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Nrf2 Regulates β-cell Mass by Suppressing β-Cell Death and Promoting β-Cell Proliferation
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posted on 2022-04-27, 17:55 authored by Sharon Baumel-Alterzon, Liora S. Katz, Gabriel Brill, Clairete Jean-Pierre, Yansui Li, Isabelle Tse, Shyam Biswal, Adolfo Garcia-Ocaña, Donald K. ScottFinding 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.