Activation of Nrf2 Is Required for Normal and ChREBPα-Augmented Glucose-Stimulated β-Cell Proliferation

Patients with both major forms of diabetes would benefit from therapies that increase beta-cell mass. Glucose, a natural mitogen, drives adaptive expansion of beta-cell mass by promoting beta-cell proliferation. We previously demonstrated that a carbohydrate response elementbinding protein (ChREBP alpha) is required for glucosestimulated beta-cell proliferation and that overexpression of ChREBP alpha amplifies the proliferative effect of glucose. Here we found that ChREBP alpha reprogrammed anabolic metabolism to promote proliferation. ChREBP alpha increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBP alpha required the presence of ChREBP beta. ChREBP alpha increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBP alpha-mediated mitochondrial biogenesis and for glucose-stimulated and ChREBP alpha-augmented beta-cell proliferation. Overexpression of Nrf2 was sufficient to drive human beta-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for beta-cell proliferation that may be exploited for therapeutic beta-cell regeneration.