Growth hormone hypersecretion is a known cause of insulin resistance. This change in insulin sensitivity is believed to be mediated directly by growth hormone binding to its receptor. Five subjects ages 28-55 years who were participating in a clinical study that had been designed to assess the effects of a growth hormone receptor antagonist (Pegvisomant) on disease activity in acromegaly were evaluated to determine the role of growth hormone hypersecretion in inducing changes in insulin sensitivity. These subjects were treated with the 15-30 mg/day of Pegvisomant for periods ranging from 14 to 23 months. These doses were adequate to normalize IGF-I in four of the five subjects. The subjects were monitored to ensure that there were no significant changes in diet, exercise, or weight. Mean pretreatment IGF-I was 1104+/-277 ng/ml and decreased to a nadir of 355+/-157 ng/ml on treatment. After a 6-week withdrawal period, mean IGF-I had increased to 549+/-142 ng/ml. Fasting insulin was 35.2+/-16 uU/ml prior to treatment then decreased to a nadir of 19.9+/-14.6 uU/ml on treatment and then increased to 24.5+/-11.3 uU/ml. Fasting glucose decreased from 187+/-68 to 122+/-38 mg/dl and then increased to 159+/-41 mg/dl. Hemoglobin A(1)C decreased from 8.1+/-1.7 to 6.3+/-1.5%. Two subjects with overt type II diabetes had decreases in hemoglobin A(1)C from 8.3 to 5.9% and from 11.4 to 8.6%. These changes were associated with decreases in the amount of medication needed to control blood glucose. Weight remained stable throughout the study. The results show that the Pegvisomant is an effective agent for improving insulin resistance in subjects who have acromegaly and that this effect is independent of weight loss. The results suggest a potential role for Pevisomant in the treatment of insulin resistant states other than acromegaly.