Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor.
OBJECTIVE
Treatment with glucocorticoids, especially at high doses, induces insulin resistance. The aims of the present study were to identify the potential defects in insulin signalling that contribute to dexamethasone-induced insulin resistance in skeletal muscles, and to investigate whether the glycogen synthase-3 (GSK-3) inhibitor CHIR-637 could restore insulin-stimulated glucose metabolism.


METHODS
Skeletal muscles were made insulin-resistant by treating male Wistar rats with dexamethasone, a glucocorticoid analogue, for 12 days. Insulin-stimulated glucose uptake, glycogen synthesis and insulin signalling were studied in skeletal muscles in vitro.


RESULTS
Dexamethasone treatment decreased the ability of insulin to stimulate glucose uptake, glycogen synthesis and glycogen synthase fractional activity. In addition, the dephosphorylation of glycogen synthase by insulin was blocked. These defects were paralleled by reduced insulin-stimulated protein kinase B (PKB) and GSK-3 phosphorylation. While expression of PKB, GSK-3 and glycogen synthase was not reduced by dexamethasone treatment, expression of the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase) was increased. Inhibition of GSK-3 by CHIR-637 increased glycogen synthase fractional activity in soleus muscle from normal and dexamethasone-treated rats, although the effect was more pronounced in control rats. CHIR-637 did not improve insulin-stimulated glucose uptake in muscles from dexamethasone-treated rats.


CONCLUSIONS
We demonstrated that chronic dexamethasone treatment impairs insulin-stimulated PKB and GSK-3 phosphorylation, which may contribute to insulin resistance in skeletal muscles. Acute pharmacological inhibition of GSK-3 activated glycogen synthase in muscles from dexamethasone-treated rats, but GSK-3 inhibition did not restore insulin-stimulated glucose uptake.
Ruzzin
J
J
Department of Physiology, National Institute of Occupational Health, P.O. Box 8149 Dep., 0033 Oslo, Norway.
Wagman
A S
AS
Jensen
J
J
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
D000906:Antibodies; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007328:Insulin; D006003:Glycogen; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose