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

Area of Science:

• Endocrinology and Metabolism
• Cell Biology
• Diabetes Research

Background:

• Protecting and expanding functional beta-cell mass is critical for diabetes therapy.
• The role of Nuclear factor erythroid 2-related factor 2 (Nrf2) in beta-cell function and survival requires further investigation.

Purpose of the Study:

• To investigate the impact of manipulating Nrf2 levels on beta-cell survival, proliferation, and mass.
• To explore Nrf2 as a potential therapeutic target for diabetes by managing beta-cell mass.

Main Methods:

• Generation of beta-cell-specific conditional knockout and gain-of-function mouse models.
• In vivo and ex vivo assessment of beta-cell proliferation, apoptosis, and mass.
• Human islet transplantation experiments with systemic administration of an Nrf2 activator (bardoxolone methyl).

Main Results:

• Nrf2 depletion in beta-cells reduced glucose-stimulated proliferation, adaptive proliferation under high-fat diet, and beta-cell mass.
• Nrf2 loss of function decreased Pdx1 abundance and insulin content, while Nrf2 protected beta-cells from apoptosis.
• Specific activation of Nrf2 in beta-cells increased proliferation, mass, and improved glucose tolerance; human islets showed increased beta-cell proliferation upon Nrf2 activation.

Conclusions:

• Nrf2 regulates beta-cell mass by managing reactive oxygen species levels.
• Targeting Nrf2 represents a promising therapeutic strategy for expanding and protecting beta-cell mass in diabetes.