Iron is known to be a crucial regulator of glucose, and several studies have demonstrated that iron overload is one of the risk factors for insulin resistance and diabetes; however, the mechanism has not yet been clarified. To investigate the effect of iron overload on glucose metabolism and the underlying mechanism, Irp2 knockout (Irp2(-/-)) mice (endogenous iron overload model) were used. We found that Irp2(-/-) mice exhibited hyperglycemia and iron overload in the liver and skeletal muscle. Increased MDA, decreased SOD levels, and increased cell apoptosis were also found in the liver and muscle of Irp2(-/-) mice. Glucose concentrations were significantly higher in Irp2(-/-) mice in insulin tolerance tests. However, early-phase insulin secretion was not altered in Irp2(-/- )mice. The expression of hepatic IRS2 and muscle GLUT4 was declined in Irp2(-/-) mice at both mRNA and protein levels when compared with those of wild-type control. In conclusions, Irp2(-/-) mice showed hyperglycemia, which might due to insulin resistance rather than due to impaired insulin secretion. (C) 2019 Published by Elsevier Inc.