Spint1 disruption in mouse pancreas leads to glucose intolerance and impaired insulin production involving HEPSIN/MAFA

• Published in: Nature communications Vol. 15; no. 1; pp. 10537 - 17
• Main Authors: Lin, Hsin-Hsien, Yu, I-Shing, Cheng, Ming-Shan, Chang, Tien-Jyun, Lin, Hsin-Ying, Chang, Yi-Cheng, Ko, Chun-Jung, Chen, Ping-Hung, Lin, Shu-Wha, Huang, Tai-Chung, Huang, Shin-Yi, Chen, Tzu-Yu, Kan, Kai-Wen, Huang, Hsiang-Po, Lee, Ming-Shyue
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.12.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/34; 14/5; 38/1; 38/109; 38/47; 38/77; 38/89; 631/45/468; 631/80/86/820; 64/60; 692/163/2743/137/773; 82/51; 82/58; Animals; Beta cells; Cell activation; Cyclic AMP; Diabetes mellitus; Disruption; Down-regulation; Epithelium; Female; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose; Glucose - metabolism; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose tolerance; Homeostasis; Humanities and Social Sciences; Humans; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Intolerance; Maf Transcription Factors, Large - genetics; Maf Transcription Factors, Large - metabolism; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Pancreas; Pancreas - metabolism; Prediabetic State - genetics; Prediabetic State - metabolism; Protease; Protease inhibitors; Proteinase inhibitors; Proteolysis; Science; Science (multidisciplinary); Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Serine proteinase; Signal Transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54927-2

SPINT1, 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. Pancreatic Spint1 disruption causes glucose intolerance, reduced islet size, and decreased insulin synthesis and secretion. SPINT1 regulates HEPSIN’s modification of GLP1R/MAFA activation, vital for glucose control by β cells, linking it to diabetes.