PDF(Pubmed)
Abstract：
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.
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.
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 Ca2+-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 Ca2+-channels. Administration of the KATP-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 KATP-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.
L-valine is a powerful stimulator of GLP-1 release in rodents. We propose that intracellular metabolism of L-valine leading to closure of KATP-channels and opening of voltage-gated Ca2+-channels are involved in L-valine induced GLP-1 secretion.
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.
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 Ca2+-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 Ca2+-channels. Administration of the KATP-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 KATP-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.
L-valine is a powerful stimulator of GLP-1 release in rodents. We propose that intracellular metabolism of L-valine leading to closure of KATP-channels and opening of voltage-gated Ca2+-channels are involved in L-valine induced GLP-1 secretion.
摘要：
背景：我们之前报道过，在所有天然存在的氨基酸中，L-缬氨酸是胰高血糖素样肽1（GLP-1）从大鼠小肠上部释放的最强大的管腔刺激剂。这使得L-缬氨酸成为基于营养的GLP-1分泌调节的令人感兴趣的靶标。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L-缬氨酸对小鼠的影响，并使用分离的灌流大鼠小肠和GLUTag细胞鉴定L-缬氨酸刺激GLP-1释放的分子细节。此外,使用灌流的大鼠结肠研究了L-缬氨酸对远端肠激素分泌的影响。
结果：口服L-缬氨酸（1g/kg）与口服葡萄糖（2g/kg）相比，增加了雄性小鼠的活性GLP-1的血浆水平。证明L-缬氨酸是体内GLP-1释放的强力刺激剂(P>0.05)。腔内L-缬氨酸（50mM）强烈刺激GLP-1从灌注的大鼠小肠释放（P<0.0001），硝苯地平（10μM）对电压门控Ca2+通道的抑制作用抑制了GLP-1反应（P<0.01）。管腔内Na+的消耗不影响L-缬氨酸诱导的GLP-1分泌(P>0.05),表明L-缬氨酸和Na的共运输对于激活电压门控Ca2通道所必需的去极化并不重要。给予KATP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），表明L-缬氨酸诱导的去极化是由KATP通道的代谢和开放引起的。类似于灌流的大鼠小肠，L-缬氨酸倾向于刺激肽酪氨酸-酪氨酸(PYY)和GLP-1从灌注的大鼠结肠释放。
结论：L-缬氨酸是啮齿动物GLP-1释放的强大刺激剂。我们认为，导致KATP通道关闭和电压门控Ca2通道开放的L-缬氨酸的细胞内代谢与L-缬氨酸诱导的GLP-1分泌有关。
方法：我们旨在研究口服L-缬氨酸对小鼠的影响，并使用分离的灌流大鼠小肠和GLUTag细胞鉴定L-缬氨酸刺激GLP-1释放的分子细节。此外,使用灌流的大鼠结肠研究了L-缬氨酸对远端肠激素分泌的影响。
结果：口服L-缬氨酸（1g/kg）与口服葡萄糖（2g/kg）相比，增加了雄性小鼠的活性GLP-1的血浆水平。证明L-缬氨酸是体内GLP-1释放的强力刺激剂(P>0.05)。腔内L-缬氨酸（50mM）强烈刺激GLP-1从灌注的大鼠小肠释放（P<0.0001），硝苯地平（10μM）对电压门控Ca2+通道的抑制作用抑制了GLP-1反应（P<0.01）。管腔内Na+的消耗不影响L-缬氨酸诱导的GLP-1分泌(P>0.05),表明L-缬氨酸和Na的共运输对于激活电压门控Ca2通道所必需的去极化并不重要。给予KATP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），表明L-缬氨酸诱导的去极化是由KATP通道的代谢和开放引起的。类似于灌流的大鼠小肠，L-缬氨酸倾向于刺激肽酪氨酸-酪氨酸(PYY)和GLP-1从灌注的大鼠结肠释放。
结论：L-缬氨酸是啮齿动物GLP-1释放的强大刺激剂。我们认为，导致KATP通道关闭和电压门控Ca2通道开放的L-缬氨酸的细胞内代谢与L-缬氨酸诱导的GLP-1分泌有关。
