This study investigates the effect of the antidiabetic drug metformin on dexamethasone-induced hyperglycaemia and insulin resistance in mice. Normal mice were treated with dexamethasone (2.5 mg/kg/day p.o.) plus metformin (250 mg/kg/day p.o.) and pair-fed to those receiving dexamethasone alone. Metformin reduced the extent of dexamethasone-induced hyperglycaemia and decreased insulin resistance as indicated by an improved insulin-hypoglycaemia test. Metformin-treated mice also showed increased basal glucose uptake into isolated diaphragm (by 38%), soleus (by 19%) and deep (red) quadriceps (by 31%). Measurements in the quadriceps showed that the increase in glucose uptake occurred without increasing either the mRNA levels or total cellular membrane abundance of the GLUT1 or GLUT4 glucose transporter isoforms. Thus metformin can ameliorate dexamethasone-induced hyperglycaemia and insulin resistance in part by increasing glucose disposal into skeletal muscle. Since this was achieved in quadriceps muscle without increasing mRNA or total membrane abundance of GLUT1 or GLUT4, it is possible that metformin might influence the intrinsic activity of glucose transporters, as well as altering their intracellular translocation.