Increased incidence of heart disease is reported in patients with diabetes. To elucidate a molecular profile of expressed genes during the progression of diabetes, a cDNA array was screened in the hearts of mice treated with streptozotocin (200 mg/kg, i.v.). Among the genes investigated, the plasma type glutathione peroxidase, GPX-3, was predominantly up-regulated in diabetic mice compared with control mice. In northern blot analysis, a significant increase in GPX-3 expression was observed as early as 5 d after the induction of hyperglycemia. On day 21, a nearly three-fold induction was demonstrated. Daily administration of insulin (0.2 U/d, s.c.) for 21 d almost completely abolished the increase in GPX-3 mRNA in streptozotocin-treated mice, suggesting that the expression level of the GPX-3 gene was dependent on insulin and serum glucose. Increased GPX-3 may play a significant role in protecting cardiomyocytes from oxidative stress caused by hyperglycemia.