To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO (n=31) and wild-type (WT) C57BL6J mice (n=45) were intravenously injected with D-glucose (0.35 g/kg). Blood was sampled for 50 minutes and assayed for glucose, insulin and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66{plus minus}0.10∙10-3 L∙min-1. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68{plus minus}0.06∙10-3 L∙min-1 in DIRKO mice vs. 0.54{plus minus}0.03∙10-3 L∙min-1 in WT mice, p=0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion (p=0.18). In conclusion, this study evaluated C peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, non-stimulated levels.