Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis

The transition from a proliferative to a functionally mature state is a critical phase in postnatal pancreatic β-cell development, yet the molecular mechanisms coordinating this shift remain poorly understood. Here, we identify tomosyn-2 as a key regulator that restrains β-cell maturation and insulin secretory capacity. Tomosyn-2 expression progressively declines in mouse islets with age, coinciding with enhanced biphasic glucose-stimulated insulin secretion and reduced β-cell proliferation. Mice lacking tomosyn-2 exhibit improved glucose clearance, elevated plasma insulin levels, and enhanced insulin secretion from isolated islets without changes in insulin action. Mechanistically, tomosyn-2 interacts with syntaxin-1A to inhibit insulin granule exocytosis by limiting SNARE complex assembly. Transcriptomic and network analyses reveal that loss of tomosyn-2 is associated with coordinated changes in insulin secretion and cell-cycle regulation, reducing β-cell proliferation and mass expansion by downregulating Akt1 signaling and cell-cycle mediators, while promoting β-cell identity and functional maturation accompanied by altered islet cytoarchitecture. These findings identify tomosyn-2 as a molecular brake that balances proliferation and insulin secretion to achieve a threshold of functionally mature β-cell mass during postnatal development. Targeting tomosyn-2 or its downstream pathways may enhance β-cell functional competence and offer new strategies to restore insulin secretion in diabetes. ARTICLE HIGHLIGHTS: The mechanisms governing the postnatal transition of pancreatic β-cells from a proliferative, immature state to a functionally mature, glucose-responsive state remain poorly understood. We investigate the role of tomosyn-2 in modulating β-cell proliferation and insulin secretion during postnatal maturation. Tomosyn-2 inhibits SNARE complex formation and insulin secretion, and its loss is associated with enhanced β-cell maturation, increased biphasic insulin secretion, reduced β-cell proliferation, and suppressed Akt1-cyclinD1 signaling. Tomosyn-2 functions as a physiological brake on insulin secretion, coordinating the balance between β-cell maturation and proliferation, with implications for diabetes pathogenesis and β-cell regenerative strategies.