The aim of this study was to compare the glycaemic threshold for onset of the clinically detectable sympatho-adrenal (autonomic) reaction (defined as 'R') to hypoglycaemia induced by Lispro human insulin, with that induced by human soluble insulin (HS). The hypoglycaemia symptom profile, counterregulatory hormonal responses, and cognitive performance at R were also compared. Sixteen patients with IDDM, aged 32.5 (20-45) (median (range)) years and duration of IDDM 3.0 (0.5-4.5) years participated in a randomized, double-blind study during which intravenous infusions of either Lispro or HS insulin (2.0 mU kg(-1) min(-1)) were used on separate occasions to lower the blood glucose to the level at which R was induced. For both HS and Lispro, significant increments in systolic blood pressure (p<0.05), heart rate (p<0.05), and in autonomic (p<0.05) and neuroglycopenic symptom scores (p<0.05) occurred at R, and a significant deterioration was observed in cognitive performance (p<0.05). In response to hypoglycaemia, a significant increase from baseline occurred in plasma concentrations of all of the counterregulatory hormones (p<0.01) and the magnitude of response and temporal pattern did not differ, nor were any significant differences apparent between HS and Lispro insulins for any of the variables studied. The autonomic reaction occurred at a blood glucose (mean +/- SD) of 2.0 (+/- 0.6) mmol(-1) for Lispro and 1.9 (+/- 0.6) mmol(-1) for HS, which did not differ significantly. Thus, at the autonomic reaction to hypoglycaemia no significant differences were evident in the glycaemic threshold, symptom profile, physiological responses, and counterregulatory hormonal responses between Lispro and human soluble insulin in IDDM patients.