Abstract

The deleterious effect of chronic activation of the IL-1β system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1β in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1β, in a glucose-dependent manner. Subsequently, IL-1β contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1β signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1β and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1β mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium–glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1β and insulin in the regulation of both metabolism and immunity.

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Acknowledgements

We thank R. Sharfmann (Université Paris-Descartes, Institut Cochin, Paris, France) for the human β-cell line ENDOC; technicians M. Borsigova, K. Dembinski and S. Haeuselmann for technical assistance; S. Dimeloe, E. Traunecker and D. Labes for technical advice; G. Bantug for technical and editorial advice; and the Center for Transgenic Models of the University of Basel and D. Klewe-Nebenius for supporting production of the Il1bfl/fl mouse. Supported by the Swiss National Research Foundation (166519 to M.Y.D.) and the European Genomic Institute for Diabetes (ANR-10-LABX-46 to F.P.).

Author information

Author notes

    • Elise Dalmas
    • , Daniel T Meier
    • , Marianne Böni-Schnetzler
    •  & Marc Y Donath

    These authors contributed equally to this work.

Affiliations

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

    • Erez Dror
    • , Elise Dalmas
    • , Daniel T Meier
    • , Constanze Thienel
    • , Katharina Timper
    • , Thierry M Nordmann
    • , Shuyang Traub
    • , Friederike Schulze
    • , Marianne Böni-Schnetzler
    •  & Marc Y Donath
  2. Deptartment of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, Zurich, Switzerland.

    • Stephan Wueest
    • , Flurin Item
    •  & Daniel Konrad
  3. Inserm, University Lille, Centre Hospitalier Universitaire, Lille, France, and Translational Research for Diabetes, European Genomic Institute for Diabetes, Lille, France.

    • Julien Thévenet
    • , Francois Pattou
    •  & Julie Kerr-Conte
  4. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

    • David Vallois
    •  & Bernard Thorens
  5. Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland, and University of Geneva School of Medicine, Geneva, Switzerland.

    • Vanessa Lavallard
    •  & Thierry Berney

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Contributions

E.Dr., M.B.-S. and M.Y.D. designed the study and wrote the manuscript; E.Dr. performed and analyzed most of the experiments; E.Da, D.T.M. and M.B.-S. performed and analyzed experiments; S.W., F.I. and D.K. performed the clamping; J.T., F.P. and J.K.-C. provided human islets and performed the islet-transplantation experiments; C.T., K.T., T.M.N., S.T., F.S. and D.V. helped with experiments; V.L. and T.B. provided human islets; B.T. provided the Gipr−/−Glp1r−/− mice; M.B.-S. and M.Y.D. supervised the research; and all authors helped with the manuscript.

Competing interests

M.Y.D. is listed as the inventor on a patent filed in 2003 for the use of an IL-1 receptor antagonist for the treatment of or prophylaxis for type 2 diabetes.

Corresponding author

Correspondence to Marc Y Donath.

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DOI

https://doi.org/10.1038/ni.3659

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