# G Protein Mediated Mechanisms of Beta Cell Death Dysfunction and Decompensation in Diabetes

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2021 · —

## Abstract

Diabetes is a costly and complex chronic illness and a serious public health problem. Currently, the prevalence
of diabetes in the VA patient population is approximately 25%, with many more Veterans at risk for diabetes
due to obesity, aging, and poor lifestyle, as well as exposure to known diabetogenic chemicals in the line of
duty. The number of Veterans with diabetes is certain to increase over the next decades, as the children of
today have an estimated overall lifetime risk of developing diabetes of nearly 50%. Therefore, developing new
methods for preventing diabetes and identifying and properly treating diabetic patients is very timely and of
great significance. By definition, diabetes occurs when insufficient insulin is produced from the β-cells of the
pancreas to properly stimulate the body cells to take up glucose from the blood and shut off production of more
glucose. While they have different etiologies, the pathophysiology of type 1 (immune-mediated) and type 2
(obesity-related) diabetes is increasingly being linked by dysfunctional cellular and molecular signaling
processes that act in the insulin-secreting β-cells. One molecule that is a cornerstone of our research program,
termed Gαz, has the potential to act as a hub in one or more signaling processes impacting on β-cell function,
replication, growth and/or survival. Thus, targeting these dysfunctional Gαz signaling processes could
potentially help to improve functional β-cell mass in both types of diabetes. Our long-term goal is to fully
characterize the Gαz activation and signaling pathways in the diabetic state at the organismal, tissue, cellular,
and molecular levels, guiding us in modulating this pathway for preventative and therapeutic purposes.
The overall objective of this work, which is the next logical step in pursuit of our goal, is to characterize the
molecular and cellular signaling pathways responsible for the impact of Gαz signaling on diabetes
pathophysiology. Our central hypothesis is activated β-cell Gαz negatively modulates specific intracellular and
autocrine/paracrine signaling pathways critical for β-cell compensation, ultimately leading to β-cell death and
dysfunction and exacerbating the diabetic condition. We will test our central hypothesis in multiple pre-clinical
models of diabetes and, thereby, accomplish the objective of this application, by pursuing the following
three specific aims: (1) Determine the differential effects of EP3 receptor variant/Gαz coupling on
mechansims mediating insulin exocytosis; (2) Elucidate the mechanisms underlying the cAMP-
independent regulation of beta-cell function by Gαz; and (3) Elucidate the effect of Gαz signaling on
intra-islet communication pathways that regulate beta-cell replication and survival. With the completion
of these aims, we anticipate a much more complete understanding of the role of the β-cell and its signaling
molecules in the pathophysiology of diabetes. Ultimately, isolating Gαz effects to the β-ce...

## Key facts

- **NIH application ID:** 10265403
- **Project number:** 5I01BX003700-04
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Michelle E Kimple
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265403

## Citation

> US National Institutes of Health, RePORTER application 10265403, G Protein Mediated Mechanisms of Beta Cell Death Dysfunction and Decompensation in Diabetes (5I01BX003700-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10265403. Licensed CC0.

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