The role of peroxisome proliferator-activated receptor γ in pancreatic β cell function and survival: therapeutic implications for the treatment of type 2 diabetes mellitus

The pathogenesis of type 2 diabetes mellitus involves both peripheral insulin resistance and dysfunctional insulin secretion from the pancreatic beta cell. Currently, there is intense research focus on delineating the etiologies of pancreatic beta cell dysfunction in type 2 diabetes. However, there remains an unmet clinical need to establish therapeutic guidelines and strategies that emphasize the preservation of pancreatic beta cell function in at-risk and affected individuals. Thiazolidinediones are orally active agents approved for use in type 2 diabetes and act as agonists of the nuclear hormone receptor PPAR-gamma. These drugs improve insulin sensitivity, but there is also a growing appreciation of PPAR-gamma actions within the beta cell. PPAR-gamma has been shown to regulate directly key beta cell genes involved in glucose sensing, insulin secretion and insulin gene transcription. Further, pharmacologic PPAR-gamma activation has been shown to protect against glucose-, lipid-, cytokine- and islet amyloid polypeptide (IAPP)-induced activation of numerous stress pathways. This article will review the mechanisms by which PPAR-gamma activation acts to maintain beta cell function and survival in type 2 diabetes mellitus and highlight some of the current controversies in this field.