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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome
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Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome

机译：胰岛素通过Pdx1和人类胰岛蛋白质组的特定变化保护胰岛免受凋亡

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摘要

Insulin is both a hormone regulating energy metabolism and a growth factor. We and others have shown that physiological doses of insulin initiate complex signals in primary human and mouse beta-cells, but the functional significance of insulin's effects on this cell type remains unclear. in the present study, the role of insulin in beta-cell apoptosis was examined. Exogenous insulin completely prevented apoptosis induced by serum withdrawal when given at picomolar or low nanomolar concentrations but not at higher concentrations, indicating that physiological concentrations of insulin are antiapoptotic and that insulin signaling is self-limiting in islets. Insulin treatment was associated with the nuclear localization of Pdx1 and the prosurvival effects of insulin were largely absent in islets 50% deficient in Pdx1, providing direct evidence that Pdx1 is a signaling target of insulin. Physiological levels of insulin did not increase Akt phosphorylation, and the protective effects of insulin were only partially altered in islets lacking 80% of normal Akt activity, suggesting the presence of additional insulin-regulated antiapoptotic pathways. Proteomic analysis of insulin-treated human islets revealed significant changes in multiple proteins. Bridge-1, a Pdx1-binding partner and regulator of, beta-cell survival, was increased significantly at low insulin doses. Together, these data suggest that insulin can act as a master regulator of islet survival by regulating Pdx1.
机译：胰岛素既是调节能量代谢的激素，又是生长因子。我们和其他人已经表明，胰岛素的生理剂量会在人的原始β细胞和小鼠β细胞中引发复杂的信号，但是胰岛素对这种细胞类型的功能意义尚不清楚。在本研究中，检查了胰岛素在β细胞凋亡中的作用。当以皮摩尔或低纳摩尔浓度而不是较高浓度给予时，外源胰岛素完全阻止了由血清停药诱导的凋亡，这表明胰岛素的生理浓度具有抗凋亡作用，并且胰岛素信号传导在胰岛中是自限性的。胰岛素的治疗与Pdx1的核定位有关，在50％Pdx1缺乏的胰岛中，胰岛素的存活率几乎不存在，这直接证明了Pdx1是胰岛素的信号传导靶标。胰岛素的生理水平并未增加Akt磷酸化，并且在缺乏80％正常Akt活性的胰岛中，胰岛素的保护作用仅被部分改变，表明存在其他胰岛素调节的抗凋亡途径。胰岛素治疗的人类胰岛的蛋白质组学分析显示多种蛋白质发生了显着变化。在低胰岛素剂量下，Pdx1结合伴侣和β细胞存活调节因子Bridge-1显着增加。总之，这些数据表明胰岛素可以通过调节Pdx1充当胰岛存活的主要调节剂。

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