20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29330456.
- Also identified by DOI 10.1038/s41467-017-02539-4 and PMC identifier 5766607.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Glucose
- Hydroxyeicosatetraenoic Acids
- Insulin
- Insulin-Secreting Cells
- Receptors, G-Protein-Coupled