FOXM1 acts sexually dimorphically to regulate functional β-cell mass

Abstract

The transcription factor FOXM1 regulates {beta}-cell proliferation and insulin secretion. Our previous work demonstrates that expressing an activated form of FOXM1 (FOXM1*) in {beta} cells increases {beta}-cell proliferation and mass in aged male mice. Additionally, FOXM1* enhances {beta}-cell function even in young mice, in which no {beta}-cell mass elevation occurs. Here, we demonstrate that FOXM1 acts in a sexually dimorphic manner in the {beta} cell. Expression of FOXM1* in female mouse {beta} cells does not affect {beta}-cell proliferation or glucose tolerance. Transduction of male but not female human islets with FOXM1* enhances insulin secretion in response to elevated glucose. Estrogen contributes to diabetes susceptibility differences between males and females, and the estrogen receptor (ER) is the primary mediator of {beta}-cell estrogen signaling. We show that FOXM1* can rescue impaired glucose tolerance in female mice with a pancreas-wide ER deletion. Further, FOXM1 and ER binding sites overlap with each other and with other {beta}-cell-enriched transcription factors, including ISL1, PAX6, MAF, and GATA. These data indicate that FOMX1 and ER cooperate to regulate {beta}-cell function and suggest a general mechanism contributing to the lower incidence of diabetes observed in women.