Serum- and glucocorticoid-inducible kinase 1 mediates salt sensitivity of glucose tolerance.
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-(3)H]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 (S422D)SGK1, but not inactive (K127N)SGK, 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.
Boini
Krishna M
KM
Department of Physiology, University of Tübingen, Gmelinstr 5, D-72076 Tübingen, Germany.
Hennige
Anita M
AM
Huang
Dan Yang
DY
Friedrich
Björn
B
Palmada
Monica
M
Boehmer
Christoph
C
Grahammer
Florian
F
Artunc
Ferruh
F
Ullrich
Susanne
S
Avram
Diana
D
Osswald
Hartmut
H
Wulff
Peer
P
Kuhl
Dietmar
D
Vallon
Volker
V
Häring
Hans-Ulrich
HU
Lang
Florian
F
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000494:pharmacology; D005260:Female; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D013148:Spironolactone / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
D001786:Blood Glucose; D003900:Desoxycorticosterone; D017874:Immediate-Early Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D013148:Spironolactone; D000099184:Serum-Glucocorticoid Regulated Kinases