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

Hsin-Hsien Lin, I-Shing Yu, Ming-Shan Cheng, Tien-Jyun Chang, Hsin-Ying Lin, Yi-Cheng Chang, Chun-Jung Ko, Ping-Hung Chen, Shu-Wha Lin, Tai-Chung Huang, Shin-Yi Huang, Tzu-Yu Chen, Kai-Wen Kan, Hsiang-Po Huang () and Ming-Shyue Lee ()
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Hsin-Hsien Lin: National Taiwan University
I-Shing Yu: National Taiwan University
Ming-Shan Cheng: National Taiwan University
Tien-Jyun Chang: National Taiwan University Hospital
Hsin-Ying Lin: National Taiwan University
Yi-Cheng Chang: National Taiwan University
Chun-Jung Ko: National Taiwan University
Ping-Hung Chen: National Taiwan University
Shu-Wha Lin: National Taiwan University
Tai-Chung Huang: National Taiwan University Hospital
Shin-Yi Huang: National Taiwan University Hospital
Tzu-Yu Chen: National Taiwan University
Kai-Wen Kan: National Taiwan University
Hsiang-Po Huang: National Taiwan University
Ming-Shyue Lee: National Taiwan University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54927-2

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