According to previous studies the glucocorticoid dexamethasone upregulates the activity of voltage-gated K+ channels in insulin secreting cells with subsequent acceleration of repolarisation, decrease of Ca2+ entry through voltage-gated Ca2+ channels and blunting of insulin release. Stimulation of the Na+ /K+ -ATPase may similarly hyperpolarize the cell and may thus contribute to the inhibition of Ca2+ entry. The present study explored whether glucocorticoids increase the Na+ /K+ -ATPase activity in insulin secreting cells. Dexamethasone (100 nmol/l for 1 d) indeed significantly increased Na+/K+ -ATPase a1/b1-subunit transcript levels and ouabain-sensitive ATP-dependent outward current reflecting Na+ /K+ -ATPase activity in INS-1 cells, effects blunted by glucocorticoid-receptor blocker RU487 (1 mmol/l). Thus, glucocorticoids increase the Na+ /K+ -ATPase activity of INS-1 cells through the stimulation of expression, an effect mediated by glucocorticoid receptors. Moreover, dexamethasone (100 nmol/l) significantly increased the outward current in ß-cells from wild type mice but not in ß-cells from gene targeted mice lacking functional serum and glucocorticoid inducible kinase SGK1. Similarly, the inhibition of insulin release by dexamethasone was significantly blunted in islets from SGK1 deficient mice. The present observations thus reveal that glucocorticoids increase Na+ /K+ -ATPase activity in insulin secreting cells, an effect requiring SGK1.