Excess salt intake decreases peripheral glucose uptake thus impairing glucose tolerance. Stimulation of cellular glucose uptake involves PI-3K kinase dependent activation of protein kinase B (PKB/Akt). A further kinase downstream of PI-3K is the serum and glucocorticoid inducible kinase SGK1, which is upregulated by mineralocorticoids and thus downregulated by salt intake. To explore the role of SGK1 in salt dependent glucose uptake SGK1 knockout mice (sgk1-/-) and their wild type littermates (sgk1+/+) were allowed free access to either tap water (control) or 1% saline (high-salt). Intraperitoneal injection of glucose (3g/kg/b.w) into sgk1+/+ transiently increased plasma glucose concentration to values ([glc]max) significantly higher in saline drinking (281±39mg/dl) than in control sgk1+/+ (164±23mg/dl). DOCA (35mg/kg/b.w) did not significantly modify [glc]max in control sgk1+/+ but significantly decreased [glc]max in high-salt sgk1+/+, an effect reversed by spironolactone (50mg/kg/b.w). [glc]max was in sgk1-/-significantly higher than in control sgk1+/+ but could not be increased further by high-salt. Uptake of 3H-deoxy-glucose into skeletal muscle and fat tissue was significantly smaller in sgk1-/-than in sgk1+/+ and decreased by high-salt in sgk1+/+. In conclusion, high salt decreases SGK1 dependent cellular glucose uptake.