20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1

Nat Commun. 2018 Jan 12;9(1):177. doi: 10.1038/s41467-017-02539-4.


The long-chain fatty acid receptor FFAR1 is highly expressed in pancreatic β-cells. Synthetic FFAR1 agonists can be used as antidiabetic drugs to promote glucose-stimulated insulin secretion (GSIS). However, the physiological role of FFAR1 in β-cells remains poorly understood. Here we show that 20-HETE activates FFAR1 and promotes GSIS via FFAR1 with higher potency and efficacy than dietary fatty acids such as palmitic, linoleic, and α-linolenic acid. Murine and human β-cells produce 20-HETE, and the ω-hydroxylase-mediated formation and release of 20-HETE is strongly stimulated by glucose. Pharmacological inhibition of 20-HETE formation and blockade of FFAR1 in islets inhibits GSIS. In islets from type-2 diabetic humans and mice, glucose-stimulated 20-HETE formation and 20-HETE-dependent stimulation of GSIS are strongly reduced. We show that 20-HETE is an FFAR1 agonist, which functions as an autocrine positive feed-forward regulator of GSIS, and that a reduced glucose-induced 20-HETE formation contributes to inefficient GSIS in type-2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Autocrine Communication / drug effects
  • COS Cells
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Chlorocebus aethiops
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Glucose / pharmacology*
  • Humans
  • Hydroxyeicosatetraenoic Acids / blood
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Hydroxyeicosatetraenoic Acids / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice, Knockout
  • Mice, Obese
  • Middle Aged
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Young Adult


  • FFAR1 protein, human
  • Hydroxyeicosatetraenoic Acids
  • Insulin
  • Receptors, G-Protein-Coupled
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Glucose