1. 20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1.
- Author
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Tunaru S, Bonnavion R, Brandenburger I, Preussner J, Thomas D, Scholich K, and Offermanns S
- Subjects
- 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, Humans, Hydroxyeicosatetraenoic Acids blood, Hydroxyeicosatetraenoic Acids pharmacology, Insulin Secretion, Insulin-Secreting Cells metabolism, Male, Mice, Knockout, Mice, Obese, Middle Aged, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled genetics, Young Adult, Glucose pharmacology, Hydroxyeicosatetraenoic Acids metabolism, Insulin metabolism, Insulin-Secreting Cells drug effects, Receptors, G-Protein-Coupled metabolism
- 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.
- Published
- 2018
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