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

Prostaglandin E 2 (PGE 2 ) is a key mediator of inflammation and is derived from the omega-6 polyunsaturated fatty acid, arachidonic acid (AA). In the β-cell, the PGE 2 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 PGE 2 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 PGE 2 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.