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Aims/hypothesis: The association of insulin detemir with non-esterified fatty acid binding sites on albumin may limit its transfer from the circulation into the extravascular extracellular space in adipose tissue and muscle, due to the capillary endothelial cell barrier. In the liver, the open sinusoids may expose hepatocytes to insulin detemir, enabling it to have a greater effect in the liver than in peripheral tissues. Methods: We investigated the effects of equipotent doses of insulin detemir and NPH insulin on hepatic glucose rate of appearance (R a ), peripheral glucose rate of disposal (R d ) and glycerol R a (a measure of lipolysis) using stable isotope techniques. We also investigated the effects of these insulins on NEFA concentrations in seven healthy volunteers during a 16-h euglycaemic clamp. A higher dose of insulin detemir was also studied. Results: There was no difference in the glucose infusion profile between insulin detemir and NPH. Insulin detemir had a greater effect on mean suppression of glucose R a (mean difference 0.24 mg kg −1 min −1; CI 0.09-0.39; p<0.01), and minimum glucose R a , with minimum low dose detemir −0.10±0.15 mg·kg −1 ·min −1 and minimum NPH 0.17±0.10 mg·kg −1 ·min −1 (p<0.02). However, it had a lesser effect on mean suppression of NEFA concentrations (mean difference −0.10 mmol/l; CI −0.03 to −0.17; ANOVA, p<0.02) than NPH. The effect of insulin detemir on glucose R d and glycerol R a was not different from NPH. Following high-dose detemir, total glucose infused and maximum glucose R d were higher (p<0.02, p<0.03) and plasma NEFA concentrations lower (p<0.01) than with low-dose determir. Conclusions/interpretation: This study suggests that insulin detemir, when compared to NPH insulin, has a greater effect on the liver than on peripheral tissues and thus has the potential to restore the physiological insulin gradient.