Peroxisome Proliferator-Activated Receptor γ Agonists as Insulin Sensitizers: From the Discovery to Recent Progress

An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferatoractivated receptor γ (PPARγ) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARγ as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARγ agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARγ agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARγ-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARγ including the significance of PPARγ as a drug target, describes the current status of a wide variety of novel PPARγ ligands including PPAR dual and pan agonists and selective PPARγ modulators (SPPARγMs), and highlights new approaches for identifying agents targeting PPARγ in the treatment of type 2 diabetes.