Mosleh, E. | Search bioRxiv

bioRxiv2023

The leptin receptor has no role in delta-cell control of beta-cell function in the mouse

Leptin inhibits insulin secretion from isolated islets from multiple species, but the cell type that mediates this process remains elusive. Mouse models have been used to explore this question. Ablation of the leptin receptor (Lepr) throughout the pancreatic epithelium results in altered glucose homeostasis, ex vivo insulin secretion, and calcium dynamics. However, the removal of Lepr from neither alpha nor beta cells mimics these results. Because Lepr is enriched in the delta cells of human islets, we used a mouse model to test whether delta cells mediate the diminished glucose-stimulated insulin secretion in response to leptin. However, ablation of Lepr within mouse delta cells had no impact on glucose homeostasis or insulin secretion. We further demonstrate that Lepr is not appreciably expressed within mouse delta cells.

molecular biology↗

bioRxiv2023

FOXM1 acts sexually dimorphically to regulate functional β-cell mass

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.

molecular biology↗