期刊
PHYSIOLOGICAL REPORTS
卷 3, 期 9, 页码 -出版社
WILEY
DOI: 10.14814/phy2.12551
关键词
G-protein-coupled receptor; incretin; longchain fatty acids
类别
资金
- Det Medicinske Selskab i Kobenhavn
- NNF Center for Basic Metabolic Research (Novo Nordisk Foundation, Denmark)
- European Union [266408]
- NNF Center for Basic Metabolic Research [Holst Group] Funding Source: researchfish
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 mu mol/L TAK-875, 10 mu mol/L AMG 837, 1 mu mol/L and 0.1 mu mol/L AM-1638, 1 mu mol/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.
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