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

Diabetes. 2017 Jun;66(6):1572-1585. doi: 10.2337/db16-1362. Epub 2017 Feb 13.


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.

MeSH terms

  • Alprostadil / analogs & derivatives*
  • Alprostadil / metabolism
  • Animals
  • Arachidonic Acid / metabolism
  • Chromatography, Gas
  • Diabetes Mellitus / metabolism*
  • Dinoprostone / metabolism*
  • Eicosapentaenoic Acid / pharmacology*
  • Gene Expression Profiling
  • Glucose / metabolism*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Interleukin-1beta / pharmacology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Mass Spectrometry
  • Mice
  • Mice, Inbred NOD
  • Mice, Obese
  • Optical Imaging
  • Phospholipids
  • Receptors, Prostaglandin E, EP3 Subtype / drug effects*
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism
  • Signal Transduction


  • Insulin
  • Interleukin-1beta
  • Phospholipids
  • Ptger3 protein, mouse
  • Receptors, Prostaglandin E, EP3 Subtype
  • Arachidonic Acid
  • prostaglandin E3
  • Eicosapentaenoic Acid
  • Alprostadil
  • Glucose
  • Dinoprostone