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bioRxiv · 10.1101/2021.03.05.434145

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

Baumel-Alterzon, S.·Katz, L. S.·Brill, G.·Jean-Pierre, C.·Li, Y.·Biswal, S.·Garcia-Ocana, A.·Scott, D. K.
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Abstract

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 resulted 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 {beta}-cell mass. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased {beta}-cell proliferation. Thus, Nrf2 regulates {beta}-cell mass and is an exciting therapeutic target for expanding {beta}-cell mass in diabetes.

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Baumel-Alterzon, S., Katz, L. S., Brill, G., Jean-Pierre, C., Li, Y., Biswal, S., Garcia-Ocana, A., Scott, D. K.. 2021-03-06. Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation. https://doi.org/10.1101/2021.03.05.434145

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