Treatment with glucocorticoids is associated with a disproportionate elevation in the PI/IRI ratio. To determine whether growth hormone--another agent capable of producing insulin resistance and changing B-cell function--also alters the PI/IRI ratio and whether growth hormone and glucocorticoids have a synergistic effect on PI and IRI levels, we examined these variables in four groups of young healthy subjects (n = 8/group) after 7 days of treatment with placebo, prednisone (0.8 mg.kg-1 x day-1), rhGH (0.1 mg.kg-1 x day-1), and the combination of prednisone and rhGH. Fasting plasma glucose levels increased significantly above those of the control group in subjects receiving prednisone or prednisone and rhGH but not in subjects receiving rhGH alone. The basal concentration of IRI increased in response to prednisone, rhGH, and the combination of prednisone and rhGH. However, this increase in IRI was largely due to an increase in PI, so that the PI/IRI ratio increased from 14.7 +/- 2.4% in control subjects to 33.9 +/- 5.3% in subjects on prednisone (P < 0.005), 40.9 +/- 4.3% in individuals receiving rhGH (P < 0.001 vs. control subjects), and 58.1 +/- 9.2% in subjects receiving both prednisone and rhGH (P < 0.001 vs. control subjects). We suggest that this change in PI/IRI with glucocorticoid and growth hormone treatment may be due to an alteration in B-cell synthesis or release of PI. This change in the PI/IRI ratio is not dependent on fasting hyperglycemia but may contribute to the hyperglycemia often observed with these agents. Furthermore, these data show that IRI is not a reliable indicator of true insulin levels or insulin sensitivity in either growth hormone- or glucocorticoid-treated subjects.