82-OR: NRF2 Regulates Neonatal ß-Cell Mass Expansion

The pediatric population suffers from increased incidence of both major types of diabetes in recent decades, highlighting the urgent need for discovering mechanisms that regulate functional β-cell mass. We found that the master antioxidant regulator, Nrf2, is required for adaptive adult β-cell expansion under hypercaloric conditions via regulation of β-cell proliferation, β-cell survival, and maintenance of β-cell identity. Additionally, we found that Nrf2 expression in β-cells of 7-day-old mice is 15-fold higher of that in adult β-cells (p<0.0001, n=6). Based on these observations, we hypothesized that Nrf2 regulates β-cell proliferation and survival at early stages of life and contributes to the maintenance of normal β-cell mass later in life. To test this, we deleted Nrf2 in β-cells by crossing Ins^Cre with Nrf2^lox/lox mice (βNrf2KO). βNrf2KO mice at 28 days of age exhibited a 65% reduction of β-cell mass compared to control mice (p<0.0005, n=6). Importantly, at 7 days of age, βNrf2KO mice displayed a 65% reduction of β-cell proliferation (p<0.0001, n=6), a 22% reduction of nuclear Pdx1 levels (p<0.0001, n=6), a 5.84-fold increase in β-cell death (±0.04, p<0.001, n=6) and a 2.93-fold increase in β-cell oxidative stress (p<0.001, n=6) compared to control mice. Surprisingly, daily administration of antioxidant NAC to 7-day-old βNrf2KO mice only partially restored β-cell proliferation but completely blunted oxidative stress compared to control mice. This suggests that neonatal β-cell proliferation induced by Nrf2 relies on additional mechanisms beyond oxidative stress. Interestingly, RNAseq of isolated islets from 7-day-old βNrf2KO mice showed decreased expression of mitochondrial encoded genes and upregulation of stress-responsive genes. This suggests that Nrf2 controls β-cell proliferation by regulating mitochondrial bioenergetics. We conclude that Nrf2 is required for β-cell mass expansion in neonatal ages by controlling β-cell proliferation, identity, and survival.