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Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

Nature Medicine volume 17, pages 1481–1489 (2011)Cite this article

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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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Figure 1: Effect of acute IL-6 on GLP-1 and insulin secretion in vivo.
Figure 2: Effect of twice daily IL-6 injections over 1 week on glucose homeostasis and GLP-1 production.
Figure 3: Effects of IL-6 on GLP-1 secretion in GLUTag cells.
Figure 4: Effects of IL-6 on GLP-1 secretion in human islets and human alpha cells.
Figure 5: Effect of acute IL-6 on insulin secretion in animal models of prediabetes and diabetes.
Figure 6: Effect of IL-6 antagonism in mice fed a high-fat diet and in db/db mice.

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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.

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Authors and Affiliations

  1. Diabetes & Metabolism and Department Biomedicine, Clinic for Endocrinology, 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. Department of Surgery, Cell Isolation and Transplantation Center, 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.

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Correspondence to Helga Ellingsgaard.

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Ellingsgaard, H., Hauselmann, I., Schuler, B. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 17, 1481–1489 (2011). https://doi.org/10.1038/nm.2513

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