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 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 (IAPP)-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.
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Gupta
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Kono
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Evans-Molina
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D047495:PPAR gamma / Q000378:metabolism* / Q000502:physiology; D017410:Practice Guidelines as Topic; D045162:Thiazolidinediones / Q000378:metabolism*
D047495:PPAR gamma; D045162:Thiazolidinediones