Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes
Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes
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DOI：
10.1677/joe.0.1730465
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发表时间：
2002-06-01
影响因子：
4
通讯作者：
Villanueva-Peñacarrillo, ML
中科院分区：
文献类型：
--
作者：
Luque, MA;González, N;Villanueva-Peñacarrillo, ML
胰高血糖素样肽-1 (GLP-1) 已被证明对大鼠肝脏、肌肉和脂肪中的葡萄糖代谢以及大鼠和人类脂肪细胞中的脂质代谢具有类似胰岛素的作用。这些作用似乎是通过特定的受体发挥的，与胰腺的受体不同，至少在肝脏和肌肉中，这些受体不与 cAMP 相关。在这里，我们研究了 GLP-1 在组织条和原代培养的肌细胞中对人类骨骼肌葡萄糖代谢的影响、其特征和可能的第二信使。在肌肉条中，GLP-1 与胰岛素一样，刺激糖原合成、糖原合酶 a 活性以及葡萄糖氧化和利用，并抑制糖原磷酸化酶 a 活性，所有这些都在肽的生理浓度下进行。在培养的肌管中，GLP-1从10（-13）mol/l开始，D-[U-C-14]葡萄糖掺入糖原的量呈剂量相关增加，与胰岛素具有相同的效力，同时激活糖原合成酶a； 10(-11) mol/l GLP-1 对这两个参数的影响与等摩尔量胰岛素诱导的影响相加。与在不存在肽的情况下维持的肌管相比，暴露于 GLP-1 2 天后，细胞中的合酶 a 仍然被激活。在人类肌肉细胞中，exendin-4 及其截短形式 9-39 酰胺 (Ex-9) 都是 GLP-1 对糖原合成和合成酶 a 活性的激动剂；但是，在没有 3-异丁基-1-甲基黄嘌呤 (IBMX) 的情况下孵育 5 分钟后，GLP-1 和 exendin-4 都不影响细胞 cAMP 含量，但 Ex-9 检测到增加。 GLP-1、exendin-4、Ex-9 和胰岛素均诱导糖基磷脂酰肌醇 (GPI) 迅速水解。这项工作显示了 GLP-1 对人体骨骼肌葡萄糖代谢的强大刺激作用，并支持了该肽的长期治疗价值。还说明了该组织中存在与胰腺不同的 GLP-1 受体的进一步证据，表明肌醇磷酸聚糖 (IPG) 至少是人体肌肉中 GLP-1 作用的可能第二信使之一。
Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not - at least in liver and muscle - cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10(-13) mol/l, a dose-related increase of the D-[U-C-14] glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10(-11) mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosyl-phosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated, suggesting a role for an inositolphosphoglycan (IPG) as at least one of the possible second messengers of the GLP-1 action in human muscle.