# FFA4 regulation of pancreatic islet function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $484,738

## Abstract

Half of US adults have diabetes or pre-diabetes, illustrating a critical need for novel diabetes treatments. There is a
fundamental gap in the understanding of the paracrine feedback in control of insulin and glucagon secretion. The long-term
goal of the research program is to elucidate the key players in (patho)physiological crosstalk within pancreatic islets in order
to identify novel therapeutic targets. The overall objective in this application is to understand the mechanisms of action for
the long chain fatty acid receptor 4 (FFA4). This G protein-coupled receptor is a promising T2D drug target that increases
insulin secretion. However, there is conflicting information with regards to the islet cell type(s) involved in the salutary
actions of FFA4. The central hypothesis is that within pancreatic islets FFA4 is predominantly expressed in d cells where
its activation inhibits somatostatin (SST) release and alleviates tonic inhibition of insulin and glucagon secretion. This
hypothesis was formulated on the basis of preliminary and recently published data produced collaboratively in the
laboratories of both PIs that place FFA4 expression predominantly on d cells. Furthermore, FFA4 stimulation inhibits d
cells and stimulates cAMP, Ca2+ and hormone secretion in b and a cells - effects that depend on d cell expression of FFA4.
Nevertheless, FFA4 agonists stimulate b cell proliferation independently of d cells and others claim direct FFA4 stimulation
of b cells. The rationale for the proposed research is to definitively resolve the mechanism(s) by which FFA4 agonists
promote insulin and glucagon secretion and beta cell proliferation. This hypothesis will be tested in 3 specific aims. Aim 1
tests the hypothesis that FFA4 activation in d cells lowers cAMP generation and inhibits SST secretion, which indirectly
enhances cAMP generation in b and a cells to stimulate insulin and glucagon secretion, respectively. SST will be deleted
genetically, or d cells will be ablated by diphteria toxin, to determine if stimulation of FFA4 stimulates b and a cells if 1)
SST is deleted, 2) d cells are ablated. Aim 2 test the hypothesis that direct FFA4 activation of a or b cells has minimal
impact on hormone secretion, but promotes b-cell proliferation. FFA4 will be selectively deleted in a or b cells to determine
whether FFA4-induced hormone release, cAMP generation, or proliferation is a or b cell-autonomous. Aim 3 tests the
hypothesis that FFA4 couples to Gaz in d cells to inhibit SST secretion and to Gas in a and/or b cells to stimulate b-cell
proliferation. The G proteins involved in FFA4-mediated islet responses will be identified by genetic deletion of Gaz in
specific islet cells combined with pharmacological inhibition and siRNA-mediated silencing of select G-protein isoforms.
The research is conceptually and technically innovative as it evaluates the important physiological role of d cells within
intact islets in attenuating a- and b-cell activity and applies...

## Key facts

- **NIH application ID:** 10590625
- **Project number:** 5R01DK132597-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Mark O. Huising
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $484,738
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590625

## Citation

> US National Institutes of Health, RePORTER application 10590625, FFA4 regulation of pancreatic islet function (5R01DK132597-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10590625. Licensed CC0.

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