Gαz-independent and -dependent Improvements With EPA Supplementation on the Early Type 1 Diabetes Phenotype of NOD Mice

Rachel J Fenske, Haley N Wienkes, Darby C Peter, Michael D Schaid, Liam D Hurley, Andrea Pennati, Jacques Galipeau, Michelle E Kimple
Journal of the Endocrine Society, Volume 8, Issue 7, July 2024, bvae100
https://doi.org/10.1210/jendso/bvae100

Abstract

Prostaglandin E₂ (PGE₂) is a key mediator of inflammation and is derived from the omega-6 polyunsaturated fatty acid, arachidonic acid (AA). In the β-cell, the PGE₂ receptor, Prostaglandin EP3 receptor (EP3), is coupled to the unique heterotrimeric G protein alpha subunit, Gɑ_z to reduce the production of cyclic adenosine monophosphate (cAMP), a key signaling molecule that activates β-cell function, proliferation, and survival pathways. Nonobese diabetic (NOD) mice are a strong model of type 1 diabetes (T1D), and NOD mice lacking Gɑ_z are protected from hyperglycemia. Therefore, limiting systemic PGE₂ production could potentially improve both the inflammatory and β-cell dysfunction phenotype of T1D. Here, we sought to evaluate the effect of eicosapentaenoic acid (EPA) feeding, which limits PGE₂ production, on the early T1D phenotype of NOD mice in the presence and absence of Gα_z. Wild-type and Gα_z knockout NOD mice were fed a control or EPA-enriched diet for 12 weeks, beginning at age 4 to 5 weeks. Oral glucose tolerance, splenic T-cell populations, islet cytokine/chemokine gene expression, islet insulitis, measurements of β-cell mass, and measurements of β-cell function were quantified. EPA diet feeding and Gɑ_z loss independently improved different aspects of the early NOD T1D phenotype and coordinated to alter the expression of certain cytokine/chemokine genes and enhance incretin-potentiated insulin secretion. Our results shed critical light on the Gα_z-dependent and -independent effects of dietary EPA enrichment and provide a rationale for future research into novel pharmacological and dietary adjuvant therapies for T1D.

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