Antiaging Gene Klotho Enhances Glucose-Induced Insulin Secretion by Up-Regulating Plasma Membrane Levels of TRPV2 in MIN6 β-Cells
Antiaging Gene Klotho Enhances Glucose-Induced Insulin Secretion by Up-Regulating Plasma Membrane Levels of TRPV2 in MIN6 β-Cells
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DOI：
10.1210/en.2012-1091
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发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
Sun, Zhongjie
中科院分区：
文献类型：
--
作者：
Lin, Yi;Sun, Zhongjie
Klotho是最近发现的一种抗衰老基因。 Klotho 在小鼠胰岛和胰岛素瘤 β 细胞（MIN6 β 细胞）中表达。本研究的目的是探讨 Klotho 是否通过 Klotho 的过度表达和沉默在 MIN6 β 细胞的胰岛素分泌调节中发挥作用。有趣的是，Klotho 的过度表达增加了 MIN6 β 细胞中葡萄糖诱导的胰岛素分泌。小鼠 Klotho 蛋白的过度表达还显着增加了瞬时受体电位 V2 (TRPV2) 的质膜水平、钙进入和葡萄糖诱导的细胞内钙增加。另一方面，通过 siRNA 敲低 Klotho 显着降低 TRPV2 的质膜水平，并减弱葡萄糖诱导的钙进入和胰岛素分泌。 Tranilast 是 TRPV2 的选择性抑制剂，消除了 Klotho 过度表达对 MIN6 细胞中葡萄糖诱导的钙进入和胰岛素分泌的促进作用。因此，TRPV2 位于 Klotho 的下游，调节葡萄糖诱导的胰岛素分泌。这项研究首次证明，Klotho 可以通过上调 TRPV2 质膜水平从而增强葡萄糖诱导的钙反应，从而增强葡萄糖诱导的胰岛素分泌。这些发现揭示了 Klotho 在调节 MIN6 β 细胞中葡萄糖诱导的胰岛素分泌中的先前未知的作用。 （内分泌学153：3029-3039，2012）
Klotho is a recently discovered antiaging gene. Klotho is expressed in mouse pancreatic islets and in insulinoma beta-cells (MIN6 beta-cells). The purpose of this study was to investigate whether Klotho plays a role in the regulation of insulin secretion in MIN6 beta-cells by overexpression and silencing of Klotho. It is interesting that overexpression of Klotho increased glucose-induced insulin secretion in MIN6 beta-cells. Overexpression of mouse Klotho protein also significantly increased plasma membrane levels of transient receptor potential V2 (TRPV2), calcium entry, and the glucose-induced increase in intracellular calcium. On the other hand, knockdown of Klotho by siRNA significantly decreased plasmamembranelevels of TRPV2 and attenuated glucose-induced calcium entry and insulin secretion. Tranilast, a selective inhibitor of TRPV2, abolished the promoting effects of overexpression of Klotho on glucose-induced calcium entry and insulin secretion in MIN6 cells. Thus, TRPV2 lies in the downstream of Klotho in the regulation of glucose-induced insulin secretion. This study demonstrated, for the first time, that Klotho may enhance glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 and thus glucose-induced calcium responses. These findings reveal a previously unidentified role of Klotho in the regulation of glucose-induced insulin secretion in MIN6 beta-cells. (Endocrinology 153: 3029-3039, 2012)