Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells.
Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells.
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DOI：
10.1038/s41598-017-15283-y
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发表时间：
2017-11-20
影响因子：
4.6
通讯作者：
Santulli G
中科院分区：
文献类型：
--
作者：
Lombardi A;Gambardella J;Du XL;Sorriento D;Mauro M;Iaccarino G;Trimarco B;Santulli G
西罗莫司（雷帕霉素）是一种用于移植的免疫抑制药物。其主要副作用之一是增加糖尿病的风险;然而，这种关联的确切机制尚未阐明。在这里，我们发现西罗莫司以剂量和时间依赖性方式损害人和小鼠胰岛以及克隆β细胞中葡萄糖刺激的胰岛素分泌。重要的是，我们证明西罗莫司显著消耗内质网中的钙（Ca 2+）含量，并显著降低葡萄糖刺激的线粒体Ca 2+摄取。至关重要的是，线粒体Ca 2+摄取的减少反映在线粒体呼吸的显著损伤上。综上所述，我们的研究结果表明，西罗莫司导致细胞内Ca 2+储存耗尽，改变线粒体适应性，最终导致胰岛素释放减少。我们的研究结果提供了一个新的分子机制，潜在的糖尿病发病率增加的患者用这种药物治疗。
Sirolimus (rapamycin) is an immunosuppressive drug used in transplantation. One of its major side effects is the increased risk of diabetes mellitus; however, the exact mechanisms underlying such association have not been elucidated. Here we show that sirolimus impairs glucose-stimulated insulin secretion both in human and murine pancreatic islets and in clonal β cells in a dose- and time-dependent manner. Importantly, we demonstrate that sirolimus markedly depletes calcium (Ca2+) content in the endoplasmic reticulum and significantly decreases glucose-stimulated mitochondrial Ca2+ uptake. Crucially, the reduced mitochondrial Ca2+ uptake is mirrored by a significant impairment in mitochondrial respiration. Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca2+ stores and alters mitochondrial fitness, eventually leading to decreased insulin release. Our results provide a novel molecular mechanism underlying the increased incidence of diabetes mellitus in patients treated with this drug.
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影响因子：
3.5
作者：
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通讯作者：
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作者：
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通讯作者：
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