Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP‐1 secretion from isolated perfused rat small intestine. Issue 9 (17th September 2015)

• Record Type: Journal Article
• Authors: Christensen, Louise W.; Kuhre, Rune E.; Janus, Charlotte; Svendsen, Berit; Holst, Jens J.
• Is Part Of: Physiological reports. Volume 3:Issue 9(2015:Sep.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-09-17
• Subjects: Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.12551
• Languages: English
• ISSNs: 2051-817X

Abstract

<abstract abstract-type="main" id="phy212551-abs-0001"> <title>Abstract</title> <p>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 (<italic>P </italic><<italic> </italic>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.</p> </abstract>