Glucagon clearance is regulated by nutritional state: evidence from experimental studies in mice

Aims/hypothesis Given the importance of glucagon in the development of type 2 diabetes and as a potential therapeutic agent, the aim of this study was to characterise glucagon kinetics in mice and its regulation by the nutritional state. Methods Anaesthetised C57BL/6 mice fed normal or high-fat diets, or fasted, were injected intravenously with glucagon (0.1, 0.3, 1.0, 10.0 or 20 mu g/kg); blood samples were withdrawn before injection and 1, 3, 5, 10, 20 min thereafter for glucagon assay by RIA. Glucagon kinetics were described by two-compartment models using a population analysis. Results The population mean and between-animal SD of glucagon clearance in the fed mice was 6.03 +/- 2.58 ml/min, with a rapid elimination half-life of 2.92 +/- 1.21 min. Fasted mice showed a slower glucagon clearance. The kinetics of glucagon in the fed and fasted group was linear across this large dose range. The mice fed a high-fat diet, however, showed non-linear kinetics with a faster terminal clearance of 20.4 +/- 5.45 ml/min (p < 0.001) and a shorter elimination half-life of 1.59 +/- 0.606 (p < 0.001) min relative to normal mice. Conclusions/interpretation This first systematic dose-ranging study of glucagon kinetics produced several findings: (1) a linear two-compartment model describes glucagon in normal C57BL/6 mice; (2) fasting reduces the clearance of glucagon and (3) high-fat diet enhances the clearance of glucagon. These results may direct future studies on glucagon physiology and indicate that there are other mechanisms, not included in the current model, needed to fully explain glucagon's kinetics.