The effect of hyperglycemia, per se, on glucose utilization and hepatic glucose production was reevaluated in eight C-peptide-negative insulin-dependent diabetic patients using primed-continuous noncontaminated 3-3H-glucose infusion and labeled glucose infusates. The night before study, euglycemia was maintained by a variable insulin infusion. During the studies, insulin was infused at basal replacement rates determined as the rate required to maintain euglycemia in the morning. After a 2-hour equilibration period, either plasma glucose level was increased to 12 mmol/L for 4 hours using a variable glucose infusion, or no glucose was infused (control day). On the hyperglycemic day, glucose utilization increased 16% (86 +/- 2 to 99 +/- 4 mg.m-2.min-1, P < .02) and glucose production decreased 45% (85 +/- 3 to 47 +/- 4 mg.m-2.min-1, P < .01). On the control day, both glucose utilization and glucose production decreased (84 +/- 3 to 68 +/- 3 and 84 +/- 3 to 65 +/- 3 mg.m-2.min-1, respectively; both P < .01). Therefore, comparing rates at the end of the hyperglycemic and control studies, glucose utilization was increased by 45% and glucose production was decreased by 28% in response to hyperglycemia (both P < .01). Thus hyperglycemia, at basal insulin levels enhanced glucose utilization and suppressed glucose production in insulin-dependent diabetic patients. Quantitatively, the enhancement of glucose utilization was more important than the suppressive effect on glucose production.