In recent years there has been great concern that human insulin (HI) may induce fewer hypoglycaemic warning symptoms than porcine insulin (PI). We addressed this issue in eight patients aged 25.6 +/- 3.3 (SEM) years with Type I (insulin-dependent) diabetes mellitus of 15.1 +/- 3.7 years duration who complained that hypoglycaemia unawareness had appeared after transferring from PI to HI. Acute induction of hypoglycaemia was induced on two occasions with semisynthetic HI and purified PI under double-blind conditions. Blood glucose was first clamped for 2 h at 4.4-6.7 mmol l-1 with an intravenous infusion of HI or PI at 50 mU kg-1 h-1 and 20% glucose at a variable rate. Thereafter, insulin infusion alone was maintained for 100 minutes. Heart rate, arterial pressure, reflex times, autonomic and neuroglycopenic signs and symptoms were assessed every 10 min. Arterialized venous blood samples were taken to measure blood glucose every 10 min and catecholamines, insulin, glucagon, growth hormone, and cortisol every 20 min. Autonomic symptoms first appeared at a plasma glucose level of 2.92 +/- 0.21 mmol l-1 with HI vs 2.92 +/- 0.48 mmol l-1 with PI (NS). There were no significant differences between the two studies concerning any of the above mentioned clinical parameters or the counterregulatory hormone responses. A differential effect of insulin species on the ability to perceive hypoglycaemia in patients who ascribed diminished perception of hypoglycaemia to the use of HI was thus not observed.