Nrf2 in Type 2 diabetes and diabetic complications: Yin and Yang

Abstract Type 2 diabetes (T2D) is a metabolic disease that is attributed to a combination of genetic, lifestyle and environmental factors. There is compelling evidence that oxidative stress plays critical roles in the two key events in the pathogenesis of T2D: insulin resistance and pancreatic β-cell dysfunction. Although cytotoxic, reactive oxygen species (ROS) also function as important intracellular signaling molecules involved in insulin signaling and glucose sensing. Too many antioxidants or persistent induction of endogenous antioxidants may result in dampened signal transduction that controls insulin secretion and action. Under oxidative stress, cellular ROS-scavenging capacity may be adaptively upregulated, mostly through activation of the nuclear factor E2-related factor 2 (Nrf2) and transcriptional induction of antioxidant enzymes. It is likely that the oxidative stress-induced antioxidant enzymes, meant to maintain intracellular redox homeostasis and limit oxidative damage, also have a potential to impede ROS that function as physiological signaling molecules. Thus, Nrf2-mediated antioxidant defense seems to play paradoxical Yin- and Yang-roles in regulating glucose homeostasis: while it protects insulin-responsive cells and β-cells from oxidative damage, it also blunts insulin- and glucose-triggered ROS signaling, resulting in insulin resistance and reduced insulin secretion. In contrast, oxidative stress has also been implicated in the pathogenesis of diabetic complications. Antioxidant therapies, either by ROS-neutralizing agents or Nrf2 inducers, display beneficial effects in treating various complications. Considering the cross-regulations among ROS, antioxidants and Nrf2 and their paradoxical roles under various diabetic conditions, site-, time- and species-specific ROS modulation strategies and approaches would be necessary to combat T2D and its complications.