L-缬氨酸是一种强有力的 GLP-1 分泌刺激物，可通过 ATP 敏感性钾通道和电压门控钙通道刺激分泌。

L-valine is a powerful stimulator of GLP-1 secretion in rodents and stimulates secretion through ATP-sensitive potassium channels and voltage-gated calcium channels.

机构信息

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Łódź, Poland.

出版信息

Nutr Diabetes. 2024 Jun 11;14(1):43. doi: 10.1038/s41387-024-00303-4.

DOI:10.1038/s41387-024-00303-4

PMID:38862477

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11166632/

Abstract

BACKGROUND

We previously reported that, among all the naturally occurring amino acids, L-valine is the most powerful luminal stimulator of glucagon-like peptide 1 (GLP-1) release from the upper part of the rat small intestine. This makes L-valine an interesting target for nutritional-based modulation of GLP-1 secretion. However, the molecular mechanism of L-valine-induced secretion remains unknown.

METHODS

We aimed to investigate the effect of orally given L-valine in mice and to identify the molecular details of L-valine stimulated GLP-1 release using the isolated perfused rat small intestine and GLUTag cells. In addition, the effect of L-valine on hormone secretion from the distal intestine was investigated using a perfused rat colon.

RESULTS

Orally given L-valine (1 g/kg) increased plasma levels of active GLP-1 comparably to orally given glucose (2 g/kg) in male mice, supporting that L-valine is a powerful stimulator of GLP-1 release in vivo (P > 0.05). Luminal L-valine (50 mM) strongly stimulated GLP-1 release from the perfused rat small intestine (P < 0.0001), and inhibition of voltage-gated Ca-channels with nifedipine (10 μM) inhibited the GLP-1 response (P < 0.01). Depletion of luminal Na did not affect L-valine-induced GLP-1 secretion (P > 0.05), suggesting that co-transport of L-valine and Na is not important for the depolarization necessary to activate the voltage-gated Ca-channels. Administration of the K-channel opener diazoxide (250 μM) completely blocked the L-valine induced GLP-1 response (P < 0.05), suggesting that L-valine induced depolarization arises from metabolism and opening of K-channels. Similar to the perfused rat small intestine, L-valine tended to stimulate peptide tyrosine-tyrosine (PYY) and GLP-1 release from the perfused rat colon.

CONCLUSIONS

L-valine is a powerful stimulator of GLP-1 release in rodents. We propose that intracellular metabolism of L-valine leading to closure of K-channels and opening of voltage-gated Ca-channels are involved in L-valine induced GLP-1 secretion.

摘要

背景

我们之前曾报道过，在所有天然存在的氨基酸中，L-缬氨酸是刺激大鼠小肠上部胰高血糖素样肽 1（GLP-1）释放的最强肠腔刺激物。这使得 L-缬氨酸成为营养调节 GLP-1 分泌的一个有趣的靶点。然而，L-缬氨酸诱导分泌的分子机制尚不清楚。

方法

我们旨在研究口服给予 L-缬氨酸对小鼠的影响，并使用分离的灌注大鼠小肠和 GLUTag 细胞来确定 L-缬氨酸刺激 GLP-1 释放的分子细节。此外，还使用灌注的大鼠结肠研究了 L-缬氨酸对远侧肠激素分泌的影响。

结果

口服给予 L-缬氨酸（1g/kg）可使雄性小鼠的活性 GLP-1 血浆水平与口服给予葡萄糖（2g/kg）相当，这表明 L-缬氨酸在体内是 GLP-1 释放的强有力刺激物（P＞0.05）。肠腔 L-缬氨酸（50mM）强烈刺激灌注大鼠小肠的 GLP-1 释放（P＜0.0001），用硝苯地平（10μM）抑制电压门控 Ca 通道抑制 GLP-1 反应（P＜0.01）。耗尽肠腔 Na 不影响 L-缬氨酸诱导的 GLP-1 分泌（P＞0.05），这表明 L-缬氨酸和 Na 的共转运对于激活电压门控 Ca 通道所需的去极化不重要。给予 K 通道开放剂二氮嗪（250μM）完全阻断 L-缬氨酸诱导的 GLP-1 反应（P＜0.05），这表明 L-缬氨酸诱导的去极化来自代谢和 K 通道的开放。与灌注大鼠小肠相似，L-缬氨酸倾向于刺激灌注大鼠结肠的肽酪氨酸-酪氨酸（PYY）和 GLP-1 释放。