Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors.

The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FE, CL; FE, CL) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CL and CL. A statistically significant difference between DIRKO and WT was found in CL (0.61 [0.48-0.82] vs. 0.51 [0.46-0.65] (median [interquartile range]); = 0.02), which was reflected in the peripheral component, CL (0.18 [0.13-0.27] vs. 0.15 [0.11-0.22]; = 0.04), but not in the hepatic component, FE (29.7 [26.7-34.9] vs. 28.9 [25.7-32.0]; = 0.18). No difference was detected between DIRKO and WT in CL (1.38 [1.13-1.75] vs. 1.69 [1.48-1.87]; = 0.10), neither in CL (0.72 [0.64-0.81] vs. 0.79 [0.69-0.87]; = 0.27) nor in FE (37.8 [35.1-43.1] vs. 39.8 [35.8-44.2]; = 0.46). In conclusion, our findings suggest that the higher insulin clearance observed in DIRKO compared with WT during the IVGTT first phase may be due to its extrahepatic component.