Nrf2 Regulates β-cell Mass by Suppressing β-Cell Death and Promoting β-Cell Proliferation

Finding therapies that can protect and expand functional b-cell mass is a major goal of diabetes research. Here we generated b-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects b-cell survival, proliferation and mass. Depletion of Nrf2 in b-cells results in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high fat diet in vivo. Nrf2 protects b-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased β-cell proliferation. Thus, by managing ROS levels, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding and protecting b-cell mass in diabetes.