We investigated the mechanism of glucose intolerance in 51 patients with Cushing's syndrome. In an oral 100g glucose tolerance test, although prevalence of decreased glucose tolerance was very high as revealed in 36 of 47 patients (77%) studied, impairment was rather mild in the majority of patients and only 10 patients (21%) were judged as diabetic. Plasma insulin was measured in 12 patients and the mean values of these patients reached above normal levels after oral glucose load. When insulin secreting capacity was assessed by measuring the ratio of the incremental area of insulin above fasting level to the corresponding area of glucose during the test, Cushing's syndrome as a whole exhibited a normal ratio compared to 9 control subjects (113 +/- 115 vs. 144 +/- 78 microU/mg, M +/- SD, ns), but in 3 patients with severe impairment of glucose tolerance reaching the diabetic range, the ratio was lower than normal (27 +/- 20 vs. 144 +/- 78 microU/mg, M +/- SD, p less than 0.05). The hypoglycemic effect of iv insulin was studied in 23 patients and was demonstrated to have decreased. Thus, we confirmed the presence of decreased insulin sensitivity, i.e. insulin resistance in Cushing's syndrome. The age of patients showed positive correlation with the degree of impairment in glucose tolerance and insulin secreting capacity, but not with that of insulin sensitivity, that is, in patients with advanced age, glucose intolerance appeared to be severe with decreased insulin secreting capacity. 125I-insulin binding to red blood cells in 8 patients was examined to elucidate the mechanism of insulin resistance in Cushing's syndrome. Percent specific binding at tracer concentration of insulin in Cushing's syndrome was not different from the value obtained in 19 normal subjects (8.2 +/- 3.0 vs. 7.7 +/- 1.0%, M +/- SD, ns). Receptor concentration and affinity were also normal. From these observations, it is likely that glucose intolerance in Cushing's syndrome is primarily due to the effects of chronic glucocorticoid excess on tissue metabolism of glucose as characterized by the presence of insulin resistance, which is not due to a defect in insulin-receptor binding but rather caused by the alteration in post-receptor mechanism, and increased secretion of insulin can be considered as a compensatory mechanism. In some patients, however, a decrease in insulin secreting capacity, the cause of which is not clear but at least related to the patient's age, is found and seems to lead to severe glucose intolerance.