Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction

Glucocorticoids reportedly induce insulin resistance. In this study, we inv estigated the mechanism of glucocorticoid-induced insulin resistance using 3T3-L1 adipocytes in which treatment with dexamethasone has been shown to i mpair the insulin-induced increase in glucose uptake. In 3T3-L1 adipocytes treated with dexamethasone, the GLUT1 protein expression level was decrease d by 30%, which possibly caused decreased basal glucose uptake. On the othe r hand, dexamethasone treatment did not alter the amount of GLUT4 protein i n total cell lysates but decreased the insulin-stimulated GLUT4 translocati on to the plasma membrane, which possibly caused decreased insulin-stimulat ed glucose uptake. Dexamethasone did not alter tyrosine phosphorylation of insulin receptors, and it significantly decreased protein expression and ty rosine phosphorylation of insulin receptor substrate (IRS)-1. Interestingly , however, protein expression and tyrosine phosphorylation of IRS-2 were in creased. To investigate whether the reduced IRS-1 content is involved in in sulin resistance, IRS-1 was overexpressed in dexamethasone-treated 3T3-L1 a dipocytes using an adenovirus transfection system. Despite protein expressi on and phosphorylation levels of IRS-1 being normalized insulin-induced 2-d eoxy-D-[H-3]glucose uptake impaired by dexamethasone showed no significant improvement. Subsequently, we examined the effect of dexamethasone on the g lucose uptake increase induced by overexpression of GLUT2-tagged p110 alpha , constitutively active Akt (myristoylated Akt), oxidative stress (30 mU gl ucose oxidase for 2 h), 2 mmol/l 5 -aminoimidazole-4-carboxamide ribonucleo side for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). Dexame thasone treatment clearly inhibited the increases in glucose uptake produce d by these agents. Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone- induced insulin resistance in glucose t ransport activity (rather than the inhibition of phosphatidylinositol 3-kin ase activation resulting from a, decreased IRS-l content) is likely to unde rlie impaired glucose transporter regulation.