NRF2 Dysregulation in Mice Leads to Inadequate Beta-Cell Mass Expansion during Pregnancy and Gestational Diabetes

Abstract

The late stages of the mammalian pregnancy are accompanied with increased insulin resistance due to the increased glucose demand of the growing fetus. Therefore, as a compensatory response to maintain the maternal normal blood glucose levels, maternal beta-cell mass expands leading to increased insulin release. Defects in beta-cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). Although the exact mechanisms that promote GDM are poorly understood, GDM strongly associates with impaired beta-cell proliferation and with increased levels of reactive oxygen species (ROS). Here, we show that NRF2 levels are upregulated in mouse beta-cells at gestation day 15 (GD15) concomitant with increased beta-cell proliferation. Importantly, mice with tamoxifen-induced beta-cell-specific NRF2 deletion display inhibition of beta-cell proliferation, increased beta-cell oxidative stress and elevated levels of beta-cell death at GD15. This results in attenuated beta-cell mass expansion and disturbed glucose homeostasis towards the end of pregnancy. Collectively, these results highlight the importance of NRF2-oxidative stress regulation in beta-cell mass adaptation to pregnancy and suggest NRF2 as a potential therapeutic target for treating GDM.