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

 
: Tunaru, S.; Bonnavion, R.; Brandenburger, I.; Preussner, J.; Thomas, D.; Scholich, K.; Offermanns, S.

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Nature Communications 9 (2018), Art.177, 11 pp.
ISSN: 2041-1723
English
Journal Article
Fraunhofer IME ()

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.

: http://publica.fraunhofer.de/documents/N-541085.html