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

Sharon Baumel-Alterzon, Liora S. Katz, Gabriel Brill, Clairete Jean-Pierre, Yansui Li, Isabelle Tse, Shyam Biswal, Adolfo Garcia-Ocaña, Donald K. Scott

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 b-cell proliferation ex vivo and decreased adaptive b-cell proliferation and b-cell mass expansion after a high-fat diet in vivo. Nrf2 protects b-cells from apo-ptosis after a high-fat diet. Nrf2 loss of function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a b-cell–specific manner increases b-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocom-promised mice and treated systemically with bardoxolone methyl, an Nrf2 activator, display increased b-cell prolifer-ation. Thus, by managing reactive oxygen species levels, Nrf2 regulates b-cell mass and is an exciting therapeutic target for expanding and protecting b-cell mass in diabetes.

Original languageEnglish
Pages (from-to)989-1011
Number of pages23
JournalDiabetes
Volume71
Issue number5
DOIs
StatePublished - May 2022

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