Mechanisms underlying the prokinetic effects of endogenous glucagon-like peptide-1 in the rat proximal colon
Mechanisms underlying the prokinetic effects of endogenous glucagon-like peptide-1 in the rat proximal colon
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内源性胰高血糖素样肽-1在大鼠近端结肠中促动力作用的机制
DOI：
10.1152/ajpgi.00175.2021
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发表时间：
2021
影响因子：
4.5
通讯作者：
Hashitani Hikaru
中科院分区：
文献类型：
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作者：
Nakamori Hiroyuki;Iida Koji;Hashitani Hikaru
胰高血糖素样肽-1 (GLP-1) 是一种众所周知的胰岛素促分泌素，由肠内分泌 L 细胞在管腔和基底外侧释放，发挥不同的作用。基底外侧释放的 GLP-1 通过激活含有 CGRP 的肠传入神经元来增加上皮离子转运。尽管沐浴时施用的 GLP-1 降低了结肠段的收缩力，但 GLP-1 诱导的传入神经元刺激也可以加速蠕动收缩。在这里，使用分离的结肠段研究内源性 GLP-1 在调节结肠蠕动中的作用。将分离的大鼠近端结肠段置于器官浴中，用含氧生理盐溶液进行浆膜灌注，并用脱气的0.9%盐水进行管腔灌注。使用摄像机记录结肠壁运动并转换成时空图。腔内给予 GLP-1 (100 nM) 刺激 L 细胞分泌 GLP-1，增加口口传播蠕动收缩的频率。 GLP-1 的加速作用可被管腔应用的 GLP-1 受体拮抗剂 Exendin-3 (9-39) (100 nM) 阻断。浴液施用 BIBN4069 (1 μM)（一种 CGRP 受体拮抗剂）也可以防止 GLP-1 诱导的蠕动收缩加速。在暴露于浴敷辣椒素 (100 nM) 的结肠段中，辣椒素使外来传入变得不敏感，GLP-1 仍然能够发挥其促动力作用。用短链脂肪酸混合物 (1 mM) 刺激内源 GLP-1 分泌，以 exendin-3 (9-39) 敏感的方式增加蠕动波的频率。因此，GLP-1 激活表达 CGRP 的内在传入神经，加速近端结肠的蠕动。短链脂肪酸似乎可以刺激 L 细胞分泌内源性 GLP-1，从而加速结肠蠕动。新的和值得注意的胰高血糖素样肽-1 (GLP-1) 激活含有 CGRP 的内在传入神经元，从而加速结肠蠕动。短链脂肪酸刺激L细胞分泌内源性GLP-1，加速结肠蠕动。因此，除了众所周知的体液促胰岛素作用外，GLP-1还通过激活肠神经系统发挥局部作用，加速结肠蠕动。 GLP-1 的这种促运动作用可能是导致接受 GLP-1 类似物治疗的 2 型糖尿病患者腹泻的机制的基础。
Glucagon-like peptide-1 (GLP-1), a well-known insulin secretagogue, is released from enteroendocrine L cells both luminally and basolaterally to exert different effects. Basolaterally released GLP-1 increases epithelial ion transport by activating CGRP-containing enteric afferent neurons. Although bath-applied GLP-1 reduced the contractility of colonic segments, GLP-1-induced stimulation of afferent neurons could also accelerate peristaltic contractions. Here, the roles of endogenous GLP-1 in regulating colonic peristalsis were investigated using isolated colonic segments. Isolated segments of rat proximal colon were placed in an organ bath, serosally perfused with oxygenated physiological salt solution, and luminally perfused with degassed 0.9% saline. Colonic wall motion was recorded using a video camera and converted into spatiotemporal maps. Intraluminal administration of GLP-1 (100 nM) stimulating the secretion of GLP-1 from L cells increased the frequency of oro-aboral propagating peristaltic contractions. The acceleratory effect of GLP-1 was blocked by luminally applied exendin-3 (9-39) (100 nM), a GLP-1 receptor antagonist. GLP-1-induced acceleration of peristaltic contractions was also prevented by bath-applied BIBN4069 (1 μM), a CGRP receptor antagonist. In colonic segments that had been exposed to bath-applied capsaicin (100 nM) that desensitizes extrinsic afferents, GLP-1 was still capable of exerting its prokinetic effect. Stimulation of endogenous GLP-1 secretion with a luminally applied cocktail of short-chain fatty acids (1 mM) increased the frequency of peristaltic waves in an exendin-3 (9-39)-sensitive manner. Thus, GLP-1 activates CGRP-expressing intrinsic afferents to accelerate peristalsis in the proximal colon. Short-chain fatty acids appear to stimulate endogenous GLP-1 secretion from L cells resulting in the acceleration of colonic peristalsis.NEW & NOTEWORTHYGlucagon-like peptide-1 (GLP-1) activates CGRP-containing intrinsic afferent neurons resulting in the acceleration of colonic peristalsis. Short-chain fatty acids stimulate the secretion of endogenous GLP-1 from L cells that accelerates colonic peristalsis. Thus, besides the well-known humoral insulinotropic action, GLP-1 exerts a local action via the activation of the enteric nervous system to accelerate colonic motility. Such a prokinetic action of GLP-1 could underlie the mechanisms causing diarrhea in patients with type-2 diabetes treated with GLP-1 analogs.