Acute impairment of insulin signalling by dexamethasone in primary cultured rat skeletal myocytes

In this study, we examined the cellular content of the insulin receptor substrate (IRS)-1, the levels of phosphorylated tyrosine (pY) and serine (pS) residues in IRS-1, and the glucose transporters GLUT-1 and GLUT-4 in primary cultured rat skeletal myocytes treated with the glucocorticoid, dexamethasone. Dexamethasone markedly increased basal and insulin-stimulated IRS-1 content 4 to 5-fold (p < 0.01). A similar level of increase was observed for IRS-1 pY content. However, dexamethasone treatment had no effect on IRS-1 pS content. Further, dexamethasone reduced the cellular content of GLUT-1 when insulin and glucose were absent (p < 0.05), but did not significantly affect the expression of GLUT-4 in the presence of insulin (p > 0.05). We conclude that dexamethasone treatment impairs insulin signalling by a mechanism independent of serine-phosphorylation-mediated IRS-1 depletion, or of impairment of GLUT-1 expression. Instead, dexamethasone-induced insulin resistance may be mediated via reduced cellular content of IRS-1 accompanied by parallel reduction in tyrosine phosphorylation in IRS-1.