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

Principal mechanisms of action for oral diabetic agents α-Glucosidase inhibitors Intestine: ↓glucose absorption Liver: ↓hepatic glucose output ↑glucose uptake Blood glucose Sulfonylureas and repaglinide Pancreas: ↑insulin secretion Muscle and adipose tissue: ↓insulin resistance ↑glucose uptake Thiazolidinediones Biguanides Basic mechanisms of action for oral antidiabetic drugs Sulfonylureas and meglitinides (repaglinide) sensitize pancreatic beta cells to glucose, and directly stimulate pancreatic secretion of insulin. The alpha-glucosidase inhibitors inhibit enzymes in the small intestine and pancreas, thereby delaying glucose absorption and decreasing the rise in postprandial glucose levels. Biguanides decrease hepatic glucose output and intestinal absorption of glucose and increase peripheral glucose uptake and sensitivity. Thiazolidinediones are PPAR  activators and work directly by enhancing insulin action in liver, skeletal muscle, and adipose tissue. Thiazolidinediones reduce insulin resistance at the sites of insulin action. They increase glucose disposal rates and decrease both hepatic glucose output and plasma insulin concentrations. Reference Krentz AJ, Bailey CJ. Drugs. 2005; 65: 385-411. Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411

Site and mode of action of oral antidiabetic medications MoA Agents Insulin secretion Sulphonylureas Other insulin secretagogues Glucose production Biguanides Thiazolidinediones Slow carbohydrate digestion - -glucosidase inhibitors Peripheral insulin sensitivity Thiazolidinediones (biguanides) Site of action Oral antidiabetics have different target organs This slide shows the primary site of action of commonly-used oral antidiabetic medications. Such considerations are useful in selecting a combination of agents which address both components of the dual endocrine defects of type 2 diabetes: insulin resistance and β-cell dysfunction. A combination of metformin with the sulphonylurea, glibenclamide, probably represents the most-used oral antidiabetic combination worldwide Metformin improves glycaemic control by improving insulin sensitivity, mainly in the liver and in skeletal muscle, decreasing hepatic glucose production, increasing splanchnic glucose turnover and improving the uptake and utilisation of glucose in the peripheral tissue Glibenclamide helps to normalize the release of insulin from the pancreas, thereby making the most of remaining β-cell function, and reducing the rate of fat oxidation and further reducing hepatic glucose production Reference DeFronzo RA. Ann Intern Med 1999;131:281-303. 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 Potential effects of PPARs PPARs are central metabolic regulators with global influence on lipid and glucose metabolism that regulate gene expression via binding of their ligands, unsaturated long-chain fatty acids and their metabolites The three PPAR isoforms share 60% to 80% homology in their ligand- and DNA-binding domains These transcription factors can also limit expression of proinflammatory genes by antagonizing the activities of other transcription factors such as nuclear factor-kappa B (NF-κB) and activator protein 1 References Li AC et al. J Clin Invest. 2004; 114: 1564-76. Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006; 26: 28-40. Li AC et al. J Clin Invest. 2004;114:1564-76. Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40.

PPARs: Overview PPAR receptor Main tissue location Regulates Alpha  Liver, skeletal muscle, heart, kidney Lipid metabolism (dyslipidemia) Inflammation/atherosclerosis Gamma  Fat cells, macrophages Insulin sensitivity/glucose metabolism Inflammation/atherosclerosis Adipocyte differentiation Delta  Widespread, including skeletal muscle and fat cells Fatty acid oxidation Inflammation PPAR receptors widespread in different tissues Although all three PPARs regulate lipid and glucose metabolism, and exert anti-inflammatory effects, the isoforms have distinct, but complex and overlapping, biological activities and expression patterns PPAR  is expressed primarily in the liver, where it regulates lipid metabolism, and, to a lesser extent, in the heart, skeletal muscle, and kidney PPAR  is present mainly in adipose tissue. It regulates glucose homeostasis and is involved in inflammation, atherosclerotic plaque development, and adipocyte differentiation PPAR  has a widespread tissue distribution and has been implicated in fat homeostasis and inflammation References Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006; 26: 28-40. Semple RK et al. J Clin Invest. 2006; 116: 581-9. Blaschke F et al. Arterioscler Thromb Vasc 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-α production  Adiponectin  Free fatty acids PPAR  activation improves multiple CV risk factors Effects include improving insulin sensitivity and preserving pancreatic β-cell function As well as improvements in a number of traditional and new CV risk factors Reference Inzucchi SE. JAMA. 2002; 287: 360-72. Inzucchi SE. JAMA. 2002;287:360-72

Beyond fat and glucose: Potential for CV benefits with PPAR  agonists PPAR  is expressed in cell 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 PPAR  expressed in tissues associated with CVD PPAR  is expressed in cells specifically associated with CV disease, including vascular endothelial and smooth muscle cells, cardiac myocytes, cells of the renal tubules, and cells of the immune system such as T-lymphocytes, monocytes, and macrophages These data bolster the hypothesis that PPAR  agonists, in addition to their metabolic effects, may potentially have direct antiatherosclerotic effects in the vasculature Reference Marx N et al. Arterioscler Thromb Vasc Biol. 1999; 19: 546-51. VSMC Monocytes Adapted from Marx N et al. Arterioscler Thromb Vasc Biol. 1999;19:546-51

PPAR activation and atherosclerosis: A hypothesis Ligand: Endogenous or synthetic Activated PPAR Direct Vascular and inflammatory cells Indirect Fat, liver, skeletal muscle cells  Cytokines  Chemokines  Cholesterol efflux  Adhesion molecules Reduces inflammation – –  FFA  Glucose  Insulin sensitivity  Triglycerides  HDL  Atherogenic LDL PPAR  may have antiatherosclerotic effects The metabolic and anti-inflammatory effects of peroxisome proliferator-activated receptor (PPAR) activation are hypothesized to be a new approach to blunting atherosclerosis PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily Direct effects via downregulation of cytokines, chemokines, and adhesion molecules in vascular and inflammatory cells within the arterial wall Indirect effects of improving glucose and lipid metabolism via adipocytes, hepatocytes, and skeletal myocytes Reference Plutzky J. Science. 2003; 302: 406-7. – – Blunts atherosclerosis Plutzky J. Science. 2003;302:406-7.