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Diabetes and Vascular Disease

MON-545 - The G Protein-Coupled Receptor GPR31 Promotes Pro-Inflammatory Responses in Pancreatic Islets and Macrophages

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Kerim B. Kaylan, MD, PhD: No financial relationships to disclose
Sarah A. Tersey, PhD: No financial relationships to disclose
In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting pancreatic β cells. During this process, β cells activate stress and inflammatory signaling pathways that augment the effects imposed by cellular autoimmunity. One pathway known to induce oxidative and endoplasmic reticulum stress within β cells is the 12-lipoxygenase (12-LOX) pathway, which produces the eicosanoid 12-hydroxyeicosatetraenoic acid (12-HETE) and causes diminished insulin secretion and β-cell apoptosis. The G protein-coupled receptor GPR31 has been identified as a receptor for 12-HETE and in mice is encoded by the Gpr31b gene. In this study, we showed that Gpr31b is expressed both in islet and myeloid cells. We generated conventional Gpr31b knockout (KO) mice on the C57BL/6J background. To elucidate the role of GPR31 in β cells during inflammation, we performed bulk RNA sequencing on islets from wildtype and Gpr31b KO mice treated with pro-inflammatory cytokines. Gpr31b KO islets showed altered expression of inflammation and oxidative stress gene sets, in agreement with functional studies which demonstrated reduced cytokine-induced oxidative stress. To examine alterations to the innate immune response, we isolated bone marrow-derived macrophages for analysis by transwell migration assay, which demonstrated reduced macrophage migration in Gpr31b KO macrophages. Using a complementary zebrafish tailfin injury assay, we demonstrated that morpholino knockdown of the zebrafish orthologue gpr31 reduced macrophage migration. This effect was not rescued with the addition of exogenous 12-HETE, whereas morpholino knockdown of the 12-LOX orthologue alox12 similarly reduced migration but was rescuable by 12-HETE, indicating that GPR31 is downstream of both 12-LOX and 12-HETE. RNA sequencing analysis of bone marrow-derived macrophages from Gpr31b KO mice showed decreased inflammatory interferon (IFN)-α and IFN-γ signaling as well as alternative splicing of genes related to actomyosin dynamics and regulation of G protein-coupled receptor signaling. To mimic islet and macrophage inflammation as seen in T1D, we treated mice with the diabetogenic toxin streptozotocin; Gpr31b KO mice demonstrated improved glucose tolerance and preserved β-cell mass compared to wildtype mice. siRNA knockdown of Gpr31b in non-obese diabetic (NOD) mice reduced insulitis, macrophage infiltration, and oxidative stress. Flow cytometry of the pancreatic lymph nodes of Gpr31b siRNA-treated NOD mice demonstrated a decrease in CD4+ IFN-γ+ T cells. Collectively, these findings corroborate prior 12-LOX KO studies and further suggest that GPR31 mediates the pro-inflammatory effects of 12-HETE by inducing oxidative stress in β cells as well as interferon signaling and pro-migratory responses in macrophages.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*