Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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-cou-
pled 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 exam-
ined the effect of FFAR1 activation on GLP-1 secretion using isolated, per-
fused 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 ago-
nists (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 mol/L TAK-875, 10 mol/L AMG 837, 1 mol/L and 0.1 mol/L AM-1638, 1
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-mole-
cule 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.
Originalsprog | Engelsk |
---|---|
Artikelnummer | e122551 |
Tidsskrift | Physiological Reports |
Vol/bind | 3 |
Udgave nummer | 9 |
Sider (fra-til) | 1-13 |
Antal sider | 13 |
ISSN | 2051-817X |
DOI | |
Status | Udgivet - 17 sep. 2015 |
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ID: 144403006