Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats
Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats
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DOI：
10.1210/en.2006-0153
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发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
D'Alessio, David A.
中科院分区：
文献类型：
--
作者：
Vahl, Torsten P.;Tauchi, Miyuki;D'Alessio, David A.
胰高血糖素样肽-1 (GLP-1) 是一种肠道激素，在膳食吸收过程中分泌，对于正常的葡萄糖稳态至关重要。然而，GLP-1 相对较低的血浆水平和快速代谢引发了这样的问题：对靶器官（例如胰岛细胞）的直接内分泌作用是否可以解释其对葡萄糖耐量的所有影响。最近，有人提出了一种由肝门区传感器启动的替代神经通路来介导 GLP-1 活性。我们假设门静脉床内脏传入神经元表达 GLP-1 受体 (GLP-1r) 并调节葡萄糖耐量。与这一假设一致，GLP-1r mRNA 存在于结状神经节中，并且支配门静脉的神经末梢也含有 GLP-1r。给予低剂量 GLP-1r 拮抗剂 [des-His(1), Glu(9)] exendin-4 门静脉输注的大鼠出现葡萄糖不耐受，与输注媒介物的对照组相比，血糖波动高出 53%。以相同的速率将[des-His(1), Glu(9)]exendin-4输注到颈静脉中对葡萄糖耐量没有影响，表明该剂量的GLP-1r拮抗剂不会因溢出到体循环中而影响血糖。这些研究表明，GLP-1r 存在于肝门床的神经末梢上，并且位于该区域的 GLP-1 拮抗作用会损害葡萄糖耐量。这些数据与 GLP-1 作用的神经介导的重要组成部分一致。
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and is essential for normal glucose homeostasis. However, the relatively low plasma levels and rapid metabolism of GLP-1 raise questions as to whether direct endocrine action on target organs, such as islet cells, account for all of its effects on glucose tolerance. Recently, an alternative neural pathway initiated by sensors in the hepatic portal region has been proposed to mediate GLP-1 activity. We hypothesized that visceral afferent neurons in the portal bed express the GLP-1 receptor (GLP-1r) and regulate glucose tolerance. Consistent with this hypothesis, GLP-1r mRNA was present in the nodose ganglia, and nerve terminals innervating the portal vein contained the GLP-1r. Rats given an intraportal infusion of the GLP-1r antagonist, [des-His(1), Glu(9)] exendin-4, in a low dose, had glucose intolerance, with a 53% higher glucose excursion compared with a vehicle-infused control group. Infusion of [des-His(1), Glu(9)] exendin-4 at an identical rate into the jugular vein had no effect on glucose tolerance, demonstrating that this dose of GLP-1r antagonist did not affect blood glucose due to spillover into the systemic circulation. These studies demonstrate that GLP-1r are present on nerve terminals in the hepatic portal bed and that GLP-1 antagonism localized to this region impairs glucose tolerance. These data are consistent with an important component of neural mediation of GLP-1 action.