Targeting Nrf2 by dihydro-CDDO-trifluoroethyl amide enhances autophagic clearance and viability of β-cells in a setting of oxidative stress

Nrf2 appears to be a critical regulator of diabetes in rodents. However, the underlying mechanisms as well as the clinical relevance of the Nrf2 signaling in human diabetes remain to be fully understood. Herein, we report that islet expression of Nrf2 is upregulated at an earlier stage of diabetes in both human and mice. Activation of Nrf2 suppresses oxidative stress and oxidative stress-induced beta-cell apoptosis while enhancing autophagic clearance in isolated rat islets. Additionally, oxidative stress per se activated autophagy in beta-cells. Thus, these results reveal that Nrf2 drives a novel antioxidant independent autophagic clearance for beta-cell protection in the setting of diabetes. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.