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NRF2 Dysregulation 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 maternal normal blood glucose levels, maternal β-cell mass expands leading to increased insulin release. Defects in β-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 β-cell proliferation and with increased levels of oxidative stress. Here, we show that NRF2 levels are upregulated in mouse β-cells at gestational day 15 (GD15) concomitant with increased β-cell proliferation. Inducible β-cell-specific Nrf2 deleted (βNrf2KO) mice display blunted β-cell proliferation, increased β-cell oxidative stress and lipid peroxidation, impaired β-cell function, and elevated β-cell death, leading to attenuated β-cell mass expansion and altered glucose homeostasis towards the end of pregnancy. Importantly, the gestational hormone, 17-β-estradiol (E2), increases NRF2 levels and the downregulation of NRF2 suppresses E2-dependent protection of β-cells against oxidative stress, suggesting that E2 exerts its antioxidant effects through activation of the NRF2 signaling in β-cells. Collectively, these data highlight the importance of NRF2 in the regulation of oxidative stress in the adaptive response of β-cells during pregnancy and identify NRF2 as a potential therapeutic target for GDM treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE289077 | GEO | 2025/03/07

REPOSITORIES: GEO

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