# Islet Beta-Cell Dysfunction Under Metabolic Stress

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2022 · —

## Abstract

It is well established that chronic exposure of the pancreatic islet β-cells to metabolic stress (e.g., high
glucose, palmitate and ceramide) induces metabolic dysfunction and loss of functional β-cell mass. Original
and ongoing investigations from our laboratory have defined novel roles for Rac1, a small G-protein, in the
pathogenesis of islet β-cell dysfunction under glucolipotoxic conditions. Based on published and compelling
preliminary evidence, we now propose to test the overall hypothesis that metabolic stress promotes functional
and transcriptional activation of Rac1 to promote intracellular oxidative stress, mitochondrial damage and
eventual demise of the effete β-cell. We propose methodical investigations to identify key signaling
proteins/factors in the Rac1 activation-deactivation cycle that might contribute to the metabolic and functional
defects in the pancreatic β-cell. Studies designed herein will demonstrate regulatory roles and cross-talk
between novel of guanine nucleotide dissociation inhibitors, namely GDI1 (RhoGDI) and GDI2 (LyGDI) (Aim 1)
and scaffolding proteins/guanine nucleotide exchange factors (α4/β-PIX; Aim 2) in the functional activation of
Rac1 in islet β-cells exposed to metabolic stress. Studies outlined in Aim 3 will investigate putative (NF-kB-
mediated) mechanisms underlying transcriptional activation of Rac1 in islet β-cells under the duress of
metabolic stress. Our goal in studies under Aim 4 is to demonstrate that aberrant transcriptional and functional
activation of Rac1 leads to mitochondrial damage and islet dysfunction in an animal model of diet-induced
obesity (DIO). Complementary studies will affirm contributory roles for intracellularly generated ceramide in the
induction of islet dysfunction in our in vitro (Aims 1-3) and in vivo (Aim 4) model systems. Stated goals are
accomplished via pharmacological, molecular biological, microscopic and lipidomics approaches in clonal
β- (INS-1 832/13) cells, rodent, and human islets. Translational relevance of our project is enhanced by
validation of our hypothesis in islets derived from T2DM human donors. The proposed studies are innovative
and carry translational impact since they will identify putative mechanisms that dictate islet β-cell dysfunction
in human diabetes. The long-standing expertise of the PI and his collaborators in this field will provide a unique
opportunity to address these important aspects of islet function in health and diabetes. The data accrued from
these investigations are also expected to provide actionable insights that will impact the prevention and
treatment of T2DM in humans including our Veterans.

## Key facts

- **NIH application ID:** 10436768
- **Project number:** 5I01BX004663-03
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Anjaneyulu Kowluru
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436768

## Citation

> US National Institutes of Health, RePORTER application 10436768, Islet Beta-Cell Dysfunction Under Metabolic Stress (5I01BX004663-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10436768. Licensed CC0.

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