# The role of Tomosyn-2 in insulin secretion and glucose tolerance

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $371,250

## Abstract

Type 2 diabetes (T2D) has reached epidemic proportions, with ~9.4% of the US adult population being diabetic,
and another 84.1 million have pre-diabetes. It is currently acknowledged that both insulin resistance and b-cell
dysfunction are early and essential events in the development of T2D. The formation of the SNARE (Soluble
NSF Attachment Protein Receptor) complex is rate limiting for insulin secretion. Our understanding of factors
that regulate the formation of the SNARE complex and how they contribute to reduced insulin secretion from b-
cells in impaired glucose tolerance is lacking. To this end, by using forward genetics approach, we have identified
Tomosyn-2, which is an endogenous inhibitor of insulin secretion and functions by binding to syntaxin. Syntaxin
is a key component of the SNARE complex that modulates the fusion of the insulin granules to the plasma
membrane for insulin secretion from b-cells. We have discovered that a gain-of-function mutation in the
Tomosyn-2 gene led to an increase in islet Tomosyn-2 protein abundance and formation of hypoinsulinemic/
hyperglycemic phenotypes in mice. Increased abundance and/or the functional activity of Tomosyn-2 causes
reduction in insulin secretion from human and mouse islets. Thus, the long-term goal is to understand how
Tomosyn-2 function in b-cells can be manipulated to improve insulin secretion in impaired glucose tolerance for
the treatment and prevention of prediabetes and T2D. The objective of this application is to determine how
Tomosyn-2 inhibits insulin secretion from b-cells in the pathophysiology, physiology, and at the molecular level,
and how its inhibitory function in b-cells is regulated. Our data show that the improved glucose tolerance in
Tomosyn-2-null mice is a direct result of enhanced insulin secretion from pancreatic islets. Further, reduced
insulin secretion is observed in islets of mice on a high-fat diet that have elevated Tomosyn-2 protein levels. We
have identified phosphorylation sites in response to major b-cell signaling pathways that modulate Tomosyn-2
inhibitory function. Also, E3-ubiquitin ligase, Hrd1 and an insulin granule protein, Syt9 bind and regulate the
protein abundance of Tomosyn-2. Our hypothesis is that Tomosyn-2 is a key protein in the exocytotic machinery
that regulates SNARE complex-mediated insulin secretion in response to nutritional and genetic cues, and that
specific post-translational modifications of Tomosyn-2 increase insulin secretion. To test this hypothesis, we
propose three aims: 1) determine the sub-cellular mechanisms by which Tomosyn-2 inhibits insulin secretion, 2)
determine Tomosyn-2 phosphorylation regulates its activity on downstream insulin secretion, and 3) determine
the role of the Tomosyn-2-binding proteins, Syt9 and Hrd1, in regulating insulin secretion. Outcomes from this
project will provide novel information on how b-cells prevent inappropriate insulin secretion, identify the molecular
target for the early phase ins...

## Key facts

- **NIH application ID:** 10090593
- **Project number:** 5R01DK120684-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Sushant Bhatnagar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2019-04-05 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090593

## Citation

> US National Institutes of Health, RePORTER application 10090593, The role of Tomosyn-2 in insulin secretion and glucose tolerance (5R01DK120684-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10090593. Licensed CC0.

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