# Regulating SNARE mechanisms to remediate glucose homeostasis

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2022 · $432,500

## Abstract

Project Summary - Type 2 diabetes (T2D) plagues nearly 10% of the US population (~30 million people); a
shocking 84 million more have prediabetes and show signs of impaired glucose tolerance. Compounding this
problem, certain insulin-sensitizing drugs are undergoing global market suspensions, leaving prediabetic and
T2D patients with few treatment options and creating an urgent need for new therapeutics. Because multi-
tissue dysfunction contributes to prediabetes and progression to T2D, prevention or reversal of these diseases
requires a multi-pronged approach. Specifically, pancreatic β-cell dysfunction and skeletal muscle (skm) insulin
resistance are primary features of human prediabetes and T2D. STX4, a primary component of the SNARE
exocytosis machinery, is reduced in β-cells and skm from humans with T2D. Furthermore, STX4 is required for
normal β-cell insulin secretion and skm insulin sensitivity in mouse models and human islets. Our long-term
goal is to understand how β-cell and skm signaling can be manipulated to prevent or reverse prediabetes and
halt the progression to T2D. Our central hypothesis is that STX4 enrichment supports β-cells and/or skeletal
muscle to prevent and reverse the damaging effects of diabetogenic stress. The rationale for the proposed
research is that once these new mechanisms of STX4 are elucidated, STX4 signaling can be manipulated to
prevent or reverse T2D. During the last funding cycle, we revealed new roles for STX4 in promoting β-cell
survival and skm function. Indeed, mice overexpressing STX4 in these tissues have a remarkable 33%
extended lifespan and are protected from aging- and diet-induced metabolic dysfunction. Also, we showed that
STX4 can reverse insulin resistance in obese mice. However, the tissue-specific role of STX4 was unknown.
Therefore, we generated inducible β-cell- and skm- specific STX4 overexpression and knockout mice, as well
as RNA-based candidate therapeutics for tissue-specific STX4 enrichment. Our provocative new preliminary
data indicate that STX4 participates in anti-inflammatory signaling in the β-cells, and localizes to the outer
mitochondrial membrane to regulate mitochondrial function in skm. Therefore, the objective of this application
is to test these candidate mechanisms linking STX4 enrichment and protection of β-cells and skm from
diabetogenic stress and to evaluate candidate STX4 enrichment therapeutics. We will use our inducible mouse
models and human tissues/cells for these studies. In Aim 1, we will evaluate the mechanisms underlying the
protective actions of STX4 in β-cells and test novel β-cell STX4 enrichment strategies; in Aim 2, we will
delineate how STX4 enrichment protects skm and how it reverses HFD-induced dysfunction. We will use
innovative molecular tools to test novel hypotheses about STX4 action in the context of a translation-focused
institutional environment at City of Hope. This work will positively impact diabetes research by evaluating a
promising can...

## Key facts

- **NIH application ID:** 10457932
- **Project number:** 5R01DK067912-17
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Debbie C Thurmond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $432,500
- **Award type:** 5
- **Project period:** 2019-09-11 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457932

## Citation

> US National Institutes of Health, RePORTER application 10457932, Regulating SNARE mechanisms to remediate glucose homeostasis (5R01DK067912-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10457932. Licensed CC0.

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