Dexamethasone treatment causes resistance to insulin-stimulated cellular potassium uptake in the rat.
Patients treated with glucocorticoids have elevated skeletal muscle ouabain binding sites. The major Na(+)-K(+)-ATPase (NKA) isoform proteins found in muscle, alpha2 and beta1, are increased by 50% in rats treated for 14 days with the synthetic glucocorticoid dexamethasone (DEX). This study addressed whether the DEX-induced increase in the muscle NKA pool leads to increased insulin-stimulated cellular K+ uptake that could precipitate hypokalemia. Rats were treated with DEX or vehicle via osmotic minipumps at one of two doses: 0.02 mg.kg(-1).day(-1) for 14 days (low DEX; n = 5 pairs) or 0.1 mg.kg(-1).day(-1) for 7 days (high DEX; n = 6 pairs). Insulin was infused at a rate of 5 mU.kg(-1).min(-1) over 2.5 h in conscious rats. Insulin-stimulated cellular K+ and glucose uptake rates were assessed in vivo by measuring the exogenous K+ infusion (K+(inf)) and glucose infusion (Ginf) rates needed to maintain constant plasma K+ and glucose concentrations during insulin infusion. DEX at both doses decreased insulin-stimulated glucose uptake as previously reported. Ginf (in mmol.kg(-1).h(-1)) was 10.2 +/- 0.6 in vehicle-treated rats, 5.8 +/- 0.8 in low-DEX-treated rats, and 5.2 +/- 0.6 in high-DEX-treated rats. High DEX treatment also reduced insulin-stimulated K+) uptake. K+(inf) (in mmol.kg(-1).h(-1)) was 0.53 +/- 0.08 in vehicle-treated rats, 0.49 +/- 0.14 in low-DEX-treated rats, and 0.27 +/- 0.08 in high-DEX-treated rats. DEX treatment did not alter urinary K+ excretion. NKA alpha2-isoform levels in the low-DEX-treated group, measured by immunoblotting, were unchanged, but they increased by 38 +/- 15% (soleus) and by 67 +/- 3% (gastrocnemius) in the high-DEX treatment group. The NKA alpha1-isoform level was unchanged. These results provide novel evidence for the insulin resistance of K+ clearance during chronic DEX treatment. Insulin-stimulated cellular K+ uptake was significantly depressed despite increased muscle sodium pump pool size.
Rhee
Michael S
MS
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9142, USA.
Perianayagam
Anjana
A
Chen
Pei
P
Youn
Jang H
JH
McDonough
Alicia A
AA
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D007527:Isoenzymes; D003907:Dexamethasone; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D011188:Potassium