Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis
Year: 2026
Type: other
Abstract: 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, reduces β-cell proliferation and mass expansion by downregulating Akt1 signaling and cell-cycle mediators, and promotes β-cell identity and functional maturation, accompanied by altered islet cytoarchitecture. These findings identify Tomosyn-2 as a molecular brake that is associated with the balance between 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.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7154910304