High serum selenium levels have been associated epidemiologically with increased incidence of type 2 diabetes. The Major fraction of total selenium in serum is represented by liver-derived selenoprotein P (SeP). This study Was undertaken to test for a hypothesized effect of hyperglycemia and the antihyperglycemic drug metformin on hepatic selenoprotein P biosynthesis. Cultivation of rat hepatocytes in the presence of high glucose concentrations (25 mmol/l) resulted in increased selenoprotein P mRNA expression and secretion. Treatment with metformin close-dependently down-regulated SeP? mRNA expression and secretion, and Suppressed glucocorticoid-stimulated production of SeP. Moreover, metformin strongly decreased mRNA levels of selenophosphate synthetase 2 (SPS-2), an enzyme essential for selenoprotein biosynthesis. Taken together, these results indicate an influence of metformin on selenium metabolism in hepatocytes. As selenoprotein P is the major transport form of selenium, metformin treatment may thereby diminish selenium supply to extrahepatic tissues. (C) 2009 Elsevier Inc. All rights reserved.