The systemic response to a glucose infusion at 2.7 mg/kg X min was evaluated in 10 undialyzed chronically uremic patients and in 5 controls after they were fasted overnight. Systemic glucose production (Ra) was measured during the steady state using [6,6-2H2]-glucose tracer. In chronic uremic subjects, basal Ra was 1.99 +/- 0.35 ml/kg X min (mean +/- SD) and was not different from that observed in the control subjects (1.86 +/- 0.23). Basal plasma insulin and betahydroxybutyrate concentrations were significantly increased (P less than 0.01) in the uremic group. Glucose infusion resulted in complete suppression of Ra (97%) in the normal subjects. Suppression of Ra in the uremic subjects was virtually complete with the exception of 3 patients who suppressed systemic glucose production by 70%, 79%, and 87%. Glucose utilization (Ru) during glucose infusion rose from the basal state to a plateau level within the 2 hours following the start of infusion and was of the same magnitude in the uremic group as it was in the control group. During the 3rd and the 4th hour of glucose infusion, there was further increase in Ru in the normal subjects, resulting in a decrease in plasma glucose concentration. Only 4 out of 10 uremic subjects showed a similar response. There was no correlation between the metabolic changes noted and the serum creatinine concentration. These data indicate that in chronic uremia, resistance to insulin action in the peripheral tissues is present but is variable, suggesting a spectrum of metabolic disturbances unrelated to the degree of chronic renal failure.