Journal Article Preprint Epublish
PubMed: 40475581 DOI: 10.1101/2025.05.19.654959
Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis.
bioRxiv
Authors: Katherine C Perez, Justin Alexander, Md Mostafizur Rahman, Haifa A Alsharif, Yanping Liu, Jeong-A Kim, Chad S Hunter, Thanh Nguyen, Sushant Bhatnagar
Affiliations
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294, USA.
- Current Address: Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical Pharmacology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
- Department of Biomedical Engineering, University of Alabama, Birmingham, AL, 35233, USA.
Abstract
The transition from proliferative to functionally mature β-cells is a critical developmental process, yet the molecular mechanisms that coordinate this shift remain poorly understood. Here, we identify Tomosyn-2 as a key regulator of β-cell maturation. Tomosyn-2 expression declines with age in mouse islets, coinciding with enhanced biphasic glucose-stimulated insulin secretion (GSIS) and reduced β-cell proliferation. Genetic deletion of Tomosyn-2 improves glucose tolerance, elevates plasma insulin levels, and augments islet insulin secretion, without altering systemic insulin sensitivity. Mechanistically, Tomosyn-2 interacts with syntaxin-1A (Stx1A) to inhibit insulin granule exocytosis by limiting SNARE complex formation. Transcriptomic and network analyses reveal that Tomosyn-2 loss reprograms gene expression to strengthen the coupling between insulin secretion and proliferative pathways. Its deletion also reduces β-cell proliferation and mass expansion, suppresses cell cycle and Akt1 signaling, and promotes β-cell identity, maturation, and altered islet architecture. These findings identify Tomosyn-2 as a crucial molecular switch that orchestrates the balance between proliferation and functional maturation during postnatal β-cell development.
MeSH
Cells, Cell Proliferation, Insulin, Homeostasis, Insulin Secretion