Cyclosporine A and Tacrolimus Reduce the Amount of GLUT4 at the Cell Surface in Human Adipocytes: Increased Endocytosis as a Potential Mechanism for the Diabetogenic Effects of Immunosuppressive Agents
Cyclosporine A and Tacrolimus Reduce the Amount of GLUT4 at the Cell Surface in Human Adipocytes: Increased Endocytosis as a Potential Mechanism for the Diabetogenic Effects of Immunosuppressive Agents
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DOI：
10.1210/jc.2014-1266
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发表时间：
2014-10-01
影响因子：
5.8
通讯作者：
Eriksson, Jan W.
中科院分区：
文献类型：
--
作者：
Pereira, Maria J.;Palming, Jenny;Eriksson, Jan W.
内容：目的：研究环孢素A（CsA）和他克莫司（Tacrolimus）对人脂肪细胞葡萄糖摄取和胰岛素信号转导的影响，以及对葡萄糖转运蛋白4（GLUT 4）细胞转运的调节作用。将分离的人脂肪细胞与治疗浓度的CsA或他克莫司孵育，并评估葡萄糖摄取和胰岛素信号蛋白的表达。结果：CsA和他克莫司对分化的人前脂肪细胞和L 6细胞的基础和胰岛素刺激的C-14-葡萄糖摄取具有浓度依赖性的抑制作用。尽管他克莫司抑制了胰岛素受体Tyr 1146的磷酸化，但CsA或他克莫司未改变胰岛素信号蛋白IRS 1/2、p85-PI 3 K、PKB、AS 160和mTORC 1以及GLUT 4和GLUT 1的磷酸化和/或蛋白水平。此外，CsA和他克莫司降低了胰岛素存在下分化的人前脂肪细胞和L 6细胞的细胞表面定位的GLUT 4量。这是由GLUT 4内吞率的增加而发生的，在胞吐率中没有变化。结论：这些结果表明，治疗浓度的CsA和他克莫司可以通过增加内吞率从细胞表面去除GLUT 4来抑制独立于胰岛素信号的葡萄糖摄取。这种机制可能有助于胰岛素抵抗和与免疫抑制治疗相关的糖尿病的发展。此外，它可能为糖尿病的治疗提供新的药理学方法。
Context: Immunosuppressive agents are associated with profound metabolic side effects including new-onset diabetes and dyslipidemia after organ transplantation.Objective: To investigate the effects of cyclosporine A (CsA) and tacrolimus on glucose uptake and insulin signaling in human adipocytes and their impact on the regulation of cellular trafficking of the glucose transporter 4 (GLUT4).Design: Isolated human adipocytes were incubated with therapeutic concentrations of either CsA or tacrolimus, and glucose uptake and expression of insulin signaling proteins were assessed. Furthermore, we studied effects of CsA and tacrolimus on the regulation of cellular trafficking of GLUT4 in differentiated human preadipocytes and L6 cells.Results: CsA and tacrolimus had a concentration-dependent inhibitory effect on basal and insulin-stimulated C-14-glucose uptake in adipocytes. Although phosphorylation at Tyr1146 of the insulin receptor was inhibited by tacrolimus, the phosphorylation and/or protein levels of the insulin signaling proteins IRS1/2, p85-PI3K, PKB, AS160, and mTORC1, as well as GLUT4 and GLUT1, were unchanged by CsA or tacrolimus. Furthermore, CsA and tacrolimus reduced the GLUT4 amount localized at the cell surface of differentiated human preadipocytes and L6 cells in the presence of insulin. This occurred by an increased rate of GLUT4 endocytosis, with no change in the exocytosis rate.Conclusions: These results suggest that therapeutic concentrations of CsA and tacrolimus can inhibit glucose uptake independent of insulin signaling by removing GLUT4 from the cell surface via an increased rate of endocytosis. This mechanism can contribute to the development of insulin resistance and diabetes associated with immunosuppressive therapy. In addition, it may provide novel pharmacological approaches for the treatment of diabetes.