Joshi S, Tough I R, Cox H M
King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
Br J Pharmacol. 2013 Nov;170(5):1092-101. doi: 10.1111/bph.12352.
l-glutamine (Gln) is an energy source for gastrointestinal (GI) epithelia and can stimulate glucagon-like peptide 1 (GLP-1) release from isolated enteroendocrine L-cells. GLP-1 and peptide YY (PYY) are co-secreted postprandially and both peptides have functional roles in glucose homeostasis and energy balance. The primary aim of this project was to establish the endogenous mechanisms underpinning Gln responses within intact GI mucosae using selective receptor antagonists.
Mouse mucosae from different GI regions were voltage-clamped and short-circuit current (Isc) was recorded to Gln added to either surface in the absence or presence of antagonists, using wild-type (WT) or PYY-/- tissues. The glucose sensitivity of Gln responses was also investigated by replacement with mannitol.
Colonic apical and basolateral Gln responses (at 0.1 and 1 mM) were biphasic; initial increases in Isc were predominantly GLP-1 mediated. GLP-1 receptor antagonism significantly reduced the initial Gln response in the PYY-/- colon. The slower reductions in Isc to Gln were PYY-Y1 mediated as they were absent from the PYY-/- colon and were blocked selectively in WT tissue by a Y1 receptor antagonist. In jejunum mucosa, Gln stimulated monophasic Isc reductions that were PYY-Y1 receptor mediated. Gln effects were partially glucose sensitive, and Calhex 231 inhibition indicated that the calcium-sensing receptor (CaSR) was involved.
Gln stimulates the co-release of endogenous GLP-1 and PYY from mucosal L-cells resulting in paracrine GLP-1 and Y1 receptor-mediated electrogenic epithelial responses. This glucose-sensitive mechanism appears to be CaSR mediated and could provide a significant therapeutic strategy releasing two endogenous peptides better known for their glucose-lowering and satiating effects.
L-谷氨酰胺（Gln）是胃肠道（GI）上皮细胞的能量来源，可刺激分离的肠内分泌L细胞释放胰高血糖素样肽1（GLP-1）。餐后GLP-1和肽YY（PYY）共同分泌，这两种肽在葡萄糖稳态和能量平衡中均起作用。本项目的主要目的是使用选择性受体拮抗剂，确定完整胃肠道黏膜中Gln反应的内在机制。
使用野生型（WT）或PYY基因敲除（PYY-/-）组织，对来自不同胃肠道区域的小鼠黏膜进行电压钳制，并记录在添加Gln到表面时，在无拮抗剂或有拮抗剂存在的情况下的短路电流（Isc）。还通过用甘露醇替代来研究Gln反应的葡萄糖敏感性。
结肠顶端和基底外侧的Gln反应（0.1和1 mM时）呈双相性；Isc的初始增加主要由GLP-1介导。GLP-1受体拮抗作用显著降低了PYY-/-结肠中Gln的初始反应。Isc对Gln的较慢降低是由PYY-Y1介导的，因为在PYY-/-结肠中不存在这种情况，并且在WT组织中被Y1受体拮抗剂选择性阻断。在空肠黏膜中，Gln刺激单相Isc降低，这是由PYY-Y1受体介导的。Gln的作用部分对葡萄糖敏感，Calhex 231抑制表明钙敏感受体（CaSR）参与其中。
Gln刺激黏膜L细胞释放内源性GLP-而且PYY共同释放，导致旁分泌GLP-1和Y1受体介导的电生性上皮反应。这种对葡萄糖敏感的机制似乎是由CaSR介导的，并且可以提供一种重要的治疗策略，释放两种以内源性降血糖和饱腹感作用而闻名的内源性肽。
