# Modulating prostaglandin E2 receptor activity to improve pancreatic islet function

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Type 2 diabetes (T2D) affects nearly 25% of US veterans and is characterized by decreased functional β-cell
mass. Individuals with T2D have increased risk for heart disease and stroke. The incidence of T2D increases
with age, in part due to a decreased ability of β cells to respond to proliferative cues as they get older.
Prostaglandin E2 (PGE2) is elevated in the setting of obesity and T2D and is associated with decreased β-cell
function. PGE2 binds four G protein-couple receptors (GPCRs) designated E-Prostanoid (EP)1-4. The incretin
GLP-1 also exerts its effects through a GPCR and agonists of the GLP-1 receptor are used to treat T2D.
However, not every patient responds positively to this class of drugs, potentially due to increased activity of
negative regulatory pathways in the β cells of these individuals. Our lab discovered that the EP3 and EP4 PGE2
receptors modulate β-cell mass dynamics. We found that pharmacological inhibition of EP3 or activation of EP4
enhances β-cell proliferation and survival in both mouse and human islets ex vivo. Thus, EP3 and EP4 play
opposing roles in β cells with EP3 inhibiting and EP4 enhancing cellular functions. In addition, our preliminary
studies in the db/db mouse model of T2D reveal that systemic treatment with EP3 antagonist enhances β-cell
proliferation and mass and reverses some of the changes in gene expression associated with β-cell dysfunction.
Multiple splice variants of the EP3 receptor exist in all species. These variants have identical ligand binding
properties, but differ in their constitutive, agonist-independent activity, with the EP3γ isoform having the most
constitutive activity in mouse. EP3 expression increases with age and T2D in mouse and human islets and
decreases in response to β-cell mitogens. In mice, we found that EP3γ is most highly upregulated with age.
Constitutively active EP3 receptor would be unaffected by strategies such as non-steroidal anti-inflammatories
(NSAIDs) that lower synthesis of the ligand, PGE2. We will use a cell-based screening strategy to identify inverse
agonists that block constitutive EP3 activity. Whole genome sequencing and proteomics will define downstream
effects of EP3 and EP4 receptor modulation in β cells of db/db mice and islets from humans with T2D. Machine
learning approaches will be used to correlate expression of PGE2/EP pathway genes with T2D patient
phenotypes and to predict patient responsiveness to GLP-1 pathway agonists. Unique Vanderbilt resources (de-
identified electronic health record and linked DNA samples) will be used to assess whether NSAID use and/or
predicted lower EP3 expression or higher EP4 expression is associated with better outcomes. We hypothesize
that increased EP3 activity impairs β-cell identity and compensation leading to decreased functional β-cell mass
and decreased responsiveness to GLP-1 receptor activation in the setting of T2D and aging.

## Key facts

- **NIH application ID:** 10360796
- **Project number:** 1I01BX005399-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Maureen A Gannon
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360796

## Citation

> US National Institutes of Health, RePORTER application 10360796, Modulating prostaglandin E2 receptor activity to improve pancreatic islet function (1I01BX005399-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10360796. Licensed CC0.

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