Reduced insulin clearance contributes to the increased insulin levels after administration of glucagon-like peptide 1 in mice

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) is known to be a potent stimulator of insulin secretion. However, whether GLP-1 also affects insulin clearance is not known. To explore this, we developed a technique to determine prehepatic insulin secretion in mice, based on deconvolution of plasma C-peptide concentrations. The estimated beta cell secretion was then related to plasma insulin levels to allow determination of clearance rate of endogenously produced insulin. Materials and methods: Kinetic parameters of C-peptide were estimated after i.v. injection of human C-peptide (0.8 or 3 nmol/ kg) or glucose ( 1 g/kg), either alone or together with GLP-1 ( 10 nmol/ kg), in anaesthetised NMRI mice. Results: C-peptide was distributed in two compartments ( distribution volume 11.4 +/- 0.4 ml, 42 +/- 2% of which was in the accessible compartment). Fractional C-peptide clearance was 8.2 +/- 0.6% of the total distribution volume per minute. GLP-1 markedly enhanced prehepatic insulin secretion; more than 80% of prehepatic secretion occurred during the first minute after injection. Fractional clearance of endogenously released insulin after glucose was 0.66 +/- 0.11 min(-1) and this was reduced to 0.36 +/- 0.10 min(-1) by GLP-1 ( p= 0.04). Conclusions/interpretation: It is possible to perform C-peptide deconvolution for estimating prehepatic insulin secretion in mice. GLP-1 reduces the clearance of endogenously released insulin; therefore, it may affect insulin levels by increasing prehepatic insulin secretion and by reducing insulin clearance.