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

Abstract

The pathogenesis of type 2 diabetes mellitus involves both peripheral insulin resistance and dysfunctional insulin secretion from the pancreatic β cell. Currently, there is intense research focus on delineating the etiologies of pancreatic β 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 β 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-γ. These drugs improve insulin sensitivity, but there is also a growing appreciation of PPAR-γ actions within the β cell. PPAR-γ has been shown to regulate directly key β cell genes involved in glucose sensing, insulin secretion and insulin gene transcription. Further, pharmacologic PPAR-γ activation has been shown to protect against glucose-, lipid-, cytokine- and islet amyloid polypeptide (lAPP)-induced activation of numerous stress pathways. This article will review the mechanisms by which PPAR-γ activation acts to maintain β cell function and survival in type 2 diabetes mellitus and highlight some of the current controversies in this field.