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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Insulin withdrawal induces apoptosis via a free radical-mediated mechanism.
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Insulin withdrawal induces apoptosis via a free radical-mediated mechanism.

机译:胰岛素戒断通过自由基介导的机制诱导凋亡。

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摘要

Diabetes is characterized by chronic hyperglycemia as well as insulin deficiency or resistance. However, the majority of research has focused on the consequences of hyperglycemia in development of diabetic complications, whereas the effects of insulin deficiency or resistance, independent of hyperglycemia, have received little attention. Since insulin is a well known cytoprotective factor, we hypothesized that its removal could significantly impact cell survival. To examine this possibility, cultured neonatal cardiomyocytes were subjected to insulin withdrawal and examined for apoptosis. Insulin deficient cells succumbed to apoptosis, an effect associated with impaired PI3-kinase/Akt signaling and reduction in the Bcl-2 to Bax ratio. Perhaps more importantly, superoxide generation was altered in cells subjected to insulin withdrawal. Removal of insulin caused a significant increase in reactive oxygen species production and resulted in oxidative mitochondrial DNA damage the latter effect is associated with impaired expression of mitochondrially encoded proteins that make up the electron transport chain. Significantly, the effects of insulin withdrawal could be mitigated by treatment with the antioxidant, Tiron. Collectively, these data demonstrate that insulin deficiency leads to apoptosis and suggest a role for oxidative mitochondrial DNA damage in this cascade.
机译:糖尿病的特征在于慢性高血糖以及胰岛素缺乏或抵抗。然而,大多数研究集中于高血糖在糖尿病并发症发展中的后果,而与高血糖无关的胰岛素缺乏或抵抗的影响却很少受到关注。由于胰岛素是众所周知的细胞保护因子,我们假设将其清除可能会显着影响细胞存活。为了检查这种可能性,对培养的新生儿心肌细胞进行胰岛素停药并检查其凋亡。胰岛素缺乏细胞会导致细胞凋亡,这与PI3-激酶/ Akt信号传导受损以及Bcl-2与Bax比例降低有关。也许更重要的是,在接受胰岛素戒断的细胞中超氧化物的产生发生了改变。胰岛素的去除导致活性氧的产生显着增加,并导致线粒体DNA氧化,后者的作用与构成电子传输链的线粒体编码蛋白的表达受损有关。重要的是,可以通过抗氧化剂Tiron的治疗减轻胰岛素戒断的影响。总的来说,这些数据表明胰岛素缺乏导致细胞凋亡,并提示该级联反应中氧化线粒体DNA损伤的作用。

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