Hyperglycemia. induces activation of glutathione peroxidase 1 (GPX1). an anti-oxidant enzyme essential for cell survival during oxidative stress. However, the mechanism of GPX1 activation is unclear. Here. we report that hyperglycemia-induced protein glycosylation by O-linked N-acetylglucosamine (O-GlcNAL) IS Crucial for activation of GPX1 and for its binding to c-Abl and Aig kinases. GPX1 itself is modified with O-GlcNAc on its C-terminus. We also demonstrate that pharmacological injection of the O-GlcNAcase inhibitor NTZ induces GPX1 activation in the Mouse liver Our findings suggest a crucial role for GPX1 and its O-GlcNAc modification in hyperglycemia and diabetes mellitus. (C) 2009 Elsevier Inc All rights reserved