Vascular, but not luminal, activation of FFAR 1 ( GPR 40) stimulates GLP ‐1 secretion from isolated perfused rat small intestine

Glucagon‐like peptide 1 ( GLP ‐1) plays a central role in modern treatment of type 2 diabetes (T2 DM ) 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, FFAR 1 (previously GPR 40), expressed on L cells and activated by long‐chain fatty acids ( LCFA s) is a potential target. A link between FFAR 1 activation and GLP ‐1 secretion has been demonstrated in cellular models and small‐molecule FFAR 1 agonists have been developed. In this study, we examined the effect of FFAR 1 activation on GLP ‐1 secretion using isolated, perfused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR 1 activation. The endogenous FFAR 1 ligand, linoleic acid ( LA ), and four synthetic FFAR 1 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 FFAR 1 agonists was ineffective. Thus, both natural and small‐molecule agonists of the FFAR 1 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.