OR12-02 NRF2 Is Essential For Expanding Pancreatic Beta-Cell Mass During Pregnancy

Disclosure: S. Baumel-Alterzon: None. A. Garcia-Ocana: None. D.K. Scott: None. 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, in order to maintain the maternal normal blood glucose levels, maternal beta-cell mass expands leading to increased insulin release. Beta-cell proliferation, beta-cell neogenesis, and decreased beta-cell apoptosis, are major contributors for the beta-cell adaptive response during pregnancy. Defects in these cellular processes can lead to gestational diabetes mellitus (GDM). GDM, which occurs in ∼7-8% of the total pregnancy cases within the U.S, results in adverse outcomes for both the mother and newborn. This highlights the urgent need for exploring the yet undefined intracellular mechanisms that regulate functional beta-cell mass expansion during pregnancy. GWAS analysis revealed several mutations in the Nrf2 antioxidant pathway that are associated with diabetes. Additionally, we previously found that Nrf2 is required for adaptive beta-cell expansion after high fat feeding via stimulation of beta-cell proliferation, increased beta-cell survival, and maintenance of beta-cell identity. Interestingly, Nrf2 expression levels are increased by 4.3-fold (+/- 6.60, p<0.05, n=3-4) in maternal beta-cells during pregnancy, peaking at gestational day (GD)19, while returning to normal levels postpartum. Based on these observations, we hypothesize that Nrf2 might play an important role in expanding beta-cell mass during pregnancy and that disruption of Nrf2 expression or function might lead to GDM. In order to test our hypothesis, we generated tamoxifen (Tam)-induced beta cell-specific deletion of Nrf2 in female mice by crossing MIP-CreERT(TAM) with Nrf2(lox/lox) mice (βNrf2KO). In order to exclude any effect of Tam on pregnancy outcomes, females mice were injected with Tam (or vehicle control) a month before gestation. Pancreata were harvested at GD15 or GD19 and immunolabeled with Ki67 and insulin (proliferation assay), TUNEL and insulin (apoptotic assay) or insulin alone (beta-cell mass analysis). Our results show that βNrf2KO mice exhibit 70% reduction (+/- 0.25, p<0.01, n=4-6) in beta-cell proliferation and a 0.13% increase in beta-cell death (+/- 0.03, p<0.05, n=4-6) at GD15 compared to littermate controls. Importantly, βNrf2KO pregnant mice display a remarkable decrease in beta-cell mass at GD19 (50%) (+/- 0.68, p<0.05, n=4) compared with control mice, accompanied by a trending decrease in plasma insulin and increase in blood glucose. No changes were observed in the average number of embryos between βNrf2KO and control pregnant mice. We conclude that Nrf2 is required for beta-cell mass expansion during pregnancy by controlling beta-cell proliferation and survival and alterations in Nrf2 action could potentially lead to development of GDM. Presentation: Friday, June 16, 2023