NRF2 deficiency leads to inadequate beta cell adaptation during pregnancy and gestational diabetes

The late stages of mammalian pregnancy are accompanied by a mild increase in insulin resistance likely due to enhanced glucose demand of the growing fetus. Therefore, as an adaptive process to maintain euglycemia during pregnancy, maternal n-cell mass expands leading to increased insulin release. Defects in functional n-cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). While the exact mechanisms that promote GDM are poorly understood, GDM is associated with inadequate functional n-cell mass expansion and with a systematic increase of oxidative stress. Here, we show that NRF2 levels are upregulated in mouse n-cells at gestational day 15 (GD15). Inducible n-cell-specific Nrf2 deleted (nNrf2KO) mice display reduced n-cell proliferation, increased n-cell oxidative stress and lipid peroxidation, compromised n-cell function, and elevated n-cell death, leading to impaired n-cell mass expansion and dysregulated glucose homeostasis towards the end of pregnancy. Importantly, the gestational hormone 17-n-estradiol (E2) increases NRF2 levels, and downregulation of NRF2 suppresses E2-induced protection of n-cells against oxidative stress, suggesting that E2 exerts its antioxidant effects through activation of NRF2 signaling in n-cells. Collectively, these data highlight the critical role of NRF2 in regulating oxidative stress during the adaptive response of n-cells in pregnancy and identify NRF2 as a potential therapeutic target for GDM treatment.