title: Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E2Signaling and Enhances Diabetic β-Cell Function.
abstract: Prostaglandin E2(PGE2) is derived from arachidonic acid, whereas PGE3is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE3on β-cell function, particularly in the diabetic state. In this work, we determined that PGE3elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared with PGE2We 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 BTBRLeptinob/obmice produced significantly less PGE2and more PGE3than 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.
authors.affiliation: Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI.|Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Neuman
authors.affiliation: Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI.|Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaid
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Brill
authors.affiliation: Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI.|Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Fenske
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Carly R
authors.initials: CR
authors.lastname: Kibbe
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Fontaine
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Integrated Program in Biochemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Sophia M
authors.initials: SM
authors.lastname: Sdao
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Brar
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Kelsey M
authors.initials: KM
authors.lastname: Connors
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Haley N
authors.initials: HN
authors.lastname: Wienkes
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.|Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.|Integrated Program in Biochemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.|Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.|Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Matthew J
authors.identifier: 0000-0003-1599-9227
authors.initials: MJ
authors.lastname: Merrins
authors.affiliation: Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.|Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.
authors.forename: Dawn B
authors.identifier: 0000-0002-0239-4715
authors.initials: DB
authors.lastname: Davis
authors.affiliation: Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI mkimple@medicine.wisc.edu.|Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI.|Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.|Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Kimple
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002849:Chromatography, Gas; D003920:Diabetes Mellitus / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D061848:Optical Imaging; D010743:Phospholipids; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D053583:Interleukin-1beta; D010743:Phospholipids; C545648:Ptger3 protein, mouse; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016718:Arachidonic Acid; C033246:prostaglandin E3; D015118:Eicosapentaenoic Acid; D000527:Alprostadil; D005947:Glucose; D015232:Dinoprostone