To determine the contribution of clinically overt diabetic autonomic neuropathy (DAN) to reduced plasma adrenaline responses to hypoglycemia in IDDM and to establish its selectivity for hypoglycemia, we studied 17 IDDM patients (7 without DAN [DAN−] and 10 with DAN [DAN+]), of whom 5 had and 5 did not have postural hypotension (DAN+PH+ and DAN+PH−, respectively), and 8 nondiabetic subjects on 2 different occasions, i.e., clamped hypoglycemia (steps from 5.0 to 2.2 mmol/l plasma glucose) and 30-min steady-state exercise at 55% VO2max. Recent antecedent hypoglycemia was meticulously prevented before the studies to exclude hypoglycemia as a cause of reduced responses of adrenaline to hypoglycemia. In DAN− patients, maximal responses of adrenaline to hypoglycemia were reduced (2.44 ± 0.58 nmol/l vs. 4.9 ± 0.54 nmol/l in nondiabetic patients) (P < 0.05). In DAN+, adrenaline responses initiated at a lower plasma glucose and were lower than in DAN− (DAN+PH−, 1.06 ± 0.38 nmol/l; DAN+PH+, 0.84 ± 0.27 nmol/l; P < 0.001, but NS between PH− and PH+). In response to exercise, adrenaline increased less in DAN− (0.89 ±0.11 nmol/l) patients than in nondiabetic subjects (1.19 ± 0.14 nmol/l; NS) and only to 0.36 ± 0.07 nmol/l in DAN+PH− and 0.23 ± 0.09 nmol/l in DAN+PH+ (P < 0.001 vs. DAN− and nondiabetic subjects). These results were confirmed when nondiabetic and DAN− subjects repeated the exercise at 60 watts (35 and 41% of Vo2max, respectively), i.e., at the same absolute workload of DAN+ patients. Thus, DAN (both PH+ and PH−) contributes to reduced responses of adrenaline to hypoglycemia independently of recent antecedent hypoglycemia. The adrenaline defect in DAN is not selective for hypoglycemia.