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 (pฯฝ0.05), heart rate (p ฯฝ0.05), and in autonomic (pฯฝ0.05) and neuroglycopenic symptom scores (pฯฝ0.05) occurred at R, and a significant deterioration was observed in cognitive performance (pฯฝ0.05). In response to hypoglycaemia, a significant increase from baseline occurred in plasma concentrations of all of the counterregulatory hormones (pฯฝ0.01) 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 ยฑ SD) of 2.0 (ยฑ 0.6) mmol -1 for Lispro and 1.9 (ยฑ0.6) 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.