A step ahead of PPARγ full agonists to PPARγ partial agonists: therapeutic perspectives in the management of diabetic insulin resistance.

Abstract

Described since long as a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands can function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPARα and PPARγ, respectively. The PPARγ is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPARγ full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPARγ partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPARγ partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPARγ partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPARγ full agonists.