Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility
Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility
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DOI：
10.2337/diabetes.54.4.1056
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发表时间：
2005-04-01
期刊：
影响因子：
7.7
通讯作者：
Seino, S
中科院分区：
文献类型：
--
作者：
Miki, T;Minami, K;Seino, S
葡萄糖诱导胰腺分泌胰岛素！P细胞对ATP敏感性K+通道（K-ATP通道）的活性依赖性很强，但KATP通道是否参与葡萄糖依赖性促胰岛素多肽（GIP）对胰岛素分泌的增强作用尚不清楚。在缺乏K-ATP通道的小鼠（Kir6.2（-/-）小鼠）中，我们发现体内GIP预处理未能减弱口服葡萄糖负荷后血糖水平的升高。在Kir6.2（-/-）小鼠中，GIP在体内对胰岛素分泌的增强作用明显减弱，表明KATP通道在GIP的促胰岛素作用中是必不可少的。相反，在Kir6.2（-/-）小鼠中用胰高血糖素样肽-1（GLP-1）预处理增强了胰岛素分泌并减弱了血糖水平的升高。我们还发现，GLP-1抑制肠道运动，而GIP没有。Kir6.2（-/-）小鼠的灌注实验显示，1 nmol/l GIP对胰岛素分泌的增强作用严重受损，1 nmol/l GLP-1对胰岛素分泌的增强作用显著。尽管GIP和GLP-1均增加细胞内cAMP浓度并增强胰岛素分泌，但这些结果表明GLP-1和GIP信号传导途径以不同方式涉及KATP通道。
Glucose-induced insulin secretion from pancreatic! P-cells depends critically on ATP-sensitive K+ channel (K-ATP channel) activity, but it is not known whether KATP channels are involved in the potentiation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP). In mice lacking K-ATP channels (Kir6.2(-/-) mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load. In Kir6.2(-/-) mice, potentiation of insulin secretion by GIP in vivo was markedly attenuated, indicating that KATP channels are essential in the insulinotropic effect of GIP. In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2(-/-) mice potentiated insulin secretion and blunted the rise in blood glucose levels. We also found that GLP-1 inhibited gut motility whereas GIP did not. Perfusion experiments of Kir6.2(-/-) mice revealed severely impaired potentiation of insulin secretion by 1 nmol/l GIP and substantial potentiation by 1 nmol/l GLP-1. Although both GIP and GLP-1 increase the intracellular cAMP concentration and potentiate insulin secretion, these results demonstrate that the GLP-1 and GIP signaling pathways involve the KATP channel differently.