# Investigating the Effects of ADGRB3 Signaling on Incretin-Mediated Insulin Secretion from Pancreatic Beta-Cells

> **NIH NIH R03** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $164,125

## Abstract

The prevalence of diabetes has reached epidemic proportions worldwide. According to the Centers for Disease
Control and Prevention, more than 37 million individuals in the US have diabetes (~10% of the adult population),
and another 84.1 million are prediabetic. Elevated blood sugar is the hallmark of diabetes, and insulin secreted
from the β-cells of the pancreatic islets is critical for maintaining proper blood sugar levels. It is currently accepted
that β-cell dysfunction is an early and essential event in the development of diabetes, including obesity-linked
type 2 diabetes (T2D). Cyclic AMP (cAMP) and ionic calcium (Ca2+) are key cellular signaling molecules that
stimulate β-cell insulin secretion. Ca2+ is the trigger for insulin secretion, while cAMP is required for the maximal
insulin secretion response. Preliminary data from our group suggests brain angiogenesis inhibitor-3 (BAI3: aka
ADGRB3), a G protein-coupled receptor for complement 1q like-3 secreted protein (C1ql3), may be a key player
in the β-cell dysfunction of T2D. BAI3 expression, and C1ql3 expression and secretion are both higher in
pancreatic islets from T2D mice and humans. BAI3 and C1ql3 are specifically expressed in islet β-cells and not
in other islet cell types. Finally, C1ql3 treatment reduces insulin secretion from islets stimulated by glucose and
drugs that raise β-cell Ca2+ or cAMP levels. Yet, the precise molecular mechanisms underlying β-cell C1ql3/BAI3
signaling, particularly in the pathophysiological states of obesity and T2D, remain uncharacterized. A full
understanding of these processes is required to achieve our long-term goal of discovering ways to modulate
BAI3 activity to improve or reverse the β-cell dysfunction of T2D. The overarching goal of this project, which is
the next logical step towards this goal, is to define BAI3 and C1ql3 levels, signaling mechanisms, and effects on
glucose-stimulated and cAMP-potentiated insulin secretion and how these change during β-cell compensation
for obesity and T2D β-cell failure. With our unique combination of scientific expertise and technically innovative
approaches, we are uniquely suited to complete this highly significant project. Tangible outcomes of the
proposed work are: i) revealing how BAI3 expression and C1ql3 expression and secretion change in response
to obesity and, ultimately, T2D; ii) quantifying the effects of BAI3 activation on β-cell Ca2+ influx and cAMP levels;
and iii) establishing how C1ql3-mediated BAI3 signaling inhibits glucose-stimulated and cAMP-potentiated
insulin secretion and the magnitude of its effects in the lean, obese, and T2D states. If successful, our work will
both define the signaling mechanisms downstream of BAI3, a poorly-characterized G protein-coupled receptor,
and provide strong preliminary data for future T2D drug development studies, leaving a high and long-lasting
impact on the field.

## Key facts

- **NIH application ID:** 10666206
- **Project number:** 1R03TR004472-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Sushant Bhatnagar
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $164,125
- **Award type:** 1
- **Project period:** 2023-08-15 → 2024-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10666206

## Citation

> US National Institutes of Health, RePORTER application 10666206, Investigating the Effects of ADGRB3 Signaling on Incretin-Mediated Insulin Secretion from Pancreatic Beta-Cells (1R03TR004472-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10666206. Licensed CC0.

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