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Altering beta‐cell phospholipid composition affects diabetic beta‐cell dysfunction (796.15)

Liberation of eicosapentaenoic acid (EPA) or arachidonic acid (AA) from membrane phospholipids is the first step in eicosanoid biosynthesis. Previously, we showed that production of the AA‐derived prostaglandin E2 (PGE2) and expression of one PGE2 receptor, EP3, are both upregulated in type 2 diabetic (T2D) islets and contribute to beta‐cell dysfunction. We also restored diabetic beta‐cell function with an EP3 antagonist, suggesting EP3 as a T2D therapeutic target. In the present study, we explored a different mechanism to improve diabetic beta‐cell function: reducing PGE2 production, thus removing the stimulation of EP3. In addition, we characterized the EPA‐derived eicosanoid, PGE3, for its effect on beta‐cell function, alone or as a competitor of PGE2. First, we optimized an incubation protocol to specifically modulate the AA or EPA composition of isolated islet and insulinoma cell membranes and then treated the cells with agents to induce expression of the PGE2 synthetic enzymes. We observed the expected effects on eicosanoid levels. Dose‐response assays revealed a differential effect of PGE2 and PGE3 on beta‐cell function, which differed in insulinoma cell lines and islets based on their complement of EP receptors. Finally, islets deficient in beta‐cell EP3 were used to confirm specificity of this signaling cascade. Thus, we confirm non‐pharmaceutically targeting PGE2 production as a T2D therapeutic strategy. This work was funded by JDRF, PhRMA Foundation, and UW Madison Department of Medicine.