Zinc levels are high in pancreatic β-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 β-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 downregulated in pancreatic β-cells in diabetic dbldb mice,obese oblob mice and high-fat diet-fed mice.Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion.In addition,SIc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2.The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1,Pgc-1α and Ppar-Y.At the mechanistic level,we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation.These findings suggest that Sic39a5 may serve as a possible therapeutic target for diabetes-related conditions.