SGK1 dependence of insulin induced hypokalemia.
Insulin stimulates cellular K+ uptake leading to hypokalemia. Cellular K+ uptake is accomplished by parallel stimulation of Na+/H+ exchange, Na+,K+,2Cl- co-transport, and Na+/K+ ATPase and leads to cell swelling, a prerequisite for several metabolic effects of the hormone. Little is known about underlying signaling. Insulin is known to activate the serum and glucocorticoid-inducible kinase SGK1, which in turn enhances the activity of all three transport proteins. The present study thus explored the contribution of SGK1 to insulin-induced hypokalemia. To this end, gene-targeted mice lacking SGK1 (sgk1-/-) and their wild-type littermates (sgk1+/+) have been infused with insulin (2 mU kg(-1) min(-1)) and glucose at rates leaving the plasma glucose concentration constant. Moreover, isolated liver perfusion experiments have been performed to determine stimulation of cellular K+ uptake by insulin (100 nM). As a result, combined glucose and insulin infusion significantly decreased plasma K+ concentration despite a significant decrease of urinary K+ excretion in sgk1+/+ but not in sgk1-/- mice. Accordingly, the plasma K+ concentration was within 60 min significantly lower in sgk1+/+ than in sgk1-/- mice. In isolated liver perfusion experiments, cellular K+ uptake was stimulated by insulin (100 nM), an effect blunted by 72% in sgk1-/- mice as compared to sgk1+/+ mice. Accordingly, insulin-induced cell hydration was 63% lower in sgk1-/- mice than in sgk1+/+ mice. Moreover, volume regulatory K+ release was 31% smaller in sgk1-/- mice than in sgk1+/+ mice. In conclusion, the serum and glucocorticoid-inducible kinase SGK1 participates in the signaling mediating the hypokalemic effect of insulin.
Boini
Krishna M
KM
Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
Graf
Dirk
D
Kuhl
Dietmar
D
Häussinger
Dieter
D
Lang
Florian
F
D000818:Animals; D005260:Female; D007008:Hypokalemia / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011188:Potassium / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D007328:Insulin; D011188:Potassium; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases