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

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

Author information

1
Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstr. 43, 61231, Bad Nauheim, Germany.
2
ECCPS Bioinformatics Facility, Max Planck Institute for Heart and Lung Research, Ludwigstr 43, 61231, Bad Nauheim, Germany.
3
Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
4
Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstr. 43, 61231, Bad Nauheim, Germany. stefan.offermanns@mpi-bn.mpg.de.
5
Centre for Molecular Medicine, Medical Faculty, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. stefan.offermanns@mpi-bn.mpg.de.

Abstract

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.

PMID:
29330456
PMCID:
PMC5766607
DOI:
10.1038/s41467-017-02539-4
[Indexed for MEDLINE]
Free PMC Article

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