FOXM1 acts sexually dimorphically to regulate functional β-cell mass.

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