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

¹ Department of Physiology, University of Tübingen, Tübingen, Germany
² Department of Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany
³ Department of Internal Medicine 4, University of Tübingen, Tübingen, Germany
⁴ Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg, Germany
⁵ Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Berlin, Germany
⁶ Departments of Medicine and Pharmacology, University of California San Diego and Veterans’ Administration San Diego Health Care System, San Diego, California

Address correspondence and reprint requests to Florian Lang, Department of Physiology, University of Tübingen, Gmelinstr 5, D-72076 Tübingen, Germany. E-mail: florian.lang{at}uni-tuebingen.de

Abbreviations: 2-DOG, 2-deoxy-D-[1,2-³H]glucose; DOCA, deoxycorticosterone acetate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PI-3K, phosphatidylinositide-3-kinase; PKB, protein kinase B; SGK, serum- and glucocorticoid-inducible kinase

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.

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