Nrf2 Regulates beta-Cell Mass by Suppressing beta-Cell Death and Promoting beta-Cell Proliferation

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