Insulin at physiological concentrations selectively activates insulin but not insulin-like growth factor I (IGF-I) or insulin/IGF-I hybrid receptors in endothelial cells
Insulin at physiological concentrations selectively activates insulin but not insulin-like growth factor I (IGF-I) or insulin/IGF-I hybrid receptors in endothelial cells
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DOI：
10.1210/en.2005-0505
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发表时间：
2005-11-01
期刊：
影响因子：
4.8
通讯作者：
Liu, ZQ
中科院分区：
文献类型：
--
作者：
Li, GL;Barrett, EJ;Liu, ZQ
在肌肉中，生理性高胰岛素血症可能作用于内皮细胞 (EC)，扩张小动脉并调节总血流量和毛细血管募集，进而影响葡萄糖的处理。然而，在培养的 EC 中，超生理（例如 >= 10 nM）胰岛素浓度通常用于研究胰岛素受体 (IR) 信号通路和一氧化氮的生成。 EC 中 IGF-I 受体 (IGF-IR) 比 IR 更丰富，并且它们也对高浓度胰岛素有反应。为了确定 IR 是否介导对生理胰岛素刺激的反应，我们检查了 IR 的胰岛素浓度依赖性和牛主动脉 EC (bAEC) 中 IGF-IR 介导的胰岛素信号传导。我们还评估了 bAEC 中是否存在胰岛素/IGF-I 杂合受体。 100 - 500 pM 的胰岛素显着刺激 IR β、Akt1、一氧化氮合酶内皮亚型和 ERK 1/ 2 的磷酸化，但不刺激 IGF-IR β 亚基的磷酸化。在1-5nM或更高的浓度下，胰岛素剂量依赖性地增强IGF-IRβ的酪氨酸磷酸化，并且这被IGF-IR中和抗体抑制。此外，IRβ的免疫沉淀降低了IGF-IRβ，并且IRβ在免疫细胞化学上与IGF-IRβ共定位，表明EC具有胰岛素/IGF-I杂合受体。我们的结论是：1）生理浓度的胰岛素选择性激活 bAEC 中的 IR 信号传导； 2) 除了IR之外，bAEC还表达IGF-IR和胰岛素/IGF-I杂合受体； 3) 高浓度胰岛素 (>= 1 - 5 nM) 激活 IGF-IR 和混合受体以及 IR； 4) 当使用高胰岛素浓度时，这种交叉激活可能会混淆 EC 中胰岛素作用研究的解释。
In muscle, physiologic hyperinsulinemia, presumably acting on endothelial cells ( ECs), dilates arterioles and regulates both total blood flow and capillary recruitment, which in turn influences glucose disposal. In cultured ECs, however, supraphysiological ( e. g. >= 10 nM) insulin concentrations are typically used to study insulin receptor ( IR) signaling pathways and nitric oxide generation. IGF- I receptors ( IGF- IRs) are more abundant than IR in ECs, and they also respond to high concentrations of insulin. To address whether IR mediates responses to physiologic insulin stimuli, we examined the insulin concentration dependence of IR and IGF- IR- mediated insulin signaling in bovine aortic ECs ( bAECs). We also assessed whether insulin/ IGF- I hybrid receptors were present in bAECs. Insulin, at 100 - 500 pM, significantly stimulated the phosphorylation of IR beta, Akt1, endothelial isoform of nitric oxide synthase, and ERK 1/ 2 but not the IGF- IR beta subunit. At concentrations 1 - 5 nM or greater, insulin dose- dependently enhanced the tyrosine phosphorylation of IGF- IR beta, and this was inhibited by IGF- IR neutralizing antibody. In addition, immunoprecipitation of IR beta pulled down the IGF- IR beta, and the IR beta immunocytochemically colocalized with IGF- IR beta, suggesting that ECs have insulin/ IGF- I hybrid receptors. We conclude that: 1) insulin at physiological concentrations selectively activates IR signaling in bAECs; 2) bAECs express IGF- IR and insulin/ IGF- I hybrid receptors in addition to IR; 3) high concentrations of insulin (>= 1 - 5 nM) activate IGF- IR and hybrid receptors as well as IR; and 4) this crossover activation can confound interpretation of studies of insulin action in ECs when high insulin concentrations are used.