# G protein mediated mechanisms of beta-cell compensation and failure in type 2 diabetes

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2024 · —

## 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 two specific aims: 1. Determine the requirement of islet CCKAR
and/or GLP1R in the T2D protection of full-body Gαz-null mice and the mechanisms behind this
protection; And 2. Determine the molecular mechanisms downstream of constitutively-active and
agonist-stimulated EP3 and how these are altered in the highly-compensating and T2D beta-cell. In both
aims, the relationship between agonist-dependent and -independent signaling of EP3 splice variants in islet
responsiveness to GLP1-RAs will be determined. With the completion of these aims, we anticipate a much more
complete understanding of t...

## Key facts

- **NIH application ID:** 10721351
- **Project number:** 5I01BX005804-02
- **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:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721351

## Citation

> US National Institutes of Health, RePORTER application 10721351, G protein mediated mechanisms of beta-cell compensation and failure in type 2 diabetes (5I01BX005804-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10721351. Licensed CC0.

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