Diabetes causes both an increase in reactive oxygen species (ROS) production, as well as impairment of the antioxidant defense system. This imbalance results in oxidative stress. A critical regulator of cellular REDOX homeostasis is the Nrf2 antioxidant response pathway, which promotes expression of an array of over 200 antioxidant proteins. In the context of diabetes complications, we observed that the suppressive effect of diabetes on the Nrf2-mediated antioxidant response was mediated at least in part by the stress response protein REDD1. We identified that hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes in part  by activating the protein kinase GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.