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Insulin and oral hypoglycemic drugs Islet of Langerhans Alpha cell: 20%, glucagon Beta cell: 75%, insulin Delta cell: 5%, somatostatin D1 cell: VIP PP cell: pancreatic polypeptide 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 Diabetes Mellitus A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both 100 million people worldwide 85-90% cases are Type II CLASSIFICATION TYPE 1 (IDDM,10%) Deficiency of insulin secretion Genetic predisposition and possible links to viral infections and environmental factors Possible autoimmune process with destruction of beta pancreatic cells Require insulin supplementation, prone to develop DKA (酮症酸中毒) CLASSIFICATION TYPE 2 Resistance to action of insulin on target organs Decrease in insulin production Increased risk with obesity high fat, high caloric diets Stronger genetic predisposition Variety of initial presentations: HHNKS (高血糖高渗 性非酮症综合征), nephropathy, retinopathy, neuropathies Disease can be delayed or prevented with life style changes Natural History of Type 2 Diabetes Obesity Glucose (mg/dL) Relative Function (%) IGT Diabetes 350 300 250 200 150 100 50 250 200 150 100 50 0 Uncontrolled hyperglycemia Post-meal Glucose Fasting Glucose Insulin Resistance Insulin Level “Beta-cell failure” -10 *IGT = impaired glucose tolerance -5 0 5 10 15 20 25 30 Years of Diabetes Adapted from International Diabetes Center (IDC) Minneapolis, Minnesota CLASSIFICATION SECONDARY CAUSES Exocrine pancreas disease: pancreatitis Genetic syndromes: Downs, Turners Infections: CMV, Congenital rubella Drugs: Glucocorticoids, Dilantin, beta agonists Endocrinopathies: Cushing's, Acromegaly Classification Gestational Presents only during pregnancy 135,000 cases annually Increased risk of developing diabetes post partum Tight glycemic control required to prevent macrosomia, fetal cardiac and CNS abnormalities CLINICAL FEATURES Polyuria Polydipsia Polyphagia Weight loss TYPE 1 DM-- acute, severe TYPE 2 DM-- chronic, less severe 正常人 糖尿病 尿崩症 Complications of diabetes mellitus Acute complications Diabetic ketoacidosis Hyperosmotic nonketotic coma Chronic complications Cardiovascular diseases Renal damage Retinal damage Nerve degeneration Myopathy Infection Rhinocerebral Mucormycosis Therapy of Diabetes Mellitus Diet Exercise Insulin and its enhancers Oral hypoglycemic drugs Insulin and its enhancers Structure of insulin Insulin and its enhancers 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) HR , myocardial contractility, renal blood flow Mechanism of insulin actions Interacting with insulin receptor Insulin promotes glucose utilization Insulin and its enhancers 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) HR , myocardial contractility, renal blood flow Mechanism of insulin actions Interacting with insulin receptor Insulin and its enhancers 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) HR , myocardial contractility, renal blood flow 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 Insulin and its enhancers 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 3. Preparations Properties Preparations Onset Peak Duration Fast-acting Regular insulin 0.5-1 h 2-3 h 6-8 h Intermmediateacting Neutral protamine hagedorn 2-4 h 6-10 h 12-18 h Long-acting Protamine zinc insulin suspension 3-6 h 6-10 h 24-36 h Hirsch IB NEJM 352:174, 2005 Rapid Acting Insulin Analogues Current agents include lispro, aspart, and glulisine. 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 60-90 minutes and duration of ~3-5 hours. Advantages include: increased convenience- can take just prior to meal. better postprandial glycemic control. Disadvantages include: short duration of action- can be problematic in Type 1 diabetic without basal insulinization, as with bedtime NPH. more expensive than regular insulin (~double the cost). Holleman and Hoekstra, NEJM, 337:176-83, 1997 Hirsch, NEJM, 352:174-83, 2005 Actions of different insulin preparations Insulin and its enhancers 4. Adverse effects (1) Hypersensitivity: treated with H1 receptor antagonist, glucocorticoids (2) Hypoglycemia: adrenaline secretion (sweating, hunger, weakenss, tachycardia, blurred vision, headache, etc.), treated with 50% glucose (3) Lipoatrophy: localized in injection sites (4) Insulin resistance: Acute: stress induced, need large dose of insulin Chronic: need >200U/d and no complication Insulin and its enhancers Insulin action enhancers Thiazolidinediones (TDs) Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮 Troglitazone 曲格列酮 噻唑烷酮类化合物 Insulin and its enhancers Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮 Insulin and its enhancers 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). (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid (3) Antihypertensive effects (4) Effect on vascular complications in type 2 patients Insulin and its enhancers 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) Oral hypoglycemic drugs Sulfonylureas(磺酰脲类) Biguanides(双胍类) -Glucosidase inhibitors(葡萄糖苷酶抑制药) Others 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: Ca2+ inflow , insulin release , stimulating insulin secretion increasing insulin sensitivity (long-term use) inhibit glucagon release (2) Antidiuretic effect (3) Effect on coagulation function Action of sulfonylureas Sulfonylureas 1. Pharmacological effects (1)Hypoglycemic effect: blocking K+ channel: Ca2+ inflow , insulin release , stimulating insulin secretion increasing insulin sensitivity (long-term use) inhibit glucagon release (2) Antidiuretic effect (3) Effect on coagulation function (Gliclazide) Sulfonylureas 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) 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. Sulfonylureas 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, warfarin (2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics: glucagon, thiazides, etc. Oral hypoglycemic drugs Biguanides(双胍类) Metformin 二甲双胍(甲福明) Phenformin 苯乙双胍(苯乙福明) Biguanides 1. Pharmacilogical 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 (less for metformin), malabsorption of vitamin B12 and folic acid Oral hypoglycemic drugs -Glucosidase inhibitors(葡萄糖苷酶抑制药) 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 Others Repaglinide 瑞格列奈 Oral insulin secretagogue Repaglinide (餐时血糖调节剂) 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 Clinical uses Type2 DM, diabetic nephropathy, elder DM patient Incretin Mimetics Mechanism of Action: Act as an incretin enhance insulin secretion in response to an oral glucose load. Suppress post-prandial glucagon secretion in a glucosedependent manner Delay gastric emptying Centrally suppress appetite Preserve beta cell mass by reducing apoptosis and increased neogenesis (animal models). Keating, Drugs. 65(12):1681-92, 2005. Riddle and Drucker. Diabetes Care 2006; 29:435-49. Incretin Mimetics Exenatide (Byetta) is first incretin mimetic on market. Synthetic version of salivary protein found in the Gila monster53% overlap with human GLP-1. Exenatide GLP-1 Human H AE G T F TSD V S SY K E F I AW A LVKGR VK R -NH2 SYLLEGQ GQAAAKE Site of DPP-IV Inactivation 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 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 is weight loss (~5 kg) as well as maintained effect (?preserved beta cell function). Efficacy: decreases A1C ~1.0%. Keating, Drugs 2005 65(12):1681-92 Dipeptidylpeptidase IV (DPP-IV) Inhibitors 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 (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%. Riddle and Drucker. Diabetes Care 2006; 29:435-49. Case 1 50y/o, Chinese Male, CC: Hyperglycemia found ×2 m PE: BMI 29 Kg/m2 WC: 102cm Lab Findings: FBG 155mg/dl, 2hPG: 276mg/dl, HbA1c: 7.5% Which DRUG or DRUGS will we order? Treatment Strategies Beyond Lifestyle In general, try to initiate pharmacotherapy with an oral agent in newly diagnosed type 2 diabetics unless: Fasting plasma glucose is >300 mg/dl with ketonemia or ketonuria Markedly symptomatic In patients who need insulin initially, often can be switched to oral agents after 6-8 weeks when glucose toxicity resolves Answer to Case 1 ( A newly diagnosed type 2 DM patient with obesity) Lifestyle intervention Metformin 500mg q.d.-t.i.d “Failure” of a Single Oral Agent Type 2 diabetes is a progressive disease, with ’d loss of beta cell function over time. Need to progress to multi-drug therapy or add insulin in order to maintain a similar level of glycemic control. If glycemic goals are not met with agent in one class, we must add second agent with different mechanism of action or add insulin 1Kahn et al. N Engl J Med, 355:2427, 2006 • ADA consensus algorithm recommends addition of a SU, thiazolidinedione, or insulin if metformin therapy is not effective in getting patients to goal A1C.2 2Nathan et al. Diabetes Care. 29:1963-1972, 2006. Algorithm for the management of T2DM Overweight or obese patients (BMI >=24Kg/m2) Diet,exercise, weight loss + Metformin 3 month later HbA1c﹥6.5% Add one or several agents below: Sulfonylurea or Meglitinide (one of the two), Glitazones , Alpha-Glucosidase Inhibitor 3 month later HbA1c > 6.5% Add insulin From: China Guideline for Type 2 Diabetes (CDS,2007) Algorithm for the management of T2DM (Cont’) Non-obese Patients (BMI﹤24kg/m2) Diet, exercise, weight loss + One or several agents below: Metformin, Sulfonylurea or Meglitinide (one of the two), Thiazolidinedione, Alpha-Glucosidase Inhibitor 3 month later HbA1c > 6.5% Add insulin From: China Guideline for Type 2 Diabetes (CDS,2007) Use of Oral Agents to Optimize Glycemic Control: Conclusions Choice of oral agents needs to be matched with patient characteristics (thin vs. obese) as well as concurrent medical issues (renal, hepatic, cardiopulmonary status). Diabetes is a progressive disease, and will require an increasing number of agents and/ or addition of insulin as the duration of diabetes increases. Each oral agent can only improve A1C a maximum of 2%, so if poor control persists on multiple agents, insulin is needed. Use Of Insulin In Type 2 Diabetes Indications When glycemic control deteriorates despite combination oral agents. Surgery in patients with type 2 DM (transient) Pregnancy Method: Start with bedtime intermediate (NPH) or long acting (glargine, detemir) insulin in addition to oral agents. If doesn’t work, switch to basal-bolus therapy as used in conventional type 1 DM treatment • Can continue metformin. • Stop insulin secretagogues. Basal/Bolus Insulin Absorption Pattern w/ Standard Insulin Preparations Plasma Insulin µU/ml) 75 Breakfast Lunch Dinner 50 REG REG REG 25 4:00 NPH 8:00 12:00 16:00 Time 20:00 24:00 4:00 8:00 Plasma Insulin Basal-Bolus Treatment with Rapid and Long Acting Analogues Breakfast Aspart Lunch Aspart Dinner Aspart or Lispro or or Lispro or or Lispro or Glulisine Glulisine Glulisine Glargine 4:00 8:00 12:00 16:00 Time 20:00 24:00 4:00 8:00 Insulin Pump and Glucose Monitoring Insulin Pump – “Open Loop” Patient sets basal infusion rate and w/ superimposed boluses Continuous Glucose Monitor “Closed Loop” insulin pump system is ultimate goal… infusion rate adjusted based on input from continuous glucose monitor. Case 2 64y/o, Chinese Male. CC:polydipsia,polyuria,polyphagia × 12y lower limb edema × 3 m Metformin 500mg bid + Glipizide 80mg tid PE: BMI 22kg/m2, WC 78cm, decreased sensation and medium pitting edema in both lower limbs Lab Findings: UA: PRO 3+,GLU 2+ ; FBG 188mg/dl, 2hPG 266 mg/dl HbA1c 8.3%; Case2 (Cont’) Liver function tests: nl transaminase, Alb 28g/l SCr:1.5mg/dl, CCr: 52ml/min Which DRUG or DRUGS should we Prescribe? Answer to case 2 (long diabetes history with diabetic Nephropathy and Chronic renal insufficiency ) Should start with insulin treatment Regimen: 1. Regular insulin or rapid acting insulin analogs tid premeal + NPH or long acting insulin analog at bedtime 2. Insulin Pump