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

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Abstract

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diets, or fasted, were injected intravenously with glucagon (0.1, 0.3, 1.0, 10.0 or 20 μg/kg); blood samples were withdrawn before injection and 1, 3, 5, 10, 20 min thereafter for glucagon assay by RIA.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.

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Abbreviations

DPP-4:

Dipeptidyl peptidase-4

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Acknowledgements

This works was presented in part in abstract form at the American Diabetes Association’s 73rd Scientific Sessions, 2013, Chicago, IL, USA. We are grateful to K. Andersson (Department of Clinical Sciences, Lund University) for her technical assistance in the conduct of the experiments.

Funding

This work was supported by Women in Science and Engineering Undergraduate Research Fellowship from Univ. of Southern California to AZ (DZD mentor), National Institutes of Health grant P41-EB001978 to DZD and Swedish Research Council (Grant no. 6834), Region Skåne and Faculty of Medicine, Lund University to BA.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

AZ and DZD performed data analysis and modelling, and contributed to interpretation of results and writing the paper. GP participated in the design of the study, in the interpretation of the results and in the revision of the manuscript. BA designed the study, performed the experiments and contributed to interpretation of results and writing the paper. All authors approved the final version of the manuscript to be published.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, DRB 140, Los Angeles, CA, 90089, USA

    Alyssa Zhou & David Z. D’Argenio

  2. Metabolic Unit, Institute of Biomedical Engineering, CNR, Padua, Italy

    Giovanni Pacini

  3. Department of Clinical Sciences, Lund University, Lund, Sweden

    Bo Ahrén

Authors
  1. Alyssa Zhou
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  2. Giovanni Pacini
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  3. Bo Ahrén
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  4. David Z. D’Argenio
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Corresponding author

Correspondence to David Z. D’Argenio.

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Zhou, A., Pacini, G., Ahrén, B. et al. Glucagon clearance is regulated by nutritional state: evidence from experimental studies in mice. Diabetologia 57, 801–808 (2014). https://doi.org/10.1007/s00125-013-3148-x

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  • DOI: https://doi.org/10.1007/s00125-013-3148-x

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