Novel Approach to Treat Insulin Resistance, Type 2 Diabetes, and the Metabolic Syndrome: Simultaneous Activation of PPAR alpha, PPAR gamma, and PPAR delta

Only a limited number of treatment options are available for insulin resistance, a major cause of type 2 diabetes (T2D) and the metabolic syndrome. None adequately address the simultaneous defects in lipid and carbohydrate metabolism. Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors that function as ligand-activated transcription factors. The PPAR family, which includes PPAR alpha, PPAR gamma, and PPAR delta, are receptors for fatty acids and their metabolites. Consequently, PPARs play a critical physiological role in the regulation of genes involved in glucose, fatty acid, and cholesterol metabolism. PPAR alpha and PPAR gamma also mediate antiinflammatory effects, which likely contribute to their anti-atherogenic activities. A number of PPAR agonist drugs are marketed for the treatment of individual aspects of the metabolic syndrome. Dual agonists that target both PPAR alpha and PPAR gamma are being developed in an effort to broaden the activities and beneficial effects of the ligands selective for PPAR gamma. To address the multiple metabolic defects associated with insulin resistance, T2D and the metabolic syndrome, the simultaneous activation of PPAR alpha, PPAR gamma, and PPAR delta by a single compound (i.e. a PPAR pan-agonist) is being pursued. Similar to PPAR alpha and PPAR gamma, PPAR delta plays a significant role in the regulation of genes that control lipid metabolism. Unlike PPAR gamma, PPAR delta is not adipogenic, and activation of PPAR delta is associated with an anti-obesity and more insulin-sensitive phenotype. While there are no currently marketed drugs known to target PPAR delta, pre-clinical studies indicate that PPAR d agonists increase energy expenditure and elevate plasma high-density lipoprotein (HDL) cholesterol. Recent studies in rodents and primates suggest that a small molecule targeting all three isoforms of PPAR would provide a significantly improved treatment option.