Growth hormone (GH) can oppose the catabolic effects of glucocorticoids. However, both hormones have adverse effects on carbohydrate metabolism. Here we examined the interactive effects of GH and the glucocorticoid methylprednisolone (MP) on glucose tolerance, insulin resistance and [3H]2,6-deoxyglucose uptake of peripheral tissues in rats. Female Wistar rats received either saline, GH (2.7 mg/kg), MP (5.0 mg/kg) or GH+MP. After 7 days treatment, animals were subjected to an i.v. glucose tolerance test. In a second experiment, animals treated as above were anesthetized and injected with human insulin (0.5 U/kg), [3H]2,6-deoxyglucose (500 microCi/kg), and [14C]mannitol (25 microCi/kg), to estimate insulin resistance and [3H]2,6-deoxyglucose uptake in fat and muscle. Weight gain in controls was 7.6+/-1.7 g, while GH treatment increased the mean body weight by 18.7+/-2.2 g (P<0.0002) and MP inhibited weight gain down to 0.0+/-1.0 g (P<0.004). This drop in weight gain was reversed back to normal when GH was given in combination with MP. After a glucose tolerance test no significant differences in glucose area under the curve were detected when comparing individual groups with the control group, but samples taken just before this test revealed that basal insulin was significantly elevated in the group treated with GH (174+/-27 pM, P<0.008), or GH+MP (209+/-21 pM, P<0.004), when compared with controls (107+/-17 pM). MP alone had no effect (122+/-19, P<0.3). After an i.v. bolus of insulin the group receiving GH+MP had a significantly (P<0.007) higher level of circulating glucose compared with controls (6.5+/-0.3 mM vs 4.4+/-0.7 mM). Despite this, there were no differences in peripheral glucose uptake between the two groups. In conclusion this study shows that a combined administration of GH and MP decreases the potency by which insulin decreases circulating glucose levels, but that peripheral tissues are not primarily involved in this insulin resistance.