Increased vulnerability to beta-cell destruction and diabetes in mice lacking NAD(P)H:quinone oxidoreductase 1

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) has been known to protect cells against stressors, including the diabetogenic reagent streptozotocin (STZ). The present study demonstrated that NQO1 deficiency resulted in increased pancreatic beta-cell death induced by multiple low dose of STZ (MLDS) injections. NQO1 knockout (KO) mice showed hyperglycemia, body weight loss, impaired glucose clearance rate and a lower plasma insulin level after MLDS treatment. Moreover, beta-cell mass and pancreatic insulin content were significantly lower in KO mice than in wild-type (WT) mice after MLDS treatment. Five days after the first STZ treatment, the islets of KO mice had substantially more TUNEL-positive beta-cells than those of WT mice, but there was no difference in the regeneration of beta-cells between KO mice and WT mice. At the same time, MLDS-treated KO mice showed significantly increased apoptotic markers in beta-cells, including cleaved caspase 3, Smac/DIABLO and AIF (apoptosis inducing factor) in the cytoplasm. These results suggest that mice deficient in NQO1 are vulnerable to MLDS-induced beta-cell destruction and diabetes, caused by increase of beta-cell apoptosis in pancreas. (C) 2013 Elsevier Ireland Ltd. All rights reserved.