title: Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine.
abstract: Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G-protein-coupled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we examined the effect of FFAR1 activation on GLP-1 secretion using isolated, perfused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 agonists (TAK-875, AMG 837, AM-1638, and AM-5262) were administered through intraluminal and intra-arterial routes, respectively, and dynamic changes in GLP-1 secretion were evaluated. Vascular administration of 10 μmol/L TAK-875, 10 μmol/L AMG 837, 1 μmol/L and 0.1 μmol/L AM-1638, 1 μmol/L AM-6252, and 1 mmol/L LA, all significantly increased GLP-1 secretion compared to basal levels (P < 0.05), whereas luminal administration of LA and FFAR1 agonists was ineffective. Thus, both natural and small-molecule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion, indicating that therapies based on activation of nutrient sensing may be more complex than hitherto expected.
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute University of Copenhagen, Copenhagen, Denmark.
authors.forename: Louise W
authors.initials: LW
authors.lastname: Christensen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rune E
authors.initials: RE
authors.lastname: Kuhre
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Janus
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute University of Copenhagen, Copenhagen, Denmark.
authors.forename: Berit
authors.initials: B
authors.lastname: Svendsen
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Panum Institute University of Copenhagen, Copenhagen, Denmark jjholst@sund.ku.dk.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
keywords: G‐protein‐coupled receptor; incretin; long‐chain fatty acids