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