Novel approach to treat insulin resistance, type 2 diabetes, and the metabolic syndrome: simultaneous activation of PPARalpha, PPARgamma, and PPARdelta.
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 PPARalpha, PPARgamma, and PPARdelta, 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. PPARalpha and PPARgamma also mediate anti-inflammatory 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 PPARalpha and PPARgamma are being developed in an effort to broaden the activities and beneficial effects of the ligands selective for PPARgamma. To address the multiple metabolic defects associated with insulin resistance, T2D and the metabolic syndrome, the simultaneous activation of PPARalpha, PPARgamma, and PPARdelta by a single compound (i.e. a PPAR pan-agonist) is being pursued. Similar to PPARalpha and PPARgamma, PPARdelta plays a significant role in the regulation of genes that control lipid metabolism. Unlike PPARgamma, PPARdelta is not adipogenic, and activation of PPARdelta is associated with an anti-obesity and more insulin-sensitive phenotype. While there are no currently marketed drugs known to target PPARdelta, pre-clinical studies indicate that PPARdelta 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.
Evans
Joseph L
JL
Medical Research Institute, 444 De Haro Street, Suite 209, San Francisco, CA 94107, USA. jevansphd@earthlink.net
Lin
Jack J
JJ
Goldfine
Ira D
ID
D054392:Adipokines / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology* / Q000628:therapy*; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D024821:Metabolic Syndrome / Q000503:physiopathology* / Q000628:therapy*; D047493:PPAR alpha / Q000819:agonists / Q000502:physiology*; D047494:PPAR delta / Q000819:agonists / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*
D054392:Adipokines; D005227:Fatty Acids; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma