We previously demonstrated that hyperinsulinemia can amplify the counterregulatory response to hypoglycemia in normal subjects. The aim of the present study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent fixed hypoglycemia in insulin-dependent-diabetic subjects (IDDM). Experiments were carried out in seven lean, overnight-fasted, moderately controlled (hemoglobin A1c, 10.9%; normal range, 5-9) IDDM subjects with a disease duration of 13 +/- 3 yr. All were maintained normoglycemic overnight so that basal plasma glucose (5.6 +/- 0.2 and 5.4 +/- 0.2 mmol/L) and insulinemia (63 +/- 18 and 48 +/- 10 pmol/L) were similar at the start of each study. Insulin was infused for 120 min in two separate randomized protocols, so that steady state levels (mean +/- SE) of 742 +/- 212 pmol/L (low) and 3360 +/- 710 pmol/L (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.09 mmol/L.min) and the hypoglycemic plateau (2.8 +/- 0.1 mmol/L) were similar. In response to hypoglycemia, plasma levels of epinephrine, norepinephrine, cortisol, GH, and pancreatic polypeptide increased similarly during both insulin infusions. During the final 30 min, despite similar levels of counterregulatory hormones, hepatic glucose production was significantly reduced in the presence of high compared to low insulin levels (1.7 +/- 2.8 vs. 8.3 +/- 1.7 mumol/kg.min; P < 0.05). Similarly, plasma nonesterified fatty acids (472 +/- 94 vs. 787 +/- 105 mumol/L) and blood 3-hydroxybutyrate levels (30 +/- 12 vs. 106 +/- 29 mumol/L) were significantly reduced (P < 0.05) during high compared to low dose infusions. Cardiovascular parameters (heart rate and systolic, diastolic, and mean arterial pressures) responded similarly during both infusions. We conclude that 1) insulin per se does not amplify the counterregulatory response to equivalent hypoglycemia in individuals with moderately controlled, long duration IDDM; and 2) there may be a relative autonomic adrenomedullary deficit in some IDDM subjects that prevents the amplified epinephrine response to hyperinsulinemia during hypoglycemia.