Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E(2) Signaling and Enhances Diabetic β-Cell Function

Prostaglandin E(2) (PGE(2)) is derived from arachidonic acid, whereas PGE(3) is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE(3) on β-cell function, particularly in the diabetic state. In this work, we determined that PGE(3) elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared with PGE(2). We tested the hypothesis that enriching pancreatic islet cell membranes with EPA, thereby reducing arachidonic acid abundance, would positively impact β-cell function in the diabetic state. EPA-enriched islets isolated from diabetic BTBR Leptin(ob/ob) mice produced significantly less PGE(2) and more PGE(3) than controls, correlating with improved glucose-stimulated insulin secretion. NAD(P)H fluorescence lifetime imaging showed that EPA acts downstream and independently of mitochondrial function. EPA treatment also reduced islet interleukin-1β expression, a proinflammatory cytokine known to stimulate prostaglandin production and EP3 expression. Finally, EPA feeding improved glucose tolerance and β-cell function in a mouse model of diabetes that incorporates a strong immune phenotype: the NOD mouse. In sum, increasing pancreatic islet EPA abundance improves diabetic β-cell function through both direct and indirect mechanisms that converge on reduced EP3 signaling.