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Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus

Nature volume 368, pages 756–760 (1994)Cite this article

Abstract

THE 37-amino-acid polypeptide amylin is the principal constituent of the amyloid deposits that form in the islets of Langerhans in patients with type-2 diabetes mellitus1–5, but its role in the pathogenesis of this disease is unresolved6–8. In view of the fact that the β-amyloid protein that forms fibrils in Alzheimer's disease is toxic to neurons 9,10, we have investigated whether amylin fibrils could be toxic to pancreatic islet cells. We show here that human amylin is toxic to insulin-producing β-cells of the adult pancreas of rats and humans. This toxicity is mediated by the fibrillar form of the amylin peptide and requires direct contact of the fibrils with the cell surface. The mechanism of cell death involves RNA and protein synthesis and is characterized by plasma membrane blebbing, chromatin condensation and DNA fragmentation, indicating that amylin induces islet cell apoptosis. These findings indicate that amylin fibril formation in the pancreas may cause islet cell dysfunction and death in type-2 diabetes mellitus.

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References

  1. Opie, E. L. J. exp. Med. 5, 397–428 (1900).

    Article  Google Scholar 

  2. Cooper, G. J. S. et al. Proc. natn. Acad. Sci. U.S.A. 84, 8628–8632 (1987).

    Article  ADS  CAS  Google Scholar 

  3. Westermark, P. et al. Proc. natn. Acad. Sci. U.S.A. 84, 3881–3885 (1987).

    Article  ADS  CAS  Google Scholar 

  4. Westermark, P., Wernstedt, C., O'Brien, T. D., Hayden, D. W. & Johnson, K. H. Am. J. Path. 127, 414–417 (1987).

    CAS  PubMed  Google Scholar 

  5. Cooper, G. J. S. et al. Proc. natn. Acad. Sci. U.S.A. 85, 7763–7766 (1988).

    Article  ADS  CAS  Google Scholar 

  6. Leighton, B. & Cooper, G. J. S. Nature 335, 632–635 (1988).

    Article  ADS  CAS  Google Scholar 

  7. Johnson, K. H., O'Brien, T. D., Betsholtz, C. & Westermark, P. New Engl. J. Med. 321, 513–518 (1989).

    Article  CAS  Google Scholar 

  8. O'Brien, T. D., Butler, P. C., Westermark, P. & Johnson, K. H. Vet. Path. 30, 317–332 (1993).

    Article  CAS  Google Scholar 

  9. Yankner, B. A. et al. Science 245, 417–420 (1989).

    Article  ADS  CAS  Google Scholar 

  10. Yankner, B. A., Duffy, L. K. & Kirschner, D. A. Science 250, 279–282 (1990).

    Article  ADS  CAS  Google Scholar 

  11. May, P. C., Boggs, L. N. & Fuson, K. S. J. Neurochem. 61, 2330–2333 (1993).

    Article  CAS  Google Scholar 

  12. Fraser, P. E., Nguyen, W. K., Surewicz, W. D. & Kirschner, D. A. Biophys. J. 60, 1190–1201 (1991).

    Article  CAS  Google Scholar 

  13. Westermark, P., Engstrom, U., Johnson, K. H., Westermark, G. T. & Betsholtz, C. Proc. natn. Acad. Sci. U.S.A. 87, 5036–5040 (1990).

    Article  ADS  CAS  Google Scholar 

  14. Betsholtz, C. et al. FEBS Lett. 251, 261–264 (1989).

    Article  CAS  Google Scholar 

  15. Leffert, J. D., Newgard, C. B., Okamoto, H., Milburn, J. L. & Luskey, K. L. Proc. natn. Acad. Sci. U.S.A. 86, 3127–3130 (1989).

    Article  ADS  CAS  Google Scholar 

  16. Nishi, M., Chan, S. J., Nagamatsu, S., Belle, G. I. & Steiner, D. F. Proc. natn. Acad. Sci. U.S.A. 86, 5738–5742 (1989).

    Article  ADS  CAS  Google Scholar 

  17. Batistatou, A. & Greene, L. A. J. Cell Biol. 115, 461–471 (1991).

    Article  CAS  Google Scholar 

  18. Wyllie, A. H., Kerr, F. F. R. & Currie, A. R. Int. Rev. Cytol. 68, 251–306 (1980).

    Article  CAS  Google Scholar 

  19. Maloy, A. L., Longnecker, D. S. & Greenberg, E. R. Hum. Path. 12, 917–922 (1981).

    Article  CAS  Google Scholar 

  20. Westermark, P. Uppsala J. Med. Sci. 77, 91–94 (1972).

    Article  CAS  Google Scholar 

  21. Yankner, B. A. & Mesulam M.-M. New Engl. J. Med. 325, 1849–1857 (1991).

    Article  CAS  Google Scholar 

  22. Forloni, G. et al. Nature 362, 543–546 (1993).

    Article  ADS  CAS  Google Scholar 

  23. DeArmond, S. J. et al. Cell 41, 221–235 (1985).

    Article  CAS  Google Scholar 

  24. Forloni, G. et al. NeuroReport 4, 523–526 (1993).

    Article  CAS  Google Scholar 

  25. Takashima, A., Noguchi, K., Sato, K., Hoshino, T. & Imahori, K. Proc. natn. Acad. Sci. U.S.A. 90, 7789–7793 (1993).

    Article  ADS  CAS  Google Scholar 

  26. Loo, D. T. et al. Proc. natn. Acad. Sci. U.S.A. 90, 7951–7955 (1993).

    Article  ADS  CAS  Google Scholar 

  27. Schuppin, G. T., Bonner-Weir, S., Montana, E., Kaiser, N. & Weir G. C. In Vitro Cell dev. Biol. 29, 339–344 (1993).

    Article  Google Scholar 

  28. Ricordi, D. et al. Surgery 107, 688–694 (1990).

    CAS  PubMed  Google Scholar 

  29. Weston, S. A. & Parish, C. R. J. immunol. Meth. 133, 87–95 (1990).

    Article  CAS  Google Scholar 

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Author notes

  1. Bruce A. Yankner: To whom correspondence should be addressed

Authors and Affiliations

  1. Department of Neurology, Harvard Medical School and The Children's Hospital, Enders 260, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Alfredo Lorenzo, Bronwyn Razzaboni & Bruce A. Yankner

  2. Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, 02215, USA

    Gordon C. Weir

Authors
  1. Alfredo Lorenzo
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  2. Bronwyn Razzaboni
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  3. Gordon C. Weir
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  4. Bruce A. Yankner
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Lorenzo, A., Razzaboni, B., Weir, G. et al. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368, 756–760 (1994). https://doi.org/10.1038/368756a0

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