Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inflammasome activation and IL-1β production induced by human IAPP.
Figure 2: IAPP oligomers activate the NLRP3 inflammasome, an effect prevented by glyburide and inhibitors that target phagocytosis, ROS and cathepsin B.
Figure 3: Priming the inflammasome requires glucose metabolism.
Figure 4: Inflammasome activation by IAPP primed with mmLDL.
Figure 5: Higher IL-1β expression in islets of mice transgenic for human IAPP.

Similar content being viewed by others

References

  1. Kahn, S.E., Hull, R.L. & Utzschneider, K.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Njajou, O.T. et al. Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health, Aging and Body Composition Study. Diabetes Metab. Res. Rev. 25, 733–739 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bendtzen, K. et al. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 232, 1545–1547 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Spranger, J. et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52, 812–817 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Larsen, C.M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Clark, A. et al. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 9, 151–159 (1988).

    CAS  PubMed  Google Scholar 

  10. Cooper, G.J. et al. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc. Natl. Acad. Sci. USA 84, 8628–8632 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Westermark, P. et al. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc. Natl. Acad. Sci. USA 84, 3881–3885 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Butler, A.E. et al. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes. Diabetes 53, 1509–1516 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Janson, J. et al. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc. Natl. Acad. Sci. USA 93, 7283–7288 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Verchere, C.B. et al. Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide. Proc. Natl. Acad. Sci. USA 93, 3492–3496 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Howard, C.F. Jr. Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia 29, 301–306 (1986).

    Article  PubMed  Google Scholar 

  16. Seino, S. S20G mutation of the amylin gene is associated with type II diabetes in Japanese. Study Group of Comprehensive Analysis of Genetic Factors in Diabetes Mellitus. Diabetologia 44, 906–909 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Ma, Z. et al. Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide. Amyloid 8, 242–249 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Udayasankar, J. et al. Amyloid formation results in recurrence of hyperglycaemia following transplantation of human IAPP transgenic mouse islets. Diabetologia 52, 145–153 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Westermark, P., Eizirik, D.L., Pipeleers, D.G., Hellerstrom, C. & Andersson, A. Rapid deposition of amyloid in human islets transplanted into nude mice. Diabetologia 38, 543–549 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Westermark, G.T., Westermark, P., Berne, C. & Korsgren, O. Widespread amyloid deposition in transplanted human pancreatic islets. N. Engl. J. Med. 359, 977–979 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Lorenzo, A., Razzaboni, B., Weir, G.C. & Yankner, B.A. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368, 756–760 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Janson, J., Ashley, R.H., Harrison, D., McIntyre, S. & Butler, P.C. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48, 491–498 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Zraika, S. et al. Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis. Diabetologia 52, 626–635 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zraika, S. et al. Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence? Diabetologia 53, 1046–1056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Badman, M.K., Pryce, R.A., Charge, S.B., Morris, J.F. & Clark, A. Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation. Cell Tissue Res. 291, 285–294 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. de Koning, E.J. et al. Macrophages and pancreatic islet amyloidosis. Amyloid 5, 247–254 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Gitter, B.D., Cox, L.M., Carlson, C.D. & May, P.C. Human amylin stimulates inflammatory cytokine secretion from human glioma cells. Neuroimmunomodulation 7, 147–152 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Yates, S.L. et al. Amyloid beta and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia. J. Neurochem. 74, 1017–1025 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Lamkanfi, M. et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 187, 61–70 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sharp, F.A. et al. Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc. Natl. Acad. Sci. USA 106, 870–875 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Keller, M., Ruegg, A., Werner, S. & Beer, H.D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Hay, D.L., Christopoulos, G., Christopoulos, A., Poyner, D.R. & Sexton, P.M. Pharmacological discrimination of calcitonin receptor: receptor activity-modifying protein complexes. Mol. Pharmacol. 67, 1655–1665 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hamon, Y. et al. Interleukin-1β secretion is impaired by inhibitors of the Atp binding cassette transporter, ABC1. Blood 90, 2911–2915 (1997).

    CAS  PubMed  Google Scholar 

  35. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Boni-Schnetzler, M. et al. Increased interleukin (IL)-1β messenger ribonucleic acid expression in beta-cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93, 4065–4074 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Maedler, K. et al. Glucose-induced beta cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Welsh, N. et al. Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes 54, 3238–3244 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Miller, Y.I. et al. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J. Biol. Chem. 278, 1561–1568 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Apolinario, E. et al. Minimally modified (electronegative) LDL– and Anti-LDL– autoantibodies in diabetes mellitus and impaired glucose tolerance. Int. J Atheroscler. 1, 42–47 (2006).

    CAS  Google Scholar 

  41. Yano, M. et al. Increased electronegative charge of serum low-density lipoprotein in patients with diabetes mellitus. Clin. Chim. Acta 340, 93–98 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Abderrahmani, A. et al. Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic beta cells. Diabetologia 50, 1304–1314 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Bauernfeind, F.G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Matveyenko, A.V. & Butler, P.C. Islet amyloid polypeptide (IAPP) transgenic rodents as models for type 2 diabetes. ILAR J. 47, 225–233 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Hull, R.L. et al. Increased dietary fat promotes islet amyloid formation and beta-cell secretory dysfunction in a transgenic mouse model of islet amyloid. Diabetes 52, 372–379 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Butler, A.E., Janson, J., Soeller, W.C. & Butler, P.C. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 52, 2304–2314 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. van de Veerdonk, F.L. et al. Reactive oxygen species-independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease. Proc. Natl. Acad. Sci. USA 107, 3030–3033 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Russell, J.C. & Proctor, S.D. Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats. Br. J. Pharmacol. 151, 216–225 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Michalska, M., Wolf, G., Walther, R. & Newsholme, P. The effects of pharmacologic inhibition of NADPH oxidase or iNOS on pro-inflammatory cytokine, palmitic acid or H2O2 -induced mouse islet or clonal pancreatic beta cell dysfunction. Biosci. Rep., published online doi:10.1042/BSR20090138 (23 February 2010).

  52. Nilsson, M.R. Techniques to study amyloid fibril formation in vitro. Methods 34, 151–160 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Wang, F., Hull, R.L., Vidal, J., Cnop, M. & Kahn, S.E. Islet amyloid develops diffusely throughout the pancreas before becoming severe and replacing endocrine cells. Diabetes 50, 2514–2520 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Seth L Masters.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 1913 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Masters, S., Dunne, A., Subramanian, S. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 11, 897–904 (2010). https://doi.org/10.1038/ni.1935

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing