The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic ?-cells via Sirt1- and Pgc-1?-mediated regulation of Glut2.

ABSTRACT: Zinc levels are high in pancreatic ?-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic ?-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly down-regulated in pancreatic ?-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, ?-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1? and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1? and Ppar-?. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1? activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.

SUBMITTER: Wang X 

PROVIDER: S-EPMC6538592 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature