Perspective: Beta Cell Glucose Toxicity in Type 2 Diabetes: Nrf2 and the Endogenous Antioxidant Response

Increasing attention is being given to the concept that mild hyperglycemia in patients with early type 2 diabetes initiates a vicious cycle in which progressively higher levels of glycemia generate higher levels of reactive oxygen species (ROS) both in the general blood circulation and within the beta cells themselves. Theoretically, over time, this might worsen already damaged beta cell function (glucose toxicity) and augment progression to frank hyperglycemia. At issue is whether in the early stages of type 2 diabetes the beta cell is simply a passive victim in this scenario or whether it might try to mount an endogenous antioxidant response to defend itself against local excessive ROS formation. Since Nrf2 is the primary regulator of endogenous antioxidant synthesis, a greater understanding of Nrf2 activity in beta cells undergoing hyperglycemic stress may lead to new therapeutic insights for type 2 diabetes.