The long acting insulin analogue Detemir has structural and physicochemical properties which differ from human insulin. The aim of the present study was therefore to test whether this leads to altered hormone and symptom response to hypoglycemia. 12 (6f/6m, age 32±6 years (mean±SD), BMI 24.2±2.5 kg/m²) healthy subjects underwent a 200 min stepwise hypoglycemic clamp (45 min steps of 4.4, 3.7, 3.0 and 2.3 mmol/l) with either insulin Detemir or Actrapid in random order. Detemir (Actrapid) was infused at a rate of 5 (2) mU/kg/min. At the start of the clamp, a bolus of 660 (60) mU/kg was given over 12 (6) minutes. Assessment of this dose was done in pilot hyperinsulinemic euglycemic clamp experiments. Blood was drawn and a semi-quantitative symptom questionnaire (20 real and 9 dummy symptoms) was administered before and alter each plateau of the hypoglycemic clamp. A stroop- and reaction time test was performed during each step. Although Detemir infusion resulted in ∼ 35 times higher peripheral total insulin levels, blood glucose levels and glucose infusion rates were similar during both conditions. No significant differences between Detemir and Actrapid in glucagon, epinephrine, norepinephrine, cortisol or growth hormone response during hypoglycaemia were observed (MANOVA for repeated measures design). There were also no significant differences in cognitive function tests. The total symptom score was higher with Detemir during the 3 and 2.3 mmol step compared to Actrapid (p=0.048). Especially sweating was increased with Detemir versus Actrapid (p=0.02), and showed an earlier and faster increase during the hypoglycemic clamp with Detemir (interaction insulin x time: p=0.04). In summary, hormonal counter-regulation and cognitive function during hypoglycemia are not different with Detemir and human regular insulin. Symptom perception, especially sweating, is increased during hypoglycemia induced by Detemir. Diabetic patients with hypoglycemia unawareness may benefit from increased sweating during hypoglycemia. [ABSTRACT FROM AUTHOR]