Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of GIP and GLP-1. Given the recent availability of drugs based on incretin hormones, such clearance effects may be important for the future treatment of type 2 diabetes. Therefore, we determined insulin clearance in response to endogenously secreted as well as exogenously administered GIP and GLP-1. Insulin clearance was estimated from the molar C-peptide/insulin ratio calculated at basal conditions and from the respective AUC's after glucose, GIP, or GLP-1 administration. Oral glucose administration led to a ~60 % reduction in the C-peptide/insulin ratio (p < 0.0001), whereas intravenous glucose administration had no effect (p = 0.09). The endogenous secretion of GIP or GLP-1 was unrelated to the changes in insulin clearance. The C-peptide/insulin ratio was unchanged after the intravenous administration of GIP or GLP-1 in the fasting state (p = 0.27 and p = 0.35, respectively). Likewise, infusing GLP-1 during a meal course did not alter insulin clearance (p = 0.87). An inverse non-linear relationship was found between the C-peptide/insulin ratio and the integrated insulin levels after oral and during intravenous glucose administration. Insulin clearance is reduced by oral, but not by intravenous glucose administration. Neither GIP, nor GLP-1 have significant effects on insulin extraction. An inverse relationship between insulin concentrations and insulin clearance suggests that the secretion of insulin itself determines the rate of hepatic insulin clearance.