Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, 940 S. L. Young Boulevard, Oklahoma City, Oklahoma 73126-0901, USA.
Endocrinology. 2012 Jul;153(7):3029-39. doi: 10.1210/en.2012-1091. Epub 2012 May 17.
Klotho is a recently discovered antiaging gene. Klotho is expressed in mouse pancreatic islets and in insulinoma β-cells (MIN6 β-cells). The purpose of this study was to investigate whether Klotho plays a role in the regulation of insulin secretion in MIN6 β-cells by overexpression and silencing of Klotho. It is interesting that overexpression of Klotho increased glucose-induced insulin secretion in MIN6 β-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 plasma membrane levels 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 β-cells.
Klotho 是一种新发现的抗衰老基因。Klotho 在小鼠胰岛和胰岛素瘤β细胞（MIN6 β 细胞）中表达。本研究旨在通过 Klotho 的过表达和沉默来研究 Klotho 是否在 MIN6 β 细胞胰岛素分泌的调节中起作用。有趣的是，Klotho 的过表达增加了 MIN6 β 细胞中葡萄糖诱导的胰岛素分泌。过表达小鼠 Klotho 蛋白还显著增加了瞬时受体电位 V2（TRPV2）、钙内流和葡萄糖诱导的细胞内钙增加的质膜水平。另一方面，siRNA 敲低 Klotho 显著降低了 TRPV2 的质膜水平，并减弱了葡萄糖诱导的钙内流和胰岛素分泌。TRPV2 的选择性抑制剂曲尼司特（tranilast）消除了 Klotho 过表达对 MIN6 细胞中葡萄糖诱导的钙内流和胰岛素分泌的促进作用。因此，TRPV2 在 Klotho 调节葡萄糖诱导的胰岛素分泌的下游。本研究首次表明，Klotho 可能通过上调 TRPV2 的质膜水平，从而增强葡萄糖诱导的胰岛素分泌，从而增强葡萄糖诱导的钙反应。这些发现揭示了 Klotho 在 MIN6 β 细胞葡萄糖诱导的胰岛素分泌调节中的一个以前未被识别的作用。
