Objective

Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues.

Methods

Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (Gcg^Gut−/-) and (2) selective reduction of Gcg expression in the distal gut (Gcg^{DistalGut−/-}).

Results

The acute GLP-1 response to olive oil or arginine administration was markedly diminished in Gcg^Gut−/- but preserved in Gcg^{DistalGut−/-} mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the Gcg^{DistalGut−/-} mice. The GLP-1 response to LPS was also markedly attenuated in the Gcg^Gut−/- mice and remained submaximal in the Gcg^{DistalGut−/-} mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the Gcg^Gut+/+ mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the Gcg^Gut−/- mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the Gcg^{DistalGut−/-} mice.

Conclusion

These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues.

中文翻译：

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肠道选择性降低Gcg表达揭示了远端肠道对于GLP-1分泌的重要性。

目的

胰高血糖素样肽1是从大小肠肠内分泌L细胞分泌的营养敏感激素。尽管GLP-1水平会因食物摄入而迅速升高，但L细胞的最大密度位于远端小肠和结肠。在这里，我们评估了远端肠道在急性L细胞对各种促分泌素反应中的重要性。

方法

在野生型小鼠和具有（1）小肠和大肠的Gcg表达遗传减少的小鼠中，对L细胞促分泌素的给药后，测量了葡萄糖和血浆GLP-1的循环水平（Gcg ^Gut-/-）和（2）选择性降低远端肠中Gcg的表达（Gcg ^DistalGut-/-）。

结果

在Gcg ^Gut-/-中，对橄榄油或精氨酸给​​药的急性GLP-1反应明显减弱，但在Gcg ^DistalGut-/-小鼠中保留了。相反，在Gcg ^DistalGut-/-小鼠中，施用GPR119激动剂AR231453或黑皮质素4受体（MC4R）激动剂LY2112688后血浆GLP-1水平的增加明显减少。的GLP-1响应于LPS也显着减弱在的Gcg^{肠- / -}小鼠和次最大保持在的Gcg ^{DistalGut - / -}小鼠。二甲双胍的剂量足以降低血糖并增加Gcg ^{Gut + / +}中的GLP-1水平小鼠保留了其糖调节活性，但未能增加Gcg ^Gut-/-小鼠的GLP-1水平。出乎意料的是，在Gcg ^DistalGut-/-小鼠中，二甲双胍增加血浆GLP-1水平的作用明显减弱。

结论

这些发现进一步确立了近端肠对于对营养相关的GLP-1促分泌素的急性反应的重要性。相比之下，我们确定了远端肠胃对（i）快速诱导循环GLP-1水平的重要贡献，以响应G蛋白偶联受体的药理选择性激动作用；（ii）激活后GLP-1水平升高具有LPS的Toll样受体，以及iii）对二甲双胍的急性GLP-1反应。总的来说，这些结果表明，远端肠道Gcg +内分泌细胞对结构和功能多样的GLP-1促分泌素具有快速反应能力。