RECENT ADVANCES ON NOVEL DUAL-ACTING PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA AND GAMMA AGONISTS

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors, and play a central role in insulin sensitivity, lipid metabolism, and inflammation. PPAR -γ appears to improve glycaemic control by increasing peripheral insulin sensitivity and reducing hepatic glucose production, thereby helping to preserve beta-cell function. However, they have modest beneficial effects on lipid parameters. It has been observed that fibrate drugs which activate PPAR- α, produce significant improvements in dyslipidaemia and decrease atherosclerotic lesions, but do not affect glycaemia. Theoretically, a compound targeting both α and γ PPARs simultaneously, might combine the benefits of thiazolidinediones (TZDs) and fibrates. Hence, there is a resurgence of interest in the development of new antidiabetic drugs that combine the insulin-sensitizing effects of PPARγ activation with the additional lipid-modifying activity of the other PPAR subtypes. Compounds that act on both receptors may represent an attractive treatment option, provided that the potential to improve both glycemic and lipid parameters can be achieved within the same therapeutic window in order to minimize the incidence of PPAR-related side effects. The ongoing basic studies have elucidated the cardio protective role of PPAR delta. Therefore, further studies are on the track to develop PPAR α/δ and PPAR γ/δ dual agonists and PPAR α/γ/δ pan agonists for the treatment of diabetic cardiovascular complications.