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Diabetic Disorders

Diabetic Disorders. 4 th Leading cause of deaths in the US 75% of those afflicted with diabetes die from CHD Major complications of diabetes Fearsome 15

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Diabetic Disorders

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  1. Diabetic Disorders • 4th Leading cause of deaths in the US • 75% of those afflicted with diabetes die from CHD • Major complications of diabetes • Fearsome 15 • Elevated triglycerides and LDL; reduced HDL; High blood pressure; obesity; kidney failure; blindness; peripheral neuropathy; decline in cognitive abilities; atherosclerosis; heart attack; stroke; peripheral vascular disease; poor wound healing; frequent infections MEDC 603 Fall 2007

  2. Diabetes Mellitus • Type I Diabetes • aka IDDM (Insulin-dependent diabetes mellitus) • Inability of b-islet cells of pancreas to produce insulin • Type II Diabetes • aka NIDDM (Non-insulin-dependent diabetes mellitus) • Either a reduced ability of pancreas to produce or secrete insulin (some residual capacity) and/or reduced ability of target cells to respond to insulin • Gestational Diabetes MEDC 603 Fall 2007

  3. Diabetes Mellitus • Insulin • two chain polypeptide connected by two S-S bonds • A chain = 21 AA residues; B chain = 30 AA residues • may exist as dimer, trimer or higher oligomers in solution • produced in b-islet of Langerhans • Regulates glucose transport • stimulates GLUTs • Regulates gene transcription • ~100 genes are known to be regulated by insulin • e.g., insulin inhibits gluconeogenesis …. Liver overproduces glucose in insulin-resistant state (type 2 DM) • Regulates glucose metabolism • phosphorylation of G to G-6-P …. Signal transduction MEDC 603 Fall 2007

  4. Overview for Controlling Hyperglycemia Absorption from Diet Biosynthesis in Liver a-Glucosidase Inhibitors Biguanides Cellular Uptake Serum Sugar Biguanides; thiazolidinediones Sulfonylureas; Benzoic Acids Pancreas Insulin {Hypoglycemia} MEDC 603 Fall 2007

  5. pKa ~5 _ Sulfonyl Ureas Structure & Ionization Mechanism of Action Stimulates release of insulin from b-cells Act through ion-channels that generate a Ca+2 influx Affinity to this receptor correlates with hypoglycemic effect In addition, there are extra-pancreatic effects, e.g., effects on glucose transporter MEDC 603 Fall 2007

  6. Structures of Sulfonyl Ureas R R’ Tolbutamide Chlorpropamide Tolazamide Glyburide Glipizide Glimepiride MEDC 603 Fall 2007

  7. Major Pharmacokinetic Properties of Sulfonyl Ureas NOTE: 1) Hypoglycemia 2) Weight Gain MEDC 603 Fall 2007

  8. Substituted Benzoic Acids or ‘Glinides’ • Structural similarity to Sus • pKa ~3-5 (close to SUs) • Functional similarity to SUs • More rapidly active • Shorter duration of action • Less problematic hypoglycemia • Reduced weight gain Meglitinide Replaglinide Nateglinide MEDC 603 Fall 2007

  9. Phenformin Metformin Biguanides (not available in the US) (introduced in the US in 1995) Mechanism of Action (Metformin) Unclear Phenformin induces lactic acidosis …. Fatal in 3% Does not depend on insulin (synthesis or secretion) Anti-hyperglycemic (not hypoglycemic …. note !!) Possibly two components: increased sugar usage and inhibition of gluconeogenesis MEDC 603 Fall 2007

  10. Thiazolidinediones (glitazones) R group Pioglitazone (racemic) Ciglitazone (racemic) Mechanism of Action Enhance glucose and lipid metabolism through action on PPARg Enhance sensitivity to insulin in target cells Troglitazone (racemic) Rosiglitazone (racemic) MEDC 603 Fall 2007

  11. Thiazolidinediones (glitazones) Some Metabolites Rosiglitazone Troglitazone Pioglitazone MEDC 603 Fall 2007

  12. a-Glucosidase Inhibitors - Acarbose Inhibitor of Sugar Absorption from the GI tract a-glucosidase MEDC 603 Fall 2007

  13. a-Glucosidase Inhibitors - Acarbose Transition State of hydrolysis Acarbose – transition state mimic MEDC 603 Fall 2007

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