Novel Approach to Treat Insulin Resistance, Type 2 Diabetes, and the Metabolic Syndrome: Simultaneous Activation of PPARα, PPARγ, and PPARδ

Joseph   L.   Evans; Jack   J.   Lin; Ira   D.   Goldfine

Abstract

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 pparα, pparγ, and pparδ, 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. pparα and pparγ 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 pparα and pparγ are being developed in an effort to broaden the activities and beneficial effects of the ligands selective for pparγ. To address the multiple metabolic defects associated with insulin resistance, T2D and the metabolic syndrome, the simultaneous activation of pparα, pparγ, and pparδ by a single compound (i.e. a PPAR pan-agonist) is being pursued. Similar to pparα and pparγ, pparδ plays a significant role in the regulation of genes that control lipid metabolism. Unlike pparγ, pparδ is not adipogenic, and activation of pparδ is associated with an anti-obesity and more insulin-sensitive phenotype. While there are no currently marketed drugs known to target pparδ, pre-clinical studies indicate that pparδ 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.

Keywords: hyperglycemia, nuclear hormone receptors, thiazolidinedione, pioglitazone, ABC-A1 gene, fenofibrate, eicosapentanoic