Page 1 of 47 Diabetes
Enriching Islet Phospholipids with Eicosapentaenoic Acid Reduces Prostaglandin E2 Signaling and Enhances Diabetic β cell Function
Short Running Title: EPA improves diabetic islet function
Joshua C. Neuman1,8, Michael D. Schaid1,8, Allison L. Brill2,8, Rachel J. Fenske1,8, Carly R. Kibbe2,8, Danielle A. Fontaine2,8, Sophia M. Sdao5,8, Harpreet K. Brar2,8, Kelsey M. Connors2,8, Haley N. Wienkes2,8, Kevin W. Eliceiri6,7, Matthew J. Merrins2,4,5,7,8, Dawn B. Davis1,2,9, & Michelle E. Kimple1,2,3,8*
1Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin Madison, Madison, WI, USA 2Department of Medicine, Division of Endocrinology, School of Medicine and Public Health, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, United States of America. 3Department of Cell and Regenerative Biology, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, United States of America. 4Department of Biomolecular Chemistry, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, United States of America. 5Integrated Program in Biochemistry, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, United States of America. 6Department of Biomedical Engineering, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, United States of America. 7Laboratory for Optical and Computational Instrumentation, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, United States of America. 8Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, United States of America. 9Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, United States of America.
*To whom correspondence should be addressed Michelle E. Kimple, PhD University of Wisconsin Madison 4148 UW Medical Foundation Centennial Building 1685 Highland Ave. Madison, WI 53705 USA Phone: 608 616 0138 email: [email protected] Word Count: 5108 Figure Count: 6 Table Count: 2 Supplemental Material: 1
For Peer Review Only Diabetes Publish Ahead of Print, published online February 13, 2017 Diabetes Page 2 of 47
Abstract:
Prostaglandin E2 (PGE2) is derived from arachidonic acid, while 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 PGE3 elicits a 10 fold weaker reduction in
glucose stimulated insulin secretion through the EP3 receptor as compared to 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 pro inflammatory cytokine known to stimulate prostaglandin production and EP3 expression. Finally, EPA feeding improved glucose tolerance and beta cell function in a mouse model of diabetes that incorporates a strong immune phenotype: the Non obese diabetic (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.
For Peer Review Only Page 3 of 47 Diabetes
Introduction:
A diet high in essential n 3 (a.k.a. ω 3 or omega 3) polyunsaturated fatty acids
(PUFAs) is proposed to be beneficial in chronic conditions such as diabetes; yet, direct
confirmation of these effects and the mechanisms mediating them remains elusive (1).
Intact PUFAs can activate beta cell G protein coupled receptors (GPCRs) that stimulate
insulin secretion (2). However, PUFAs are metabolized, and the regulatory action of their
bioactive compounds, particularly those of the 3 series, on beta cell biology is not well
understood.
Previous work from our lab and others’ demonstrates an increase in the
production of prostaglandin E2 (PGE2), an eicosanoid derived from the n 6 PUFA
arachidonic acid (AA), and/or its receptor, EP3, from islets isolated from diabetic mice
and humans (3 8) (see Table 1 for a list of abbreviations of all fatty acid species,
metabolites, metabolic enzymes, and signaling enzymes used in this manuscript). Up
regulation of this signaling pathway actively contributes to diabetic beta cell dysfunction
(3; 6; 7). The n 3 PUFA, eicosapentaenoic acid (EPA), competes with AA for the same
eicosanoid biosynthetic enzymes, yielding PGE3 instead of PGE2. We therefore
questioned whether shifting plasma membrane PUFA composition to favor EPA would
alter eicosanoid production and limit EP3 signaling, resulting in enhanced β cell function
in two mouse models of diabetes: the BTBR Ob mouse, a strong model of obesity