Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice
Abstract Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35g/kg i.v.) and following glucose plus glucagon (10μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC 0-20 ) compared to that with glucose alone ( p Highlights Glucagon effects on insulin kinetics in mice were assessed using population modeling analysis approach. Glucagon was shown to enhance prehepatic insulin secretion, but there was no effect on insulin clearance in mice. Our findings therefore show that the increase in circulating insulin achieved by glucagon is due to increased insulin secretion without any further influence on insulin clearance.
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