Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms.
Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms.
复制标题
雷帕霉素对胰腺 β 细胞毒性的证据以及潜在分子机制的回顾。
DOI：
10.2337/db13-0106
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发表时间：
2013-08
期刊：
影响因子：
7.7
通讯作者：
Herbert TP
中科院分区：
文献类型：
--
作者：
Barlow AD;Nicholson ML;Herbert TP
雷帕霉素经常用于移植和肿瘤学。虽然历史上认为几乎没有致糖尿病作用，但越来越多的证据表明β细胞毒性。本综述从胰岛和肾移植的临床研究、雷帕霉素作为抗癌剂的临床研究以及实验研究中得出了雷帕霉素毒性的证据。总之，这些研究提供了雷帕霉素对β细胞功能和存活以及外周胰岛素抵抗具有显著不利影响的证据。雷帕霉素的作用机制是通过抑制哺乳动物雷帕霉素靶蛋白（mTOR）。本综述描述了复杂的mTOR信号通路，其控制重要的细胞功能，包括mRNA翻译，细胞增殖，细胞生长，分化，血管生成和凋亡，并检查β细胞中雷帕霉素毒性的分子机制。这些机制包括β细胞大小、质量、增殖和胰岛素分泌的减少以及细胞凋亡、自噬和外周胰岛素抵抗的增加。这些数据提出了问题，雷帕霉素作为免疫抑制剂在胰岛移植和作为二线药物在其他移植受者发展新的发病糖尿病移植后钙调磷酸酶抑制剂。它还强调了在服用雷帕霉素作为抗癌治疗的患者中密切监测血糖水平的重要性，特别是那些先前存在葡萄糖耐受不良的患者。
Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of β-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal transplantation, and of rapamycin as an anticancer agent, as well as from experimental studies. Together, these studies provide evidence that rapamycin has significant detrimental effects on β-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This Review describes the complex mTOR signaling pathways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in β-cells. These mechanisms include reductions in β-cell size, mass, proliferation and insulin secretion alongside increases in apoptosis, autophagy, and peripheral insulin resistance. These data bring into question the use of rapamycin as an immunosuppressant in islet transplantation and as a second-line agent in other transplant recipients developing new-onset diabetes after transplantation with calcineurin inhibitors. It also highlights the importance of close monitoring of blood glucose levels in patients taking rapamycin as an anticancer treatment, particularly those with preexisting glucose intolerance.
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