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SPINT1 is a membrane-anchored serine protease inhibitor with incompletely defined tissue-specific functions. Using Spint1-lacZ knock-in and pancreas-specific Spint1-disrupted mice, we show that SPINT1 is expressed in embryonic pancreatic epithelium and is required for normal islet size, insulin expression, and glucose tolerance. Mechanistically, SPINT1 restrains HEPSIN activity to preserve GLP1R-associated cyclic AMP signaling and MAFA/insulin expression. Spint1 disruption also impairs Exendin-4-induced insulin secretion. These findings identify SPINT1 as a regulator of β-cell function and glucose homeostasis.