The insulin receptor is expressed and functional in cultured blood-brain barrier endothelial cells but does not mediate insulin entry from blood to brain
The insulin receptor is expressed and functional in cultured blood-brain barrier endothelial cells but does not mediate insulin entry from blood to brain
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DOI：
10.1152/ajpendo.00350.2016
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发表时间：
2018-10-01
影响因子：
5.1
通讯作者：
Brodin, Birger
中科院分区：
文献类型：
--
作者：
Hersom, Maria;Helms, Hans C.;Brodin, Birger
已知胰岛素及其受体存在于大脑中并发挥作用。胰岛素脑脊液浓度已被证明与胰岛素的血浆水平以非线性方式相关，表明从血液到脑间质液的可饱和转运途径。本研究的目的是研究胰岛素是否通过胰岛素受体依赖性途径在体外跨脑内皮细胞转运。研究表明，胰岛素受体在牛脑内皮细胞中在mRNA和蛋白水平上都有表达。发光应用放射性标记的胰岛素显示胰岛素受体介导的内皮细胞结合。这引起Akt磷酸化的剂量依赖性增加，其被胰岛素受体抑制剂s961的共同应用抑制，表明胰岛素受体信号通路的激活。胰岛素在体外穿过血脑屏障的转运率很低，与类似大小的细胞旁标记物相当。此外，胰岛素转运没有被抑制的共同应用过量的未标记的胰岛素或胰岛素受体抑制剂。在小鼠脑内皮细胞中重复胰岛素转运和摄取研究，结果相似。虽然不能排除细胞模型中培养诱导的变化可能损害了潜在的胰岛素转运机制，但这些体外数据表明，外周胰岛素必须通过替代途径到达脑实质，而不是通过受体介导的胞吞转运穿过血脑屏障。
Insulin and its receptor are known to be present and functional in the brain. Insulin cerebrospinal fluid concentrations have been shown to correlate with plasma levels of insulin in a nonlinear fashion, indicative of a saturable transport pathway from the blood to the brain interstitial fluid. The aim of the present study was to investigate whether insulin was transported across brain endothelial cells in vitro via an insulin receptor-dependent pathway. The study showed that the insulin receptor was expressed at both the mRNA and protein levels in bovine brain endothelial cells. Luminally applied radiolabeled insulin showed insulin receptor-mediated binding to the endothelial cells. This caused a dose-dependent increase in Akt-phosphorylation, which was inhibited by coapplication of an insulin receptor inhibitor, s961, demonstrating activation of insulin receptor signaling pathways. Transport of insulin across the blood-brain barrier in vitro was low and comparable to that of a similarly sized paracellular marker. Furthermore, insulin transport was not inhibited by coapplication of an excess of unlabeled insulin or an insulin receptor inhibitor. The insulin transport and uptake studies were repeated in mouse brain endothelial cells demonstrating similar results. Although it cannot be ruled out that culture-induced changes in the cell model could have impaired a potential insulin transport mechanism, these in vitro data indicate that peripheral insulin must reach the brain parenchyma through alternative pathways rather than crossing the blood-brain barrier via receptor mediated transcytosis.