Antiaging gene Klotho enhances glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 in MIN6 β-cells

Endocrinology. 2012 Jul;153(7):3029-39. doi: 10.1210/en.2012-1091. Epub 2012 May 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging
  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism*
  • Cell Membrane / metabolism*
  • Cytosol / metabolism
  • Gene Expression Regulation*
  • Glucose / metabolism*
  • Glucuronidase / metabolism*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology*
  • Islets of Langerhans / cytology
  • Mice
  • RNA, Small Interfering / metabolism
  • TRPV Cation Channels / metabolism*
  • Up-Regulation

Substances

  • Calcium Channels
  • Insulin
  • RNA, Small Interfering
  • TRPV Cation Channels
  • Trpv2 protein, mouse
  • Glucuronidase
  • klotho protein
  • Glucose
  • Calcium