Pancreatic hormones & antidiabetic drugs Huifang Tang Department of pharmacology Email: tanghuifang@zju.edu.cn

History of Diabetes 1869 Paul Langerhans discovers islet cells in the pancreas. 1889 Mehring and Minkowski produce DM in dogs by removing the pancreas. 1921 Banting and Best find a pancreatic extract that lowers blood glucose in pancreatectomized dogs. VOL 101 / NO 4 / APRIL 1997 / POSTGRADUATE MEDICINE

Dr. F. G. Banting, Mr. C. H. Best, Mr. J. B. Collip and Prof. J. J. R Dr. F.G. Banting, Mr. C.H. Best, Mr. J.B. Collip and Prof. J.J.R. MacLeod discovered insulin in 1921 at the University of Toronto.

Defective insulin secretion Overview of Glucose Regulation Alpha glucosidase inhibitors Glucose Defective insulin secretion Sulfonylureas Meglitinides b-cell insulin secretion Persistent Hepatic Glucose Output In nondiabetic individuals, glucose is absorbed from the gut and stimulates beta cell insulin secretion. Insulin then acts on its three main target tissues: the liver, where it blunts hepatic glucose output; the muscle, where it stimulates glucose disposal; and the adipocyte, where it diminishes lipolysis and enhances lipogenesis. There are three main defects in diabetes, and these include diminished insulin secretion; resistance to insulin action in insulin responsive tissues, and persistent elevation of glucagon with resultant persistent hepatic glucose output Incretin analogs DPP-IV Inhibitors Insulin action Thiazolidinediones Resistance to insulin action Metformin Amylin analogs Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24. 8

Different forms of diabetes mellitus

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 Insulin secretagogues α-glucosidase inhibitors

A. Insulin

Insulin A. Insulin 1. Pharmacological effects (1) Carbohydrate metabolism: reducing blood glucose levels by gycogenolysis , 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

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

Insulin promotes the translocation of glucose transporters into the membrane

A. Insulin 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 3. Preparations

Approximate Pharmacokinetic Profiles of Human Insulins and Insulin Analogues Hirsch. NEJM. 2005; 352:174-83.

A. Insulin 4. Adverse effects (1) Hypersensitivity: treated with H1 receptor antagonist, glucocorticoids (2) Hypoglycemia: adrenaline secretion (sweeting, hunger, weakenss, tachycardia, blurred vision, headache, etc.), treated with 50% glucose (3) Insulin resistance: Acute: stress induced, need large dose of insulin Chronic: need >200U/d and no complication (4) Lipoatrophy: localized in injection sites

B. Oral hypoglycemic drugs History In 1942, Janbon and colleagues noted that some sulfonamides (磺胺 类)caused hypoglycemia in experiment animal.---Carbutamide （氨磺丁 脲）became the first clinically useful sulfonylurea （磺酰脲类）for treatment of diabets. In the early 1950s, Clinical trials of tolbutamide（甲苯磺丁脲）, the first widely used member of this group, were instituted in type 2 DM patients. During the 1920s, biguanides were investigated for use in diabets, but they are overshadowed by the discovery of insulin. In 1997, the first member of a new class of oral insulin secretagogues called meglitinide(美格替奈) was approved for clinical use. In 1997, Thiazolidinediones were introduced as the second major class of insulin sensitizers.In 2000, the first of these agents, troglitazone was withdrawn from use in the United Stats.

B. Oral hypoglycemic drugs Insulin secretagogues(促胰岛素分泌剂): Sulfonylureas(磺酰脲类) Repaglinide (瑞格列奈) GLP-1 receptor agonist DPP-4 inhibitor Insulin sensitizers （胰岛素增敏剂）: Thiazolidinediones (TDs) Biguanides α-glucosidase inhibitors

B. Oral hypoglycemic drugs -1 1. Sulfonylureas Tolbutamide (D860) 甲苯磺丁脲 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)

甲苯磺丁脲 氯磺丙脲 格列本脲 (优降糖) 格列吡嗪 格列齐特 (达美康) 格列美脲

Mechanisms of Action of sulfonylureas

B. Oral hypoglycemic drugs -1 Sulfonylureas 1. Pharmacological effects Act by binding to specific receptors (SUR1) on the beta cells and promoting insulin secretion. Blocking K+ channel: Ca2+ inflow , insulin release , Stimulating insulin secretion Increasing insulin sensitivity (long-term use) 1st generation agents (tolbutamide, tolazemide, chlorpropamide) rarely used today 2nd generation agents (glyburide, glipizide and glimeperide) are more potent and all ~equally effective in maximal dose.

Sulfonylureas – Caveats in Use B. Oral hypoglycemic drugs -1 Sulfonylureas – Caveats in Use Glyburide(格列本脲) Longer duration of action, active hepatic metabolites, renally excreted May want to avoid in adults >65 years old Glipizide（格列吡嗪） Shorter duration of action Glimepiride（格列美脲） Largely excreted in bile All are hepatically metabolized and should be used cautiously with advanced liver disease Start with lowest dose and titrate slowly

B. Oral hypoglycemic drugs -1 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-1 3. Adverse effects Major side effects - weight gain - hypoglycemia, especially in the elderly or in patients with impaired renal function. Major advantages - low price (generic glip $10-20/month) - long track record of safety. Others: leukopenia, cholestatic jaundice(胆汁淤积性黄疸), hepatic damage

B. Oral hypoglycemic drugs -1 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, warfaren (2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics: glucagon, thiazides, etc.

2.Meglitinides (Non-SU Insulin Secretagogues) B. Oral hypoglycemic drugs -2 2.Meglitinides (Non-SU Insulin Secretagogues) Prandial glucose regulators (餐时血糖调节剂) Act by binding to SUR1 on beta cells to promote insulin secretion. Repaglinide (Prandin，瑞格列奈) and Nateglinide (Starlix， 那格列奈) are current agents in class. Major side effect is hypoglycemia. Major advantage is rapid onset and offset Can dose just prior to meals with better post-prandial control Fewer overnight lows Ability to skip the dose if skip the meal. Efficacy for repaglinide appears to be similar to SU’s

Mechanism of action

3. GLP-1 （glucogen-like peptide1)receptor agonist and DPP-4 inhibitor B. Oral hypoglycemic drugs -3 3. GLP-1 （glucogen-like peptide1)receptor agonist and DPP-4 inhibitor

GLP-1 receptor agonist and DPP-4 inhibitor B. Oral hypoglycemic drugs-3 GLP-1 receptor agonist and DPP-4 inhibitor

GLP-1 receptor agonist and DPP-4 inhibitor B. Oral hypoglycemic drugs GLP-1 receptor agonist and DPP-4 inhibitor

GLP-1 （glucogen-like peptide1)receptor agonist 依克那肽 利拉鲁肽

GLP-1 （glucogen-like peptide1)receptor agonist B. Oral hypoglycemic drugs GLP-1 （glucogen-like peptide1)receptor agonist Exenatide(依克那肽) Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster that was first isolated by Dr. John Eng in 1992. a 39-amino-acid peptide, an insulin secretagogue, with glucoregulatory effects Mechanism of action: It displays biological properties similar to human glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion

B. Oral hypoglycemic drugs Exenatide(依克那肽) 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. 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 : weight loss (~5 kg) as well as maintained effect (preserved beta cell function). Efficacy: decreases A1C ~1.0%.

DPP-4 (dipeptidyl peptidase 4 enzyme) inhibitor B. Oral hypoglycemic drugs DPP-4 (dipeptidyl peptidase 4 enzyme) inhibitor Sitagliptin phosphate(磷酸西列他汀） Mechanism of action: Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal GLP-1 levels Acts as an incretin enhances insulin secretion in response to an oral glucose load. Suppresses post-prandial glucagon secretion in a glucose- dependent manner Preserves beta cell mass by reducing apoptosis and increased neogenesis (animal models).

Sitagliptin phosphate(磷酸西列他汀） B. Oral hypoglycemic drugs Sitagliptin phosphate(磷酸西列他汀） 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%.

B. Oral hypoglycemic drugs-2 Insulin sensitizers Biguanides Metformin 二甲双胍 Phenformin 苯乙双胍 1. Pharmacological effects increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut and glucagon release  2. Clinical uses mild insulin-independent patients with obesity  3. Adverse effects severe lactic acidosis, malabsorption of vitamin B12 and folic acid 

Mechanism of action

B. Oral hypoglycemic drugs -2 Biguanides Mechanism of action not well understood, but causes inhibition of hepatic glucose production. Metformin is only agent in this class available in US. Major side effect GI intolerance (20-30%): bloating, anorexia, diarrhea, and flatulence. Lactic acidosis is rare, but may be severe. Major advantages: Lack of weight gain Absence of hypoglycemia Low cost with generic prep.

B. Oral hypoglycemic drugs-2 Thiazolidinediones (TZDs) 噻唑烷酮类化合物 Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮 Troglitazone 曲格列酮

B. Oral hypoglycemic drugs-2 Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮

B. Oral hypoglycemic drugs -2 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), by enhancing peripheral insulin sensitivity, esp. at muscle and adipose tissue, via activation of PPARγ, increasing glucose transport into muscle and adipose tissue. (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid  (3) Antihypertensive effects

Mechanism of action

B. Oral hypoglycemic drugs-2 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)

B. Oral hypoglycemic drugs -3 Alpha-Glucosidase inhibitors Acarbose-Precose 阿卡波糖 1996 Miglitol-Glyset 米格列醇 1998 Voglibose 伏格列波糖

B. Oral hypoglycemic drugs -3 Acarbose 阿卡波糖 Reducing intestinal absorption of starch (淀粉), dextrin (糊精), and disaccharides (二糖) by inhibiting the action of alpha- glucosidase enzymes in the brush border of the small intestines.

B. Oral hypoglycemic drugs-3 Mechanism of Acarbose

Alpha-Glucosidase Inhibitors – Caveats in Use Acarbose has minimal systemic absorption, but some hepatic metabolism occurs. Contraindicated with advanced liver disease Miglitol has greater systemic absorption Not metabolized by the liver Renally excreted, and hence should not be used in renal failure (creatinine >2) Voglibose in contrast to acarbose, has less of GI side effects. It is also more economical compared to acarbose.

B. Oral hypoglycemic drugs -3 Alpha-Glucosidase inhibitors Major side effect : GI intolerance, including bloating, cramping, and flatulence, diarrhea… need to titrate very slowly. Major advantage: absence of hypoglycemia when used as monotherapy.

Summary Medication Site of Action/Mechanism Side-Effects Sulfonylurea (eg. glyburide) Augments insulin secretion, binds SUR Hypoglycemia, caution renal insufficiency, elderly Thiazolidinediones (eg. rosiglitazone) PPARg receptor/increased insulin sensitivity Liver, LE edema, congestive heart failure, MI Biguanide (metformin) Reduced hepatic gluconeogenesis GI upset, Lactic acidosis (very rare), only use if creatinine<1.5 mg/dl Glinides (repaglinide) Bind SUR, short action Hypoglycemia, caution in renal insufficiency Alpha-glucosidase inhibitors (acarbose) Inhibits brush border enzyme/Reduce glucose absorption Flatulence, diarrhea Incretins/GLP-1 (exenatide) Stimulates insulin, delays gastric emptying, satiety Nausea, vomiting (given by injection) DPP4 Inhibitors (vildagliptin) Inhibits GLP1 breakdown GI side effects

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