The relationship between altered glucose-insulin interaction in the hyperglycemic period of oral glucose tolerance test (oGTT) and impaired posthyperglycemic glucose homeostasis was studied in 9 obese females. They underwent 6-hour oGTT following 72-96 hour total fast, and the results of blood glucose, insulin, growth hormone, cortisol, glucagon and free fatty acids were compared to those of the control test. Blood glucose values in the hyperglycemic period of oGTT were higher during the post-fasting than in the control study. Posthyperglycemic glucose levels following fast dropped below the control values and four patients showed subjective symptoms of reactive hypoglycemia. Mean maximum blood glucose irrespective of time was significantly higher, mean glucose nadir lower after fast than in the control experiment (138.4 +/- 7.1 mg/dl vs. 112.4 +/- 5.2 and 47.3 +/- 1.4 vs. 61.3 +/- 3.0, respectively). Insulin response following fast was significantly reduced in 0-2 h period with delayed maximum value obtained at 123.3 +/- 14.5 min vs. 60.0 +/- 10.0 min in the basal experiment. Post-fasting counter-regulatory cortisol response was higher when compared to control, but there was no difference in growth hormone and glucagon secretion. Basal and post-glucose values of free fatty acids were significantly higher after fast than in the control study. The data suggest that fasting-induced impairment of glucose-insulin interaction in the hyperglycemic period of oGTT decreases the ability of obese subjects to maintain posthyperglycemic glucose homeostasis and provokes reactive hypoglycemia in some of them. Examination of glucose metabolism in fasted subjects is a convenient experimental model for the investigation of reactive hypoglycemia.