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Diabetes: Insulin and Hypoglycemic Agents

Diabetes: Insulin and Hypoglycemic Agents. Kurt Varner, Ph.D. and Robert Richards, M.D. 3-05-2009. LEARNING OBJECTIVES Compare Type 1 and Type 2 Diabetes List commonly use insulin preparations and their majaor adverse effects List the three main classes of hypoglycemic agents

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Diabetes: Insulin and Hypoglycemic Agents

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  1. Diabetes: Insulin and Hypoglycemic Agents Kurt Varner, Ph.D. and Robert Richards, M.D. 3-05-2009

  2. LEARNING OBJECTIVES • Compare Type 1 and Type 2 Diabetes • List commonly use insulin preparations and their majaor adverse effects • List the three main classes of hypoglycemic agents • Describe the mechanism of action of -glucosidase inhibitors their adverse effects, drug-drug interactions and contraindications • Explain the actions of sulfonylureas and meglitinides, drug-drug interactions and contraindications • Describe the actions of Metformin, its drug-drug interactions and contraindications • Explain the actions of Thiazolidinediones, their adverse effects, drug-drug interactions and contraindications

  3. Types of Diabetes Diabetes Mellitus Type 1 Insulin Dependent Diabetes Mellitus (IDDM) caused by destruction of pancreatic β cells Diabetes Mellitus Type 2 Non-insulin Dependent Diabetes mellitus (NIDDM) cause by insulin resistance

  4. Type I vs Type II Diabetes Usually Ineffective Oral Hypoglycemics Effective Required Insulin Therapy may be required

  5. Consequences of Diabetes Acute Hyperglycemia ketoacidosis diabetic coma (hyperglycemia or hypoglycemia)

  6. Chronic Complications of Diabetes • Coronary and cerebrovascular Disease • 2–4 fold increased risk of coronary heart disease and stroke; 75% have hypertension Retinopathy Most common cause of blindness in people of working age Nephropathy 16% of all new patients needing renal replacement therapy Foot Problems 15% of people with diabetes develop foot ulcers; 5–15% of people with diabetic foot ulcers need amputations • Erectile Dysfunction • May affect up to 50% of men with long-standing diabetes

  7. Regulation of Insulin Secretion from the Pancreas Glucose Ca2+ GLUT-2 K+ Depolarization Glucose Ca2+ ATP Glucokinase Insulin Glucose-6-Phosphate

  8. Structure of Insulin

  9. Insulin -Mechanism of Action

  10. Insulin Insulin Insulin Normal Insulin Function: Fuel Storage Glucose Storage Gluconeogenesis TG Glucose and FFA Uptake Glucose Glucose Uptake Muscle Gluconeogenic amino acid release to liver Pancreas

  11. Treatment of Type 1 Diabetes Insulin replacement

  12. COMMONLY USED INSULIN PREPARATIONS

  13. Insulin Delivery Systems Exubera Inhaled

  14. Split-Mixed regimen involving the prebreakfast and presupper injection of a mixture of regular and intermediate-acting insulins Divide evening dose into a presupper dose of regular insulin followed by NPH or lente insulin at bedtime Basal/Bolus Premeal short-acting insulin with intermediate-acting insulin at breakfast and bedtime Continuous subcutaneous insulin infusion.

  15. Major Adverse Effect of Insulin Therapy: Insulin in the Absence of Carbohydrate can Lead to Severe Hypoglycemia 1. First discerned at a plasma glucose level of 60 to 80 mg/dl (3.3 to 4.4 mM). - Sweating, hunger, paresthesia (numbness) , palpitations, tremor, and anxiety, -principally of autonomic origin 2. At < 60 mg/dl - Difficulty in concentrating, confusion, weakness, drowsiness, a feeling of warmth, dizziness, blurred vision, and loss of consciousness - Neuroglycopenic symptom: occur at lower plasma glucose levels than do autonomic symptoms.

  16. Treatment of Type 2 Diabetes

  17. Type 2 Diabetes Mellitus

  18. Oral Drug Therapy for Type 2 DM } Inhibitors of CHO absorption Acarbose Miglitol Sulfonylureas Repaglinide Nateglinide Biguanides Thiazolidinediones Incretin mimetics DPP-4 inhibitors } Insulinsecretagogues } Insulin sensitizers } Increase insulin release

  19. Inhibitors of Intestinal Glucose Absorption: Acarbose (Precose) and Miglitol (Glyset) • Acts as an -glucosidase inhibitor: prevent cleavage of disaccharides to monosaccharides in the intestine • Delays carbohydrate absorption and reduced postprandial plasma glucose. • No effect on lipid profiles • Tends not to cause weight gain • GI side effects include flatulence (80%), diarrhea (27%) and nausea (8%) . Titrating the dose of drug slowly reduces GI side effects. • Additive effect when used in combination with sulfonylureas and metformin

  20. - - Sulfonylureas: Mechanism of Action Sulfonylureas GLUT2 Na+ K+ K+ KIR Na+ K+ Vm K+ Ca2+ Pancreatic ß cell Voltage-gated Ca2+ channel ↑ Ca2+ Insulin granules

  21. Sulfonylureas: Mechanism of Action

  22. SULFONYLUREAS • Oral administration and bind to plasma proteins • Actions can be enhanced by alcohol • ~50% of new onset Type II diabetic can reach appropriate glycemic control • First Generation: less potent but longer half lives • Acetohexamide rapidly metabolized, but active metabolite 4-7 hrs • Chlorpropamide (24-48 hours) • Tolazamide (4-7 hrs) • Tolbutamide(4-7 hrs) • 2nd Generation: 100x more potent, but shorter half-life (3-5 hrs) • Glyburide (glibenclamide) (may cause hypoglycemia) • Glimeperide • Glipizide

  23. Insulin Secretagogue: Repaglinide and Nateglinide • Chemically Unrelated to Sulfonylureas but same mechanism of action • Rapid absorption with half-life of 1 hr. • Can be taken right before meal • Less likely to cause hypoglycemia • Metabolized by liver. Caution in pts. with insufficiency. Repaglinide approved for mild to moderate liver failure Nateglinide for moderate liver failure.

  24. Biguanides: Insulin Sensitizers In medieval Europe, a plant locally known as Goat’s Rue (Galegaofficinalis) was used to treat symptoms of diabetes. The plant contained the compound guanidine. In the 1950’s, the biguanide Phenformin was introduced for treating type 2 diabetes in the U.S.. It was withdrawn from the market due to cases of fatal lactic acidosis.

  25. 2nd Generation Biguanide Metformin: Mechanism of Action

  26. METFORMIN • Major mechanism of action:  AMP-dependent kinase. • - Inhibits conversion of acetyl CoA to malonyl CoA, by acetyl- CoA carboxylase, the rate-limiting step in lipogenesis. Net result is a faster rate of fatty acetyl-CoA influx into the mitochondria where it undergoes oxidation to ketone bodies • Increases expression or activity of glycolytic enzymes and GLUT-4, decreases activity of gluconeogenic enzymes • Net: hepatic glucose production and  glucose uptake in muscle and adipose. • Can reduce plasma glucose levels by 25% and decrease hemoglobin A1c by 1-2%. Also lowers plasma triglyceride levels • Does not lead to hypoglycemia when used alone i.e. is anti-hyperglycemic • Adherence to prescribing guidelines is crucial to minimize risk of metabolic acidosis. (reason why phenformin taken off the market)

  27. METFORMIN (cont.) CONTRAINDICATIONS Parenteral radiographic contrast administration: may cause acute renal failure and lactic acidosis in patients on metformin. Must withhold metformin just prior to and for 48 hours after the completion of the procedure. Metabolic acidosis, lactic acidosis and diabetic ketoacidosis Metformin is substantially eliminated by the kidney and is absolutely contraindicated for use in patients with renal failure or renal impairment (creatinine ≥1.5 in men, or ≥ 1.4 in women).

  28. Thiazolidinediones:Pioglitazone, Rosiglitazone • Activate nuclear receptors: peroxisome proliferator-activator receptors (PPAR-g). • Increases gene expression in muscle, liver and fat to increase insulin sensitivity. • Seem to have additional beneficial effects on blood vessels to reduce hypertension and atherosclerosis • Can be used as monotherapy or in combination with metformin or sulfonylureas

  29. PPARg: Sites of Metabolic Action Insulin Sensitivity Insulin Sensitivity  Glucose output

  30. Thiazolidinediones:Pioglitazone • Some metabolites pharmacologically active • Excreted primarily in the feces • Half-life: plasma half-life is 3 to 7 hours • 16 to 24 hours for metabolites • Extensively (>99%) bound to albumin • No evidence of drug-induced hepatotoxicity • Should not be used in patients who experienced jaundice while taking troglitazone Can worsen or cause heart failure. Also cause edema, decrease hematocrit

  31. Thiazolidinediones:Rosiglitazone (Avandia) • Some evidence of drug-induced hepatotoxicity • Rosiglitazone linked to fatal ischemic heart disease • Don’t use in class 3 or 4 failure. • Can worsen or cause heart failure. Also cause edema, decrease hematocrit

  32. NEW CLASSES OF HYPOGLYCEMICS Amylin: 37-aa peptide produced by β cells and co-secreted with insulin. Inhibits glucagon secretion, delays gastric emptying and suppress appetite. Pramlintide: Modified amylin peptide used with insulin to prevent postparandial hyperglycemia . Must be injected. Incretin: Glucagon-like peptide (GLP-1 released from the gut to augment glucose-dependent insulin secretion from pancreas). - same effects as amylin plus increases Beta cell number Incretin is rapidly broken down by dipeptidyl peptidase-4 enzyme (DPP-4) Exenatide; Incretin mimetic (injected) Sitagliptin: DPP-4 inhibitorb (oral) Vildagliptin: DPP-4 inhibitor (oral)

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