Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine
Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine
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DOI：
10.14814/phy2.12551
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发表时间：
2015-09-01
影响因子：
2.5
通讯作者：
Holst, Jens J.
中科院分区：
文献类型：
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作者：
Christensen, Louise W.;Kuhre, Rune E.;Holst, Jens J.
胰高血糖素样肽1（GLP-1）以GLP-1增强剂和GLP-1模拟物的形式在2型糖尿病（T2 DM）的现代治疗中发挥着核心作用。另一种治疗策略是使用靶向方法刺激肠内分泌L细胞的内源性GLP-1分泌。G蛋白偶联受体FFAR 1（以前称为GPR 40）在L细胞上表达，并被长链脂肪酸（LCFA）激活，是一个潜在的靶点。FFAR 1激活和GLP-1分泌之间的联系已在细胞模型中得到证实，并已开发出小分子FFAR 1激动剂。在本研究中，我们使用大鼠离体灌注小肠（一种生理学相关模型，可区分FFAR 1激活的直接和间接效应）检查了FFAR 1激活对GLP-1分泌的影响。分别通过管腔内和动脉内途径给予内源性FFAR 1配体、亚油酸（LA）和4种合成FFAR 1激动剂（TAK-875、AMG 837、AM-1638和AM-5262），并评价GLP-1分泌的动态变化。与基础水平相比，10 μ mol/L TAK-875、10 μ mol/L AMG 837、1 μ mol/L和0.1 μ mol/L AM-1638、1 μ mol/L AM-6252和1 mmol/L LA血管给药均显著增加GLP-1分泌（P < 0.05），而LA和FFAR 1激动剂管腔给药无效。因此，天然和小分子FFAR 1受体激动剂似乎都需要在刺激GLP-1分泌之前吸收，这表明基于激活营养感知的治疗可能比迄今预期的更复杂。
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.