Serum- and Glucocorticoid-Inducible Kinase 1 Mediates Salt Sensitivity of Glucose Tolerance

Abstract

Excess salt intake decreases peripheral glucose uptake, thus impairing glucose tolerance. Stimulation of cellular glucose uptake involves phosphatidylinositide-3-kinase (PI-3K)–dependent activation of protein kinase B/Akt. A further kinase downstream of PI-3K is serum- and glucocorticoid-inducible kinase (SGK)1, 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). According to Western blotting, high salt decreased and deoxycorticosterone acetate (DOCA; 35 mg/kg body wt) increased SGK1 protein abundance in skeletal muscle and fat tissue of sgk1^+/+ mice. Intraperitoneal injection of glucose (3 g/kg body wt) into sgk1^+/+ mice transiently increased plasma glucose concentration approaching significantly higher values ([glucose]p,max) in high salt (281 ± 39 mg/dl) than in control (164 ± 23 mg/dl) animals. DOCA did not significantly modify [glucose]p,max in control sgk1^+/+ mice but significantly decreased [glucose]p,max in high-salt sgk1^+/+ mice, an effect reversed by spironolactone (50 mg/kg body wt). [Glucose]p,max was in sgk1^−/− mice insensitive to high salt and significantly higher than in control sgk1^+/+ mice. Uptake of 2-deoxy-d-[1,2-³H]glucose into skeletal muscle and fat tissue was significantly smaller in sgk1^−/− mice than in sgk1^+/+ mice and decreased by high salt in sgk1^+/+ mice. Transfection of HEK-293 cells with active ^S422DSGK1, but not inactive ^K127NSGK, stimulated phloretin-sensitive glucose uptake. In conclusion, high salt decreases SGK1-dependent cellular glucose uptake. SGK1 thus participates in the link between salt intake and glucose tolerance.