Increasing the dietary ratio of omega 3:omega 6 polyunsaturated fatty acids positively impacts inflammation and islet outcomes in Type 1 Diabetes
Authors: Peter Darby , Fenske Rachel , Wienkes Haley , Kimple Michelle 
Published: June 2021

Type 1 Diabetes (T1D) pathophysiology fundamentally involves both immune system dysregulation and β‐cell dysfunction. Prostaglandin E2 (PGE2), a metabolite of the ω‐6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), influences immune cell polarization. In the β‐cell, PGE2 activates E prostanoid receptor 3 (EP3), specifically coupled to the inhibitory G protein subunit, Gαz, to negatively regulate β‐cell function and proliferation. Mice lacking Gαz are protected from hyperglycemia in a number of mouse models of diabetes, including the T1D model, non‐obese diabetic (NOD). We hypothesized signaling mediated by PGE2 contributes to both the immune cell and β‐cell phenotype of T1D; the latter through EP3/Gαz signaling. A dietary intervention study to reduce AA content by displacement with the equivalent chain‐length ω‐3 PUFA, eicosapentaneoic acid (EPA), was completed in non‐obese diabetic (NOD) mice, both wild‐type or Gαz‐KO. Upon weaning, mice were fed a semi‐purified EPA‐enriched or control diet for 19 weeks. Random‐fed blood glucose, weight, and food consumption were tracked weekly, and, at study end, pancreatic islets, whole pancreas, and splenic T cells isolated for ex vivo analyses. Islets isolated from wild‐type NOD animals fed an EPA‐enriched diet had a robust increase in insulin content, but did not secrete more insulin as a percent of total content when challenged with stimulatory glucose. EPA‐enrichment did not further modulate β‐cell function in the absence of Gαz. EPA‐fed Gαz‐KO mice exhibited significantly enhanced glucose tolerance that, interestingly, was not associated with an increase in the insulin‐positive area of pancreas sections. Although the mean infiltration score of islets isolated from Gαz‐KO NOD mice were lower than those of wild‐type controls, EPA enrichment had no further effect on immune cell infiltration. EPA‐fed NOD animals, whether wild‐type or Gαz‐KO−, did exhibit a dramatic reduction in circulating fasting PGE2 and Th‐1 positive splenic T‐cells. Surprisingly, the percentage of splenic Th‐17+ cells increased substantially with EPA‐enriched feeding. Our results highlight a shift in the inflammatory environment stimulated by EPA enrichment and changes in β‐cell biology that are independent of any signaling mediated by EP3/Gαz. As very few studies on the impact of ω‐3 PUFAs on T1D or immune phenotypes have been performed (1) with physiologically‐relevant concentrations of PUFAs and (2) in a way that allows isolation the effect(s) of specific dietary components on downstream metabolite production and/or cell function, our results are worthy of future study.Support or Funding InformationAmerican Diabetes Association Innovative Basic Science Award 1‐14‐BS‐115; NIH/NIDDK R01 DK102598 and F31 DK109698‐01A1; VA BLR&D I01 BX003700‐01A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.