The PPAR System in Diabetes

Peroxisome proliferator-activated receptors (PPARs), with three existing isoforms (PPAR α, PPAR β/δ, and PPAR γ), belong to the nuclear receptors subfamily. The PPAR machinery involves the binding of natural (fatty acids and prostaglandins), synthetic (mainly fibrates for PPAR α and thiazolidinediones for PPAR γ and new dual and pan-PPAR agonists), and selective PPAR modulators, coactivators, and corepressors with enzymatic activities and various metabolic transformations turning PPARs toward activation or to degradation. Among PPAR activators in clinical development for type 1 or type 2 diabetes and dyslipidemia, some have been discontinued for safety reasons or for no additional benefit over existing drugs. Knowing the pleiotropic effects of PPAR agonists, search for new natural PPAR ligands and clinical development of new target indications represent the main future of this class of drugs.