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

ABSTRACT: The long-chain fatty acid receptor FFAR1 is highly expressed in pancreatic ?-cells. Synthetic FFAR1 agonists can be used as antidiabetic drugs to promote glucose-stimulated insulin secretion (GSIS). However, the physiological role of FFAR1 in ?-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 ?-linolenic acid. Murine and human ?-cells produce 20-HETE, and the ?-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.

SUBMITTER: Tunaru S 

PROVIDER: S-EPMC5766607 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other