Inhibition of the receptor for advanced glycation endproducts (RAGE) protects pancreatic β-cells

Advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE) have been linked to the pathogenesis of diabetic complications, such as retinopathy, neuropathy, and nephropathy. AGEs may induce beta-cell dysfunction and apoptosis, another complication of diabetes. However, the role of AGE-RAGE interaction in AGE-induced pancreatic beta-cell failure has not been fully elucidated. In this study, we investigated whether AGE-RAGE interaction could mediate beta-cell failure. We explored the potential mechanisms in insulin secreting (INS-1) cells from a pancreatic beta-cell line, as well as primary rat islets. We found that glycated serum (GS) induced apoptosis in pancreatic beta-cells in a dose- and time-dependent manner. Treatment with GS increased RAGE protein production in cultured INS-1 cells. GS treatment also decreased bcl-2 gene expression, followed by mitochondrial swelling, increased cytochrome c release, and caspase activation. RAGE antibody and knockdown of RAGE reversed the beta-cell apoptosis and bcl-2 expression. Inhibition of RAGE prevented AGE-induced pancreatic beta-cell apoptosis, but could not restore the function of glucose stimulated insulin secretion (GSIS) in rat islets. In summary, the results of the present study demonstrate that AGEs are integrally involved in RAGE-mediated apoptosis and impaired GSIS dysfunction in pancreatic beta-cells. Inhibition of RAGE can effectively protect beta-cells against AGE-induced apoptosis, but cannot reverse islet dysfunction in GSIS. (C) 2010 Elsevier Inc. All rights reserved.