RAGE ligands induce apoptotic cell death of pancreatic β-cells via oxidative stress

Activation of the receptor for advanced glycation endproducts (RAGE) by its ligands leads to cellular damage contributing to diabetic complications. It is not clearly known whether RAGE ligands influence pancreatic beta-cells. In this study, we investigated the expression of RAGE in islet cells and the effect of RAGE ligands, S100b and HMG-1, on islet cells. RAGE was expressed in INS-1 cells and isolated rat and human islets at mRNA and protein levels. RAGE and its ligand, S100b, were detected on islet cells in 28-week-old diabetic OLETF rats. Both S100b and HMG-1 induced apoptotic cell death of INS-1 and islet cells. This INS-1 cell apoptosis was accompanied by increased intracellular oxidative stress and inhibited by antioxidants or a NADPH oxidase inhibitor. Our results showing S100b/RAGE expression on islets of diabetic rat model and RAGE ligands-induced islet cell apoptosis via NADPH oxidase-mediated ROS generation suggest that RAGE ligands-RAGE interaction may contribute not only to the development of diabetic complications but also to the progressive beta-cell loss in type 2 diabetes by inducing oxidative stress.