Independent mechanisms underlie the protective effect of dietary polyunsaturated fatty acid supplementation and Gαz deficiency on the early type 1 diabetes phenotype of Non-obese diabetic (NOD) mice

Abstract

AbstractNon-obese diabetic (NOD) mice deficient in Gz alpha subunit (Gαz) are protected from developing hyperglycemia, even with early islet insulitis similar to wild-type mice. Similarly, wild-type (WT) NOD mice are protected from glucose intolerance when fed a diet enriched in eicosapentaneoic acid (EPA). In the beta-cell, Prostaglandin EP3 receptor (EP3), whose primary endogenous ligand is the arachidonic acid (AA) metabolite, prostaglandin E2, is specifically coupled to Gαz. In this work, we tested whether dietary EPA supplementation, thereby reducing systemic PGE2 levels, would complement Gαz loss in the NOD mouse model. WT and Gαz-null NOD mice were fed an AA-enriched diet, EPA-enriched diet, or control diet upon weaning. After 12 weeks of diet feeding, glucose tolerance tests were performed and pancreatic islets and whole pancreas collected for ex vivo analyses, with the longer-term effect of an EPA-enriched diet on splenic T-cell populations quantified via flow cytometry. Our results reveal a polyunsaturated fatty acid-enriched diet, whether AA or EPA, improves wild-type NOD glucose tolerance by the same magnitude as Gαz loss, but through almost completely different physiological and cellular mechanisms. Our results shed critical light on future research into novel pharmacological and dietary adjuvant therapies for T1D.