Abstract

Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes.

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Acknowledgements

We acknowledge O. Madsen and D. Steiner for their suggestion to investigate the role of IL-6 on GLP-1 and PC1/3. We thank R. Prazak and M. Borsigova for technical assistance and M. Niessen for discussions. This work was supported by grants from the Swiss National Science Foundation and by the Merck Investigator Studies Program. J.A.E. was supported by grants from the Hartman Muller organization, the Child and Family Research Institute and the University of British Columbia and has salary support from the Canadian Diabetes Association. We obtained human islets thanks to grant 31-2008-416 from the Juvenile Diabetes Research Foundation. D.J.D. is supported by the Canada Research Chair in Regulatory Peptides, the Banting and Best Diabetes Centre–Novo Nordisk Chair in Incretin Biology and Canadian Institutes of Health Research operating grant 93749. F.M.G., F.R. and A.M.H. are supported by grants from the Wellcome Trust (WT088357 to F.M.G. and WT084210 to F.R.) and EU FP7 grant 266408.

Author information

Affiliations

  1. Clinic for Endocrinology, Diabetes & Metabolism and Department Biomedicine, University Hospital Basel, Basel, Switzerland.

    • Helga Ellingsgaard
    • , Irina Hauselmann
    • , Daniel T Meier
    •  & Marc Y Donath
  2. Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

    • Beat Schuler
    •  & Max Gassmann
  3. Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.

    • Abdella M Habib
    • , Frank Reimann
    •  & Fiona M Gribble
  4. Department of Medicine, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.

    • Laurie L Baggio
    •  & Daniel J Drucker
  5. Research Group Neuro-Endocrine-Immune Interactions, Institute of Anatomy, University of Zurich, Zurich, Switzerland.

    • Elisabeth Eppler
    •  & Manfred Reinecke
  6. Department of Genetic Medicine and Development, University Medical Center, University of Geneva, Geneva, Switzerland.

    • Karim Bouzakri
    •  & Philippe A Halban
  7. Division of Pediatric Endocrinology and Diabetology, University Children's Hospital and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

    • Stephan Wueest
    •  & Daniel Konrad
  8. Cell Isolation and Transplantation Center, Department of Surgery, University Medical Center, University of Geneva, Geneva, Switzerland.

    • Yannick D Muller
  9. Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.

    • Ann Maria Kruse Hansen
  10. Cardiovascular and Metabolism Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.

    • Jesper Gromada
  11. Department of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute, Vancouver, British Columbia, Canada.

    • Jan A Ehses

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Contributions

H.E. designed and performed experiments, analyzed data and wrote the manuscript. I.H., B.S., A.M.H., L.L.B., D.T.M., E.E., J.G., S.W., A.M.K.H., D.K., M.R., M.G., D.J.D., F.R. and F.M.G. performed experiments. Y.D.M. isolated human islets. K.B. and P.A.H. provided FACS-sorted human islet cells. D.J.D., F.M.G. and F.R. provided mice for this study. J.A.E. and M.Y.D. designed experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Helga Ellingsgaard.

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DOI

https://doi.org/10.1038/nm.2513

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