Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E2 Signaling and Enhances Diabetic β-Cell Function

Abstract

Prostaglandin E2 (PGE2) is derived from arachidonic acid, whereas PGE3 is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE3 on β-cell function, particularly in the diabetic state. In this work, we determined that PGE3 elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared with PGE2. 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 Leptinob/ob mice produced significantly less PGE2 and more PGE3 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.

The role of Cox‐2 and prostaglandin E 2 receptor EP3 in pancreatic β‐cell death

“…PGE 2 signaling via EP3 results in impaired b-cell proliferation in old mice (30). Neuman et al (52) presented a different approach of showing the involvement of EP3 in b-cell function. In this study, reduction of PGE 2 production and EP3 expression due to dietary eicosapenaenoic acid (another COX-2 substrate) enrichment led to enhancement of BTBR diabetic mouse islets function and improved glucose tolerance and b-cell function in the NOD mouse model of type 1 diabetes.…”

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…[110][111][112] Interestingly, diet rich in omega-3 polyunsaturated eicosapentaenoic acids (EPA) was shown to change the cell membrane composition of pancreatic islets, reduce AA production, and improve beta cell function in BTBR leptin ob/ob mice, indicating a significant contribution of membrane lipids for beta cell failure in diabetes. 113 Dilation of the ER and swelling of mitochondria were reported in an electron micrscopic study of human beta cells in T2D. 114 In a study of INS1 cells, PA increased dynaminrelated protein 1 (DRP1) phosphorylation and led to ER enlargement and mitochondrial fragmentation, providing one potential pathway by which FA alter the ER and mitochondria morphology.…”

“…109 As ER maintains higher calcium concentration compared with cytosol to support protein folding and to regulate [Ca 2+ ] i , [Ca 2+ ] ER depletion results in ER stress and dysregulates insulin secretion. 113 Dilation of the ER and swelling of mitochondria were reported in an electron micrscopic study of human beta cells in T2D. [110][111][112] Interestingly, diet rich in omega-3 polyunsaturated eicosapentaenoic acids (EPA) was shown to change the cell membrane composition of pancreatic islets, reduce AA production, and improve beta cell function in BTBR leptin ob/ob mice, indicating a significant contribution of membrane lipids for beta cell failure in diabetes.…”

Differential Effects of Prostaglandin E2Production and Signaling through the Prostaglandin EP3 Receptor on Human Beta-cell Compensation

“…COX-1 and COX-2 (officially known as prostaglandin-endoperoxidase 1 and 2: PTGS1 and PTGS2), catalyze the rate-limiting step in the production of PGE2 derived from arachidonic acid (AA) incorporated in plasma membrane phospholipids. High glucose, free fatty acids, and/or pro-inflammatory cytokines have all been shown to upregulate the expression and/or activity of enzymes involved in the PGE2 synthetic pathway, including phospholipase A2 (PLA2: which cleaves AA from membrane phospholipids); COX-1 and COX-2 (which convert arachidonic acid to the intermediate, PGH2); and PTGES, PTGES2, and PTGES3, which convert PGH2 to PGE2 [1, [11][12][13][14][15][16]. Using BMI as a marker of obesity/insulin resistance, we found a weak correlation with PTGS2 expression ( Figure 1B), consistent with results of a previous study [1].…”