinc insulin 珠蛋白锌胰岛素 • Start working 1-1.5h after injection, reach peak 8-12h, and last 24h. A. Insulin 3. Preparations Long-acting insulin (ultralente) Protamine zinc insulin (PZI) 精蛋白锌胰岛素 • Start working 4-8h after s.c. injection, reach peak 1420h, and last 24-36h. A. Insulin 3. Preparations Super-long acting insulin analogs Insulin glargine 甘精胰岛素(B链C端加两个精氨酸,A21甘氨酸替代门冬酰胺) Insulin detemir地特胰岛素(去除B30苏氨酸,B29赖氨酸加脂肪酸侧链) •Less soluble than native human insulin at physiological pH, and precipitates in skin following subcutaneous injection, resulting in delayed absorption. •Onset 1-2 h after injection and continues to work for as long as 24 hours. • Used to treat type 1 or type 2 diabetes mellitus. A. Insulin 3. Preparations Mixed insulin Human insulin isophane 低精蛋白锌胰岛素+ Human insulin 人胰岛素 • Start working 0.5h after injection, reach peak 2-12h, and last 16-24h. • For patients who eat meals out, may consider use of an insulin pen. • Most insulins now available as pen Insulin Pump and Glucose Monitoring Insulin Pump – “Open Loop” Patient sets basal infusion rate and superimposed boluses Continuous Glucose Monitor “Closed Loop” insulin pump system is ultimate goal: infusion rate adjusted based on input from continuous glucose monitor. A. Insulin 4. Adverse effects (1) Hypoglycemia: adrenaline secretion (sweating, hunger, weakness, tachycardia, blurred vision, headache, etc.), treated with 50% glucose. (2) Hypersensitivity: treated with H1 antagonists, glucocorticoids (3) Insulin resistance: acute, chronic (4) Lipoatrophy脂肪萎缩 and lipohypertrophy脂肪增生 (5) Others: weight gain, refractive errors (屈光不正), edema B. Oral hypoglycemic drugs Insulin action enhancers 胰岛素增敏剂: Biguanides 双胍类 Thiazolidinediones (TDs,噻唑烷二酮类) Insulin secretagogues (促胰岛素分泌药): Sulfonylureas 磺酰脲类 Meglitinides (Non-SU) 格列奈类(苯丙胺酸衍生物) GLP-1 agonists and DPP-4 inhibitors α-glucosidase inhibitors α-葡萄糖苷酶抑制剂 Amylin analogue 胰淀粉样多肽类似物 Aldose reductase inhibitor 醛糖还原酶抑制剂 Insulin action enhancers Biguanides (双胍类) Metformin 二甲双胍 Thiazolidinediones (TZDs) 噻唑烷酮类化合物 Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮 Metformin 1. Pharmacologicla effects Increases insulin sensitivity, enhances glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles; Decreases glucose absorption in gut and glucagon release, inhibits hepatic gluconeogenesis Metformin 2. Clinical uses First line drug for type II diabetes, esp. patients with obesity; polycystic ovary syndrome Major advantages: lack of weight gain, absence of hypoglycemia, decrease in risk of CV events, low cost with generic prep. 3. Adverse effects GI reactions, severe lactic acidosis, malabsorption of vitamin B12 and folic acid Thiazolidinediones 1. Pharmacological effects Selective agonists for nuclear peroxisome proliferator activated receptor- (PPAR , 过氧化物酶增殖体激活受体), increase glucose transport into muscle and adipose tissue. (1) Lower insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid (3) Prevent diabetic complications: anti-platelet, renal protection, anti-atherosclerosis (4) Improve cell function Thiazolidinediones 2. Clinical uses • Used for treatment of insulin-resistant diabetic patients or type 2 patients; • Delayed onset of action – takes 8-12 weeks to achieve maximal effect; • Absence of hypoglycemia when used as monotherapy; • No reliance on renal excretion Thiazolidinediones 3. Adverse effects Edema: at higher doses and used with insulin, in older patients, patients with multiple medical problems, patients with underlying CAD or CHF Increased risk of cardiac events Headache Myalgia (肌痛) GI reactions Hepatic damage (troglitazone). Contraindicated with Class III or IV heart failure or significant liver disease. Sulfonylureas(磺酰脲类) Tolbutamide (D860) 甲苯磺丁脲 Chlorpropamide 氯磺丙脲 Gliburide 格列本脲 (优降糖) Glipizide 格列吡嗪(美吡达) Gliclazide 格列齐特 (达美康) Glimepiride 格列美脲(亚莫利) Sulfonylureas 1. Pharmacological effects 1) Increase insulin release: block ATP sensitive K+ channel, Ca2+ inflow Sulfonylureas 1. Pharmacological effects 2) Increase receptor affinity to insulin (longterm use) 3) Promote glucose uses(促进合成糖原和脂肪) 4) Increase sensitivity of β cells to glucose 5) Anti-uretic effect (格列本脲/氯磺丙脲) :ADH 6) Anti-platelet effect (格列齐特) Sulfonylureas 2. Clinical uses (1) Type II diabetic mellitus: first line oral hypoglycemic drug, alone or combined with insulin (2) Diabetes insipidus (尿崩症): 氯磺丙脲 Sulfonylureas 3. Adverse effects (1) GI reactions (2) CNS reactions(嗜睡、眩晕) (3) Hypoglycemia: especially in elderly, with hepatic or renal insufficiencies (4) Others: leukopenia (白细胞减少), cholestatic jaundice (胆汁郁积性黄疸), hepatic damage Non-SU Insulin Secretagogues • Act by binding to SUR1 on beta cells to promote insulin secretion. • Repaglinide (瑞格列奈) and Nateglinide (那格列奈) are currently available agents. • Efficacy of repaglinide appears to be similar to SU’s • Major advantage is rapid onset and offset, can dose just prior to meals with better postmeal control. • Lower risk to induce hypoglycemia than SUs. • Are additive with metformin (二甲双胍). • Used for type 2 patients. Non-SU Insulin Secretagogues • Hepatic metabolism permits use in patients with impaired renal function. • Many drug interactions. Most concerning is gemfibrozil (吉非罗齐) which increases repaglinide concentration and may result in prolonged effect. • Cost may be an issue (1 or 2 mg tabs: $122.09/month at drugstore.com) GLP-1 agonists and DPP-4 inhibitors • GLP-1: glucogons-like protein-1 • Exenatide (依可那肽): GLP-1 agonist, stimulates insulin secretion, only available as injection. • Sitagliptin (西他列汀), vildagliptin (维格列汀): DPP-4(二肽基肽酶Ⅳ)inhibitor. Alpha-Glucosidase inhibitors Acarbose-Precose 阿卡波糖 Miglitol-Glyset 米格列醇 Voglibose 伏格列波糖 Alpha-Glucosidase inhibitors • Acarbose (阿卡波糖) is an oligosaccharide (低聚糖), hardly absorbed • Miglitol (米格列醇) resembles a monosaccharide, fairly well-absorbed. • Reducing intestinal absorption of starch (淀粉), dextrin (糊 精), and disaccharides (二糖) by inhibiting the action of intestinal brush border -glucosidase(葡萄糖苷酶). • Acarbose also blocks pancreatic alpha-amylase (淀粉酶). • Used for diabetes mellitus type 2, particularly with regard to postprandial餐后的 hyperglycemia. Alpha-Glucosidase inhibitors • Must be taken at the start of main meals to have maximal effect. • Efficacy will depend on the amount of complex carbohydrates in the meal. • Absence of hypoglycemia when used as monotherapy. • Side effects: gastrointestinal side effects such as flatulence and diarrhea; voglibose (伏格列波糖), in contrast to acarbose, has less of GI side effects and more economical. Amylin analogues 淀粉样多肽类似物 • Mechanism of action: – Inhibits glucagon secretion, thereby reducing hepatic glucose production – Slows gastric emptying – Promotes satiety reduces caloric intake • Pramlintide (Symlin普兰林肽) is the only amylin analog on the market • As adjunct therapy for patients with type 1 or 2 diabetes to control postprandial glucose • Increases the risk of severe hypoglycemia • The other main side effect is nausea. Riddle and Drucker. Diabetes Care 2006; 29:435-49. Alsose reductase inhibitors 醛糖还原酶抑制剂 – Rational: aldose reductase activity increases in those tissues that are not insulin sensitive, including lenses, peripheral nerves and glomerulus, may be involved in diabetic complications. – Epalrestat (依帕司他) inhibits aldose reductase, delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease. 中国 2 型糖尿病防治指南(2013 年版) Case report • A 45-year-old man first consulted his physician because of nocturia (夜尿), mild thirst, and some fatigue. At the time, he was somewhat overweight and sedentary (久坐) in his habits. Laboratory tests showed an elevated fasting blood glucose level of 15 mmol/L, glucose but no ketones in the urine. Diabetes was diagnosed and he was placed on diabetic diet low in free sugar and fat. Two months later, he was found to have higher fasting blood glucose, 2-hr postlunch glucose, glycosylated hemoglobin (HbA1C). Therefore, He was started on glyburide 5mg before breakfast and 5 mg before dinner, but the blood glucose remained elevated. The dosage was therefore raised to 10 mg twice daily, and this achieved a good result. Case report • After 3 years, he developed unstable angina pectoris, and the blood glucose and HbA1C levels were again found to be elevated. Addition of metformin to his treatment produced some improvement, but his cardiac symptoms gradually worsened over the next 3 years. He showed intermittent glycosuria and proteinuria. His weight had fallen to a normal level. His physician therefore decided to transfer him to insulin therapy, started on a regimen of 22 units of Lente insulin and 12 units of regular insulin every morning before breakfast. The dosage was gradually raised to 35 units according to the glucose level in the blood and urine. During the next year he had three mild hypoglycemic reactions. He was found to have stable background retinopathy, mild nephropathy and mild numbness and tingling in both feet, but the blood pressure remained normal.