Lin, Hsin-HsienHsin-HsienLinYu, I-ShingI-ShingYuCheng, Ming-ShanMing-ShanChengTIEN-JYUN CHANGLin, Hsin-YingHsin-YingLinYI-CHENG CHANGChun-Jung KoChen, Ping-HungPing-HungChenHuang, Shin-YiShin-YiHuangTAI-CHUNG HUANGChen, Tzu-YuTzu-YuChenSHU-WHA LINKan, Kai-WenKai-WenKanHSIANG-PO HUANGMING-SHYUE LEE2024-12-162024-12-162024-12-03https://scholars.lib.ntu.edu.tw/handle/123456789/723862Article number 10537SPINT1, a membrane-anchored serine protease inhibitor, regulates cascades of pericellular proteolysis while its tissue-specific functions remain incompletely characterized. In this study, we generate Spint1-lacZ knock-in mice and observe Spint1 expression in embryonic pancreatic epithelium. Pancreas-specific Spint1 disruption significantly diminishes islet size and mass, causing glucose intolerance and downregulation of MAFA and insulin. Mechanistically, the serine protease HEPSIN interacts with SPINT1 in β cells, and Hepsin silencing counteracts the downregulation of Mafa and Ins1 caused by Spint1 depletion. Furthermore, we demonstrate a potential interaction between HEPSIN and GLP1R in β cells. Spint1 silencing or Hepsin overexpression reduces GLP1R-related cyclic AMP levels and Mafa expression. Spint1-disrupted mice also exhibit a significant reduction in Exendin-4-induced insulin secretion. Moreover, SPINT1 expression increases in islets of prediabetic humans compared to non-prediabetic groups. The results unveil a role for SPINT1 in β cells, modulating glucose homeostasis and insulin production via HEPSIN/MAFA signaling.entrue[SDGs]SDG2[SDGs]SDG3journal article10.1038/s41467-024-54927-2396272292-s2.0-85211367837