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

Sorin Tunaru, Remy Bonnavion, Isabell Brandenburger, Jens Preussner, Dominique Thomas, Klaus Scholich and Stefan Offermanns ()
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Sorin Tunaru: Department of Pharmacology
Remy Bonnavion: Department of Pharmacology
Isabell Brandenburger: Department of Pharmacology
Jens Preussner: Max Planck Institute for Heart and Lung Research
Dominique Thomas: Klinikum der Goethe-Universität Frankfurt
Klaus Scholich: Klinikum der Goethe-Universität Frankfurt
Stefan Offermanns: Department of Pharmacology

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02539-4

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