Klotho Enhances Glucose‐induced Insulin Secretion by Upregulating Plasma Membrane Retention of TRPV2

Abstract

BackgroundKlotho is a recently discovered anti‐aging gene. Our recent studies indicated that Klotho gene is expressed in mouse pancreatic islets and in an insulinoma cell line (MIN6 β cells) as evidenced by expression of Klotho mRNA and protein. The purpose of this study was to investigate if Klotho is involved in the regulation of insulin secretion in β cells.ResultsOverexpression of mouse Klotho protein significantly increased plasma membrane retention of TRPV2 (transient receptor potential V2), calcium entry, the glucose‐induced increase in intracellular calcium, and the glucose‐induced insulin secretion in MIN6 β cells. On the other hand, knockdown of Klotho by siRNA significantly decreased plasma membrane retention 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.ConclusionThe present study demonstrated, for the first time, that Klotho may increase glucose‐induced insulin secretion by up‐regulating membrane retention of TRVP2 and thus glucose‐induced calcium response. The findings reveal a previously unidentified role of Klotho in the regulation of insulin secretion in MIN6 β cells.