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.
Highlights
Glucagon-like peptide 1 (GLP-1) is a gut hormone that has gained a central position in modern treatment of type 2 diabetes mellitus (T2DM)
The main finding of this study is that vascular FFAR1 activation stimulates GLP-1 secretion, whereas luminal FFAR1 stimulation is without effect in the isolated perfused rat small intestine
Fat is a known stimulator of GLP-1 secretion (Elliott et al 1993; Beglinger et al 2010; Lindgren et al 2011)
Summary
Glucagon-like peptide 1 (GLP-1) is a gut hormone that has gained a central position in modern treatment of type 2 diabetes mellitus (T2DM). Increased postprandial levels of endogenous GLP-1 following the bariatric procedure, Roux-en-Y gastric bypass (RYGB) (Korner et al 2007), have already been linked to the substantial weight loss and the remission of type 2 diabetes observed postsurgery (le Roux et al 2006; Jorgensen et al 2012). This indicates that there is an extra capacity in the GLP-1 axis which could be mobilized through pharmacological L-cell stimulation. A number of FFAR1 selective agonists have been developed (Negoro et al 2010; Lin et al 2011; Houze et al 2012; Wang et al 2013) and several studies have confirmed the antidiabetic potential of FFAR1 activation through the direct insulinotropic effect on the b-cells (Christiansen et al 2008; Tan et al 2008; Lin et al 2011; Tsujihata et al 2011; Araki et al 2012; Burant et al 2012; Yashiro et al 2012; Kaku et al 2013)
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