1829-P: Tomosyn-2 Regulates Beta-Cell Proliferation and Insulin Secretion in Neonatal Islets

Introduction and Objective: Proliferating islet β-cells are functionally immature, while matured β-cells demonstrate enhanced glucose-stimulated insulin secretion (GSIS) with diminished replication rates. The transition from immature to mature β-cell population requires fine-tuning between proliferation and insulin secretion during the neonatal growth phase, yet the underlying molecular mechanisms governing this relationship remain poorly defined. Methods: Herein, using the tomosyn-2 gene deletion mouse model, we identify tomosyn-2 as a key regulator of this balance in neonatal mouse islets. Results: Tomosyn-2 expression declines with age in islets of 2-, 6-, 16-, and 20-week-old mice, coinciding with increased biphasic GSIS and reduced β-cell proliferation. Loss of tomosyn-2 improves glucose tolerance and plasma insulin levels without affecting insulin sensitivity. Tomosyn-2-deficient islets exhibit enhanced biphasic GSIS without changes in basal secretion. Mechanistically, tomosyn-2 inhibits insulin granule exocytosis by interacting with syntaxin-1A and preventing the formation of the insulin granule fusion complex. Transcriptomic analysis reveals that tomosyn-2 loss upregulates genes associated with β-cell identity, maturation, and insulin secretion while downregulating proliferation-related genes. Immunostaining confirms reduced Ki67-positive β-cells, altered islet architecture, and enhanced β-cell identity in tomosyn-2-deficient neonatal islets. Conclusion: These findings demonstrate that tomosyn-2 suppresses insulin secretion while promoting β-cell proliferation, mass, identity, and islet architecture, which are critical for establishing functional β-cell populations for maintaining glycemic control in adults. Excitingly, this study uncovers a novel link between exocytotic regulation modulating global changes in β-cell gene expression, identity, maturation, and islet architecture, highlighting tomosyn-2 as a pivotal modulator of β-cell maturation and function. Disclosure K. Perez: None. J.B. Alexander: None. M. Rahman: None. H. Alsharif: None. T.M. Nguyen: None. S. Bhatnagar: None. Funding NIDDK (2R56DK120684-06); NIH( R01DK120684-01); NIH (1R21DK129968-01)