The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on beta-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment with biosynthetic GH 2 IU/m2s.c. daily (n =13) or placebo (n =11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study period, body weight decreased 1.6 kg from 94.0 +/- 18.7 to 92.4 +/- 19.4 kg (mean +/- SD) (P<0.05) in the GH-treated group, but remained unchanged in the placebo group. Fat mass decreased from 32.4 +/- 9.6 to 28.1 +/- 10.5 kg (P<0.001), whereas lean body mass increased from 58.3 +/- 11.5 to 61.0 +/- 11.7 kg (P<0.01) in the GH-treated group. Treatment with GH for 4 months resulted in a significant increase in fasting blood glucose (before GH 5.0 +/- 0.3 and after 5.4 +/- 0.6 mmol/l, P<0.05), fasting plasma insulin (before GH 38.4 +/- 30.2 and after 55.3 +/- 34.7 pmol/l, P<0.02) and fasting proinsulin (before 8. 1 +/- 6.7 and after 14.6 +/- 16.1 pmol/l, P<0.05). The insulin sensitivity index SI, estimated by Bergmans Minimal Model, decreased significantly [before GH 1.1 +/- 0.7 and after 0.4 +/- 0.2 10(-4)(min x pmol/l), P<0.003]. The non-insulin-dependent glucose uptake (glucose effectiveness SG did not change (before GH 0.017 +/- 0.005 and after 0.015 +/- 0.006 min-1, NS). Insulin secretion was enhanced during GH therapy, but insufficiently to match the changes in SI, resulting in a higher blood glucose level during an OGTT. Blood glucose at 120 min was 5.5 and 6.3 mmol/l before and after GH treatment, respectively (P = 0.07). One patient developed impaired glucose tolerance. Short-term GH replacement therapy in a dose of about 2 IU/m2 daily in GHD adults induces a reduction in insulin sensitivity, despite favourable changes in body composition, and an inadequate enhancement of insulin secretion.