α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion

作者：Canqi Cui, Danielle C. Leander, Sarah M. Gray, Kimberley El, A. Y. Chen, Paul A. Grimsrud, Jessica O. Becker, Austin J. Taylor, Guofang Zhang, Kyle W. Sloop, C. Bruce Verchere, Andrew N. Hoofnagle, David A. D’Alessio, Jonathan E. Campbell · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.ady8048 · 被引用次数：6 · 研究领域：Pancreatic function and diabetes、Diabetes Treatment and Management、Diabetes Management and Research

α cells secrete proglucagon peptides to regulate nutrient metabolism. Recent findings support an α cell–to–β cell axis that is mediated by paracrine signaling through the glucagon receptor and glucagon-like peptide 1 (GLP-1) receptor in β cells. To address which proglucagon peptides stimulate insulin secretion, we developed an assay to quantify levels of GLP-1(7–36)NH 2 . We also generated three transgenic mouse lines that allow α cell-specific, inducible deletion of the genes for the two prohormone convertase enzymes that process proglucagon . Our studies reveal that both mouse and human islets contain GLP-1(7–36)NH2, but glucagon mediates α cell–to–β cell communication in mice. However, in the absence of normal production of glucagon, α cells up-regulate prohormone convertase 1 (PC1/3) to generate GLP-1 and enhance glucose tolerance. Human islets have substantially higher levels of GLP-1 than mice, which positively correlate with rates of insulin secretion. These studies show plasticity in proglucagon processing to support α cell–to–β cell communication.