Nrf2 Is Essential for Expanding Neonatal Pancreatic Beta-Cell Mass

Patients with both major forms of diabetes suffer from insufficient functional β-cell mass. Moreover, the sharp increase in the annual incidence of both type 1 (1.8%) and type 2 (4.8%) diabetes in the pediatric population in the last decades highlights the urgent need for discovering the mechanisms that regulate functional β-cell mass. β-cell proliferation, which reaches its maximal peak during postnatal stages is the major mechanism for increasing β-cell mass in early postnatal ages. We previously found that induction of the antioxidant regulator, Nrf2, is required for adaptive β-cell expansion under hypercaloric conditions via stimulation of β-cell proliferation, increased β-cell survival, and maintenance of β-cell identity in adult mice. Based on these observations, we hypothesize that Nrf2 regulates β-cell proliferation and survival at early stages of life and contribute to maintain normal β-cell mass later in life. Nrf2 expression levels were found to correlate with β-cell proliferation in wild type neonatal mice. Importantly, 28 day-old β-cell specific Nrf2 knockout mice (Ins1Cre-Nrf2lox/lox) exhibited 50% reduction in β-cell mass, 58% reduction in total islet number, 43% decrease in extra-large islets, 46% decrease in large islets and 53% decrease in extra small islets, compared to control mice. No changes in pancreas weight were observed. Additionally, depletion of Nrf2 in β-cells increased β-cell death in 7 (5.8-fold) and 14 (12.5-fold) day-old mice and attenuated β-cell proliferation in 1- and 7-day-old mice. Surprisingly, we also found a marked decrease in islet size in 1- and 7-day-old mice, suggesting that Nrf2 may affect β-cell proliferation, survival and/or development during embryonic stages. We conclude that Nrf2 is required for β-cell mass expansion in postnatal ages by controlling β-cell proliferation and survival. Disclosure S. Baumel-alterzon: None. A. Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. D. Scott: None.