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New perspectives in cardio protection: Focus on PPAR  activation

New perspectives in cardio protection: Focus on PPAR  activation. α -Glucosidase inhibitors. Thiazolidinediones. Muscle and adipose tissue: ↓insulin resistance ↑glucose uptake. Intestine: ↓glucose absorption. Blood glucose. Liver: ↓hepatic glucose output ↑glucose uptake.

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New perspectives in cardio protection: Focus on PPAR  activation

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  1. New perspectives in cardio protection: Focus on PPAR activation

  2. α-Glucosidase inhibitors Thiazolidinediones Muscle and adipose tissue: ↓insulin resistance ↑glucose uptake Intestine: ↓glucose absorption Blood glucose Liver: ↓hepatic glucose output ↑glucose uptake Pancreas: ↑insulin secretion Sulfonylureas and repaglinide Principal mechanisms of action for oral diabetic agents Biguanides Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411

  3. Site of action MoA Agents SulphonylureasOther insulinsecretagogues Insulinsecretion BiguanidesThiazolidinediones Glucoseproduction -glucosidaseinhibitors Slow carbohydratedigestion - Peripheral insulinsensitivity Thiazolidinediones(biguanides) Site and mode of action of oral antidiabetic medications DeFronzo RA. Ann Intern Med 1999;131:281-303

  4. Peroxisome proliferator-activator receptors (PPARs) • PPAR , , and  belong to the nuclear hormone receptor superfamily • PPAR agonists appear to play a critical role in regulating inflammation, lipoprotein metabolism, and glucose homeostasis • Studies suggest that PPAR agonists exert antiatherogenic effects by inhibiting proinflammatory gene expression and enhancing cholesterol efflux • PPAR agonists have potential in the treatment of obesity, diabetes, and atherosclerosis Li AC et al. J Clin Invest. 2004;114:1564-76. Blaschke F et al. ArteriosclerThrombVasc Biol. 2006;26:28-40.

  5. PPARs: Overview Blaschke F et al. ArteriosclerThrombVasc Biol. 2006;26:28-40 Semple RK et al. J Clin Invest. 2006;116:581-9

  6. Focus on PPAR  activation • Reduces insulin resistance • Preserves pancreatic -cell function • Improves CV risk profile Improves dyslipidemia ( HDL,  LDL density,  or  TG)  Renal microalbumin excretion  Blood pressure  VSMC proliferation/migration in arterial wall  PAI-1 levels • C-reactive protein levels • TNF-αproduction  Adiponectin  Free fatty acids Inzucchi SE. JAMA. 2002;287:360-72

  7. Beyond fat and glucose: Potential for CV benefits with PPAR  agonists PPAR  is expressed incell types associated with CV disease: • Vascular endothelial cells (EC) • Vascular smooth muscle cells (VSMC) • T-lymphocytes • Monocyte/macrophages • Cardiac myocytes • Renal tubule cells Lumen Lumen Necrotic core EC VSMC Monocytes Adapted from Marx N et al. ArteriosclerThrombVasc Biol. 1999;19:546-51

  8. – – – – PPAR activation and atherosclerosis: A hypothesis Ligand:Endogenous or synthetic Activated PPAR DirectVascular and inflammatory cells IndirectFat, liver, skeletal muscle cells Reducesinflammation  Cytokines  Chemokines Cholesterol efflux Adhesion molecules  FFA Glucose  Insulin sensitivity Triglycerides HDL Atherogenic LDL Blunts atherosclerosis Plutzky J. Science. 2003;302:406-7.

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