Context:Roux-en-Y gastric bypass (RYGB) improves glucose tolerance and ameliorates fasting hyperinsulinemia within days after surgery. Improvements in hepatic insulin sensitivity and insulin clearance could contribute importantly to these effects.Objective:The objective of the investigation was to study changes in insulin clearance after RYGB.Design:This was a prospective study of fasting hepatic insulin clearance and, in a subgroup of patients, postprandial insulin clearance after a meal test before and 1 week, 3 months, and 1 year after RYGB.Setting:The study was conducted at Hvidovre Hospital (Hvidovre, Denmark).Patients:Patients included 2 groups of obese RYGB-patients: 1) type 2 diabetes (T2D) group: 32 patients with T2D (meal test, n = 13), 2) normal glucose tolerance (NGT) group: 32 patients with NGT (meal test, n = 12).Intervention:The intervention was RYGB.Main Outcome Measure:Fasting hepatic insulin clearance (fasting C-peptide/fasting insulin). Postprandial insulin clearance (incremental areas under the curve of insulin secretion rates/incremental areas under the curve of insulin).Results:Fasting hepatic insulin clearance increased after 1 week (P < .01) and further at 3 months (P < .01), remaining elevated 1 year postoperatively (P < .01) with no difference between the T2D and NGT groups. Postprandial insulin clearance changed only in the T2D group with an increase at 1 week (P < .01) that was maintained at 3 months (P = .06) and 1 year (P < .01).Conclusions:RYGB increases insulin clearance within 1 week after surgery, highlighting the liver as a key organ involved in the early beneficial effect on glucose metabolism. Postprandial insulin secretion may be underestimated postoperatively in patients with type 2 diabetes when evaluated by peripheral insulin concentrations instead of insulin secretion rates or C-peptide.