The criteria for biochemical control of acromegaly that will best reduce disease-related morbidity in acromegaly are debated. We therefore studied the relationship of biochemical markers with an important metabolic parameter, insulin sensitivity, and clinical parameters reflecting disease activity in acromegaly. Newly diagnosed and postoperative patients with acromegaly underwent assessment of fasting IGF-I and fasting and postoral glucose tolerance test GH and insulin levels and completed a numeric signs and symptoms questionnaire. Insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and the composite insulin sensitivity index. Patients were divided into three groups: group I, normal IGF-I and nadir GH less than 0.14 mug/liter (n = 21); group II, normal IGF-I and nadir GH 0.14 mug/liter or more (n = 20); group III (active), elevated IGF-I (n = 25). Age, sex, and body mass index were comparable in these groups. Insulin sensitivity was reduced in group III (QUICKI: 0.33 +/- 0.01 and composite index: 3.44 +/- 0.54), compared with group II (0.38 +/- 0.01, P = 0.002 and 8.18 +/- 1.21, P = 0.0008), group I (0.38 +/- 0.01, P = 0.0008 and 8.91 +/- 1.34, P = 0.00001), and healthy controls (0.37 +/- 0.008, P = 0.009). When other nadir GH cut-offs were analyzed, insulin sensitivity remained relatively reduced in the elevated IGF-I group. IGF-I was a significant predictor for decreasing insulin sensitivity as calculated by QUICKI (r = 0.6, P < 0.0001) independently of nadir GH. Signs and symptom scores were higher in group III (mean 38.5 +/- 3.6%), compared with group II (mean 23.5 +/- 3.2%, P = 0.004) and group I (mean 20.5 +/- 3.7%, P = 0.0008) but not between the latter two groups. Our data indicate that overall and specifically in the presence of discordant serum IGF-I and nadir GH levels, IGF-I was more predictive than GH levels of insulin sensitivity and clinical symptom score in patients with acromegaly.