To assess the effect of autonomic and sensorineural dysfunction on O2 uptake kinetics, we studied the exercise response of seven diabetic humans having peripheral sensory and cardiac autonomic neuropathy, eight diabetics without neuropathy, and eight normal subjects. Maximal O2 uptake (VO2max), ventilatory anaerobic threshold, and O2 uptake kinetics were assessed. Metabolic control was optimized 12 h prior to and during testing by intravenous insulin infusion. Patients with diabetic neuropathy had a reduced VO2max [83 +/- 6% predicted vs. 104 +/- 6% (nonneuropathic diabetics) and 107 +/- 5% (normals); P less than 0.05]. However, there was no difference in ventilatory anaerobic threshold [14.8 +/- 0.9 (neuropathic diabetics) vs. 18.0 +/- 1.0 (nonneuropathic diabetics) and 16.7 +/- 1.5 ml O2.kg-1.min-1 (normals); P greater than 0.25]. The phase I increment in O2 uptake (VO2) and estimated cardiac output and the time constant of VO2 during constant-load exercise at 40% VO2max also were similar in all groups. We propose that the instantaneous increase in VO2 and cardiac output at exercise onset in diabetes with impaired neurogenic reflexes is caused primarily by mechanical and metabolic events in exercising muscle that cause venous compression and vasodilation.