NRF2 deficiency leads to inadequate beta cell adaptation during pregnancy and gestational diabetes. 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 β-cell mass expands leading to increased insulin release. Defects in functional β-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 β-cell mass expansion and with a systematic increase of oxidative stress. Here, we show that NRF2 levels are upregulated in mouse β-cells at gestational day 15 (GD15). Inducible β-cell-specific Nrf2 deleted (βNrf2KO) mice display reduced β-cell proliferation, increased β-cell oxidative stress and lipid peroxidation, compromised β-cell function, and elevated β-cell death, leading to impaired β-cell mass expansion and dysregulated glucose homeostasis towards the end of pregnancy. Importantly, the gestational hormone 17-β-estradiol (E2) increases NRF2 levels, and downregulation of NRF2 suppresses E2-induced protection of β-cells against oxidative stress, suggesting that E2 exerts its antioxidant effects through activation of NRF2 signaling in β-cells. Collectively, these data highlight the critical role of NRF2 in regulating oxidative stress during the adaptive response of β-cells in pregnancy and identify NRF2 as a potential therapeutic target for GDM treatment. Overall design: Bulk RNA-seq profiling of pancreatic islets from non-pregnant and pregnant (gestational day 15) wildtype and beta-cell specific Nrf2-KO female mice generated by crossing MIP-CreERTAM mice85 (RRID: IMSR_JAX:024709) with Nrf2lox/lox mice (RRID: IMSR_JAX:025433).