Counterregulatory hormone responses to hypoglycemia are impaired in subjects with insulin-dependent diabetes mellitus (IDDM) in strict glycemic control. To determine whether these defects are specific for hypoglycemia, we examined counterregulatory hormone responses during a 3-h hypoglycemic hyperinsulinemic clamp (14.4 pmol/kg.min) that lowered plasma glucose from 5.0 to 2.2 mmol/L in 9 well controlled IDDM patients (hemoglobin-A1, 7.5 +/- 0.8%), 9 poorly controlled patients (hemoglobin-A1, 12.5 +/- 1.5%), and 10 healthy volunteers. Counterregulatory hormone secretion was compared with responses to non-glucose secretagogues for epinephrine and norepinephrine (cold pressor test), ACTH (overnight metyrapone test), and GH (L-arginine infusion). During hypoglycemia, epinephrine and cortisol responses were lower in the IDDM group in strict glycemic control than those in the poorly controlled IDDM group or healthy volunteers (P < 0.05). In response to the cold pressor test, the areas under the curve for epinephrine and norepinephrine were also reduced in the well controlled IDDM group (P < 0.05 vs. healthy volunteers). The ACTH response to hypoglycemia was not significantly reduced in the well controlled IDDM, whereas the response to metyrapone was actually greater in this group (P < 0.05 vs. poorly controlled IDDM). GH responses to both hypoglycemia and arginine were highest in the well controlled diabetic patients. These data suggest that 1) the reduced epinephrine responses in well controlled IDDM may not be specific for the hypoglycemic stimulus alone, but may also occur in response to other nonhypoglycemic stimuli; 2) cortisol responses to hypoglycemia are reduced in well controlled IDDM, whereas the ACTH response to a non-hypoglycemic stimulus remains intact; and 3) GH responses to both hypoglycemic and nonhypoglycemic stimuli are preserved in well controlled IDDM. The preservation of ACTH and GH responses to metyrapone and arginine, respectively, suggests adequate pituitary functional reserve in IDDM patients in strict glycemic control in response to nonhypoglycemic stimuli.