Insulin and oral hypoglycemic drugs

§A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both §194 million people worldwide §90% cases are Type 2 Diabetes Mellitus

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 Require insulin supplementation, prone to develop DKA ( 酮症酸中毒）

CLASSIFICATION §TYPE 2 (NIDDM,90%) 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

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

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

Insulin and its action enhancers

Structure of insulin

Insulin 1. Pharmacological effects (1)Carbohydrate metabolism: reducing blood glucose levels by glucose oxidation and glycolysis ,glycogenolysis , glycogen synthesis , gluconeogenesis  (1)Carbohydrate metabolism: reducing blood glucose levels by glucose oxidation and glycolysis , glycogenolysis , glycogen synthesis , gluconeogenesis  (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)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

Insulin 1. Pharmacological effects (1)Carbohydrate metabolism: reducing blood glucose levels by glycose oxidation and glycolysis ,glycogenolysis , glycogen synthesis , gluconeogenesis  (1)Carbohydrate metabolism: reducing blood glucose levels by glycose oxidation and glycolysis , glycogenolysis , glycogen synthesis , gluconeogenesis  (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)HR , myocardial contractility , renal blood flow  Mechanism of insulin actions Interacting with insulin receptor Interacting with insulin receptor

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

2. Clinical uses (1)Type 1 diabetes mellitus (2) Type 2 diabetes mellitus: failure to other drugs or diet control (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: intracellular lack of K + Insulin

3. Preparations PropertiesPreparationsOnsetPeakduration RapidLispro, aspart5-15min30- 60min 2-5h FastRegular insulin0.5-1h2-4h5-7h FastNovolin R, Humulin R0.5-1h2-4h5-7h Intermediate Neutral protamine hagedorn (NovolinN, Humulin N) 1-2h8-12h24h LongProtamine zinc insulin suspension 4-8h14-20h24-36h LongGlargine1-2hno20-24h

Rapid Acting Insulin Analogues §Current agents include lispro ( 赖脯胰岛素 ), aspart ( 门冬胰岛素 ), and glulisine ( 赖谷胰岛素 ). （人胰岛素 类似物） §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 minutes and duration of ~2-5 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).

3. Preparations PropertiesPreparationsOnsetPeakduration RapidLispro, aspart5-15min30- 60min 2-5h FastRegular insulin0.5-1h2-4h5-7h FastNovolin R, Humulin R0.5-1h2-4h5-7h Intermediate Neutral protamine hagedorn (NovolinN, Humulin N) 1-2h8-12h24h LongProtamine zinc insulin suspension 4-8h14-20h24-36h LongGlargine1-2hno20-24h

Regular Insulin §Referred to as clear or unmodified insulin. §Onset of action minutes, Peak action 2-4 hours, Duration of action: 5-7 hours. §Advantages: l Inexpensive l Long track record of safety. §Disadvantages: l Need to take doses minutes prior to eating a meal. l Effect is not truly rapid… it is delayed which can result in postprandial hyperglycemia, late hypoglycemia.

3. Preparations PropertiesPreparationsOnsetPeakduration RapidLispro, aspart5-15min30- 60min 2-5h FastRegular insulin0.5-1h2-4h5-7h FastNovolin R, Humulin R0.5-1h2-4h5-7h Intermediate Neutral protamine hagedorn (NovolinN, Humulin N) 1-2h8-12h24h LongProtamine zinc insulin suspension 4-8h14-20h24-36h LongGlargine1-2hno20-24h

Glargine (Lantus 甘精胰岛素 ) §Long acting insulin analogue. §Onset is ~90 minutes, and it is virtually peakless. §Duration is hours. §Provides ~flat basal insulinization. §More expensive §Cannot be mixed with other insulins. The Medical Letter, Vol 43, August 6, 2001

Mixed insulin §70-30: human monocomponent insulin ( 单组份人胰岛 素 ) 30%, Human Insulin Isophane Suspension ( 精蛋 白锌人胰岛素） 70%. §50-50: human monocomponent insulin ( 单组份人胰岛 素 ) 50%, Human Insulin Isophane Suspension ( 精蛋 白锌人胰岛素） 50%. §Onset:0.5h, peak 2-12h, duration:16-24h. 30min before breakfast.

4. Adverse effects (1) Hypersensitivity: treated with H 1 receptor antagonist, glucocorticoids, replaced by human or high purity insulin (2) Hypoglycemia: (sweating, hunger, weakenss, tachycardia, blurred vision, headache, coma, shock, etc.), drink glucose contained water, or treated with 50% glucose (3) Lipoatrophy: localized in injection sites (4) Insulin resistance: Acute: stress etc. induced, need large dose of insulin Chronic: need >200U/d and no complication Insulin

4. Adverse effects (5) Increase body weight (6) Ametropic eye 屈光不正 (7) Edema Insulin

Thiazolidinediones (TDs) 噻唑烷酮类化合物 Biguanides ( 双胍类 ) Insulin action enhancers (oral hypoglycemic drugs)

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 action enhancers

Rosiglitazone罗格列酮 Pioglitazone Pioglitazone吡格列酮 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) Fat cells differentiate to a lot of small fat cells, and increase GLUT-4 expression (2) Increase signal transmission of insulin (Rosiglitazone increase insulin receptors) (3) Decrease leptin, IL-6 and TNF-alpha expression in fat cells (4) increase GLUT1,4 transcription and expression (5) Inhibit VEGF mediated angiogenesis, to prevent the complications. (6) Increase adiponectin level, recover the function of B cells Insulin action enhancers

1. Pharmacological effects (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fat acid, LDL  (3) Antihypertensive effects (4) Effect on vascular complications in type 2 patients (5) Recover the function of B cells Insulin action enhancers

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 action enhancers

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） Insulin action enhancers

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, gluconeogenesis, and glucagon release. decreasing glucose absorption in gut, gluconeogenesis, 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

Other oral hypoglycemic drugs Oral insulin secretagogues Sulfonylureas ( 磺酰脲类 ) Repaglinide Incretin (GLP-1) Mimetics Dipeptidylpeptidase IV (DPP-IV) Inhibitors

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 )

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 increase the binding of insulin and its receptors (still effective after long-term use to recover insulin level) increase the binding of insulin and its receptors (still effective after long-term use to recover insulin level) glucose utilization , glycogen and fat synthesis , insulin receptor number and affinity , insulin metabolism↓ glucose utilization , glycogen and fat synthesis , insulin receptor number and affinity , insulin metabolism↓ (2) Antidiuretic effect (3) Effect on coagulation function

Action of sulfonylureas

Sulfonylureas 1. Pharmacological effects 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, increase the binding of insulin and its receptors (still effective after long-term use to recover insulin level) increase the binding of insulin and its receptors (still effective after long-term use to recover insulin level) glucose utilization , glycogen and fat synthesis , insulin receptor number and affinity , insulin metabolism ↓ glucose utilization , glycogen and fat synthesis , insulin receptor number and affinity , insulin metabolism ↓ (2) Antidiuretic effect (chlorpropamide): effect of antiuretic hormone (ADH)  (3) Effect on coagulation function (gliclazide)

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 ) Sulfonylureas

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

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: glucocorticoids, thiazides, etc. interactions in pharmacodynamics: glucocorticoids, thiazides, etc. Sulfonylureas

 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 §Protect beta cell §Clinical uses § Type2 DM, diabetic nephropathy, elder DM patient § less hypoglycemia Repaglinide ( 餐时血糖调节剂 )

Incretin (GLP-1) 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 l Increase insulin secretion in a glucose-dependent manner l Increase somatostatin secretion which inhibit glucagon release 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): , Riddle and Drucker. Diabetes Care 2006; 29:

Incretin (GLP-1) 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 (12): Site of DPP-IV Inactivation Exenatide A SYLGQAKE R VK A HGFVEATTSDSSYLEG Q AAKEFIAWLVK G R-NH2H2 GLP-1 Human

Dipeptidylpeptidase IV (DPP-IV) Inhibitors §Mechanism of Action: l Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal GLP-1 levels §Sitagliptin (Januvia) is first DPP-IV inhibitor on market. §Effective as monotherapy or when used in conjunction with metformin or a thiazolidinedione. §Efficacy: decreases A1C ~0.8%. Riddle and Drucker. Diabetes Care 2006; 29:

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

Oral hypoglycemic drugs Pramlintide acetate Pramlintide acetate ( 醋酸普兰林肽 ) an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal. an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal. delay glucose absorption, inhibit secretion of glucagon delay glucose absorption, inhibit secretion of glucagon Symlin has been approved by the FDA, for use by Type 1 and Type 2 Diabetics who use insulin. Symlin allows patients to use less insulin, lowers average blood sugar levels, and blood sugar after eating.Symlin has been approved by the FDA, for use by Type 1 and Type 2 Diabetics who use insulin. Symlin allows patients to use less insulin, lowers average blood sugar levels, and blood sugar after eating. Apart from insulin analogs, symlin is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s Apart from insulin analogs, symlin is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s

Oral hypoglycemic drugs Aldose reductase inhibitor Epalrestat Epalrestat ( 依帕司他 ) Treatment of Diabetic Neuropathy