Abstract

Interleukin 1β (IL-1β) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1β. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low-density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1β in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.

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Acknowledgements

We thank A. Mori for assistance with Nlrp3−/− mice; J. Tschopp (University of Lausanne) for Nlrp3−/− mice; and E. Latz (University of Bonn) for YFP-ASC BMDMs. Supported by the National Health and Medical Research Council (516783 to S.L.M.), Science Foundation Ireland (for work at Trinity College Dublin), the United States Department of Veterans Affairs (for work at the VA Puget Sound Health Care System), the US National Institutes of Health (DK-75998 to S.E.K. for work at VA Puget Sound Health Care System, and AI063331 for work at the University of Michigan) and the Crohn's and Colitis Foundation (L.F.).

Author information

Affiliations

  1. Immunology Research Centre, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

    • Seth L Masters
    • , Aisling Dunne
    • , Lisa A Mielke
    • , James Harris
    • , Kingston H G Mills
    • , Ed C Lavelle
    •  & Luke A J O'Neill
  2. Inflammation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

    • Seth L Masters
    • , Gillian M Tannahill
    • , Christine Becker
    • , Rebecca C Coll
    •  & Luke A J O'Neill
  3. Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

    • Aisling Dunne
    • , Lisa A Mielke
    •  & Kingston H G Mills
  4. Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington, USA.

    • Shoba L Subramanian
    • , Rebecca L Hull
    •  & Steven E Kahn
  5. Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

    • Fiona A Sharp
    • , James Harris
    •  & Ed C Lavelle
  6. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • Luigi Franchi
    •  & Gabriel Nuñez
  7. Department of Biological Responses, Institute for Virus Research, Kyoto University, Japan.

    • Eiji Yoshihara
    • , Zhe Chen
    •  & Junji Yodoi
  8. School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.

    • Niamh Mullooly
    •  & Philip Newsholme
  9. Protein Folding and Biomolecular NMR Spectroscopy Group, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

    • K Hun Mok

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Contributions

S.L.M. designed and did experiments, analyzed data and wrote the paper; L.A.J.O. and E.C.L. conceived ideas and oversaw research; A.D., S.L.S., R.L.H., G.M.T., F.A.S., C.B., L.F., E.Y., Z.C., N.M., L.A.M., J.H. and R.C.C. did experiments; and K.H.G.M., K.H.M., P.N., G.N., J.Y. and S.E.K. provided advice and reagents.

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The authors declare no competing financial interests.

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Correspondence to Seth L Masters.

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https://doi.org/10.1038/ni.1935

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