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 ß-cell mass expands leading to increased insulin release. Defects in functional ß-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 ß-cell mass expansion and with a systematic increase of oxidative stress. Here, we show that NRF2 levels are upregulated in mouse ß-cells at gestational day 15 (GD15). Inducible ß-cell-specific Nrf2 deleted (ßNrf2KO) mice display reduced ß-cell proliferation, increased ß-cell oxidative stress and lipid peroxidation, compromised ß-cell function, and elevated ß-cell death, leading to impaired ß-cell mass expansion and dysregulated glucose homeostasis towards the end of pregnancy. Importantly, the gestational hormone 17-ß-estradiol (E2) increases NRF2 levels, and downregulation of NRF2 suppresses E2-induced protection of ß-cells against oxidative stress, suggesting that E2 exerts its antioxidant effects through activation of NRF2 signaling in ß-cells. Collectively, these data highlight the critical role of NRF2 in regulating oxidative stress during the adaptive response of ß-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).