Impairment of glucose tolerance and muscle wasting indicating a disorder of glucose metabolism are characteristic features of Cushing's syndrome. We have examined glucose and amino acid metabolism in eleven patients with pituitary dependent Cushing's disease in comparison to nine healthy controls. Furthermore, the therapeutic effect of selective pituitary microsurgery was studied by repeated stable isotope measurements of hepatic glucose production and leucine turnover rates. Eight patients remitted after surgery and 3 had persistent disease. All patients were investigated prior to surgery and again 1 week and 3 months after the operation with (6,6-2H2)-glucose and (5,5,5-2H3)-leucine by means of a primed (4 mg/kg.min and 0.27 mg/kg.min), continuous (0.05 mg/kg.min and 0.005 mg/kg.min) infusion. In Cushing's disease, both the preoperatively elevated mean glucose production rate (2.34 +/- 0.63 mg/kg.min) and the reduced mean leucine turnover (0.213 +/- 0.025 mg/kg.min) were found to be linked with hepatic insulin resistance and an insulin-induced reduction in protein breakdown combined with a reduced protein synthesis. Mean glucose production and leucine flux both normalized after surgery in the remitting patients (2.18 +/- 0.15 mg/kg.min and 0.244 +/- 0.047 mg/kg.min 3 months after the operation). The metabolic disorders thus were reversible following successful correction of hormonal oversecretion by transsphenoidal surgery.