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Islet Amyloid Development in a Mouse Strain Lacking Endogenous Islet Amyloid Polypeptide (IAPP) but Expressing Human IAPP

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Abstract

Background

Several mouse strains expressing human islet amyloid polypeptide (IAPP) have been created to study development of islet amyloid and its impact on islet cell function. The tendency to form islet amyloid has varied strongly among these strains by factors that have not been elucidated. Because some beta cell granule components are known to inhibit IAPP fibril formation in vitro, we wanted to determine whether a mouse strain expressing human IAPP but lacking the nonamyloidogenic mouse IAPP is more prone to develop islet amyloidosis.

Materials and Methods

Such a strain was created by cross-breeding a transgenic mouse strain and an IAPP null mouse strain.

Results

When fed a fat-enriched diet, male mice expressing only human IAPP developed islet amyloid earlier and to a higher extent than did mice expressing both human and mouse IAPP. Supporting these results, we found that mouse IAPP dose-dependently inhibits formation of fibrils from human IAPP.

Conclusions

Female mice did not develop amyloid deposits, although small extracellular amorphous IAPP deposits were found in some islets. When cultivated in vitro, amyloid deposits occurred within 10 days in islets from either male or female mice expressing only human IAPP. The study shows that formation of islet amyloid may be dependent on the environment, including the presence or absence of fibril inhibitors or promoters.

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References

  1. Westermark P, Johnson KH, O’Brien TD, Betsholtz C. (1992) Islet amyloid polypeptide a novel controversy in diabetes research. Diabetologia 35: 297–303.

    Article  CAS  PubMed  Google Scholar 

  2. Schmitz O, Nyholm B, Juhl CB, Lund S, Ørskov L. (1999) Aspects on secretion and actions of amylin: interplay between amylin and other hormones. J. Endocrin. Invest. 22(suppl 5): 33–36.

    CAS  Google Scholar 

  3. Westermark P, Wernstedt C, Wilander E, Sletten K. (1986) A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas. Biochem. Biophys. Res. Commun. 140: 827–831.

    Article  CAS  PubMed  Google Scholar 

  4. Westermark P. (1996) Islet pathology of non-insulin-dependent diabetes mellitus (NIDDM). Diabet. Med. 13: S46–48.

    PubMed  CAS  Google Scholar 

  5. Kahn SE, Andrikopoulos S, Verchere CB. (1999) Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 48: 241–253.

    Article  CAS  PubMed  Google Scholar 

  6. Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC. (1999) The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48: 491–498.

    Article  CAS  PubMed  Google Scholar 

  7. Betsholtz C, Svensson V, Rorsman F, et al. (1989) Islet amyloid polypeptide (IAPP): cDNA cloning and identification of an amyloidogenic region associated with the species-specific occurrence of age-related diabetes mellitus. Exp. Cell Res. 183: 484–493.

    Article  CAS  PubMed  Google Scholar 

  8. Westermark P, Engström U, Johnson KH, Westermark GT, Betsholtz C. (1990) Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc. Natl. Acad. Sci. U.S.A. 87: 5036–5040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. D’Alessio DA, Verchere CB, Kahn SE, et al. (1994) Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse. Diabetes 43: 1457–1461.

    Article  PubMed  Google Scholar 

  10. de Koning EJ, Höppener JW, Oosterwijk C, et al. (1993) Localisation of islet amyloid polypeptide (IAPP) in pancreatic islets of transgenic mice expressing the human or rat IAPP gene. Biochem. Soc. Trans. 21: 26S.

    Article  PubMed  Google Scholar 

  11. Fox N, Schrementi J, Nishi M, et al. (1993) Human islet amyloid polypeptide transgenic mice as a model of non-insulin-dependent diabetes mellitus (NIDDM). FEBS Lett. 323: 40–44.

    Article  CAS  PubMed  Google Scholar 

  12. Yagui K, Yamaguchi T, Kanatsuka A, et al. (1995) Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. Eur. J. Endocrinol. 132: 487–496.

    Article  CAS  PubMed  Google Scholar 

  13. Verchere CB, D’Alessio DA, Palmiter RD, et al. (1996) Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide. Proc. Natl. Acad. Sci. U.S.A. 93: 3492–3496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Soeller WC, Janson J, Hart SE, et al. (1998) Islet amyloid-associated diabetes in obese A(vy)/a mice expressing human islet amyloid polypeptide. Diabetes 47: 743–750.

    Article  CAS  PubMed  Google Scholar 

  15. Janson J, Soeller WC, Roche PC, et al. (1999) Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc. Natl. Acad. Sci. U.S.A. 93: 7283–7288.

    Article  Google Scholar 

  16. Höppener JWM, Oosterwijk C, Nieuwenhuis MG, et al. (1999) Extensive islet amyloid formation is induced by development of type 2 diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model. Diabetologia 42: 427–434.

    Article  PubMed  Google Scholar 

  17. Westermark G, Arora MB, Fox N, et al. (1995) Amyloid formation in response to beta cell stress occurs in vitro, but not in vivo, in islets of transgenic mice expressing human islet amyloid polypeptide. Mol. Med. 1: 542–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. de Koning EJ, Morris ER, Hofhuis FM, et al. (1994) Intra- and extracellular amyloid fibrils are formed in cultured pancreatic islets of transgenic mice expressing human islet amyloid polypeptide. Proc. Natl. Acad. Sci. U.S.A. 91: 8467–8471.

    Article  PubMed  PubMed Central  Google Scholar 

  19. MacArthur DLA, de Koning EJP, Verbeek JS, Morris JF, Clark A. (1999) Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets. Diabetologia 42: 1219–1227.

    Article  CAS  PubMed  Google Scholar 

  20. Westermark P, Li ZC, Westermark GT, Leckström A, Steiner DF. (1996) Effects of beta cell granule components on human islet amyloid polypeptide fibril formation. FEBS. Lett. 379: 203–206.

    Article  CAS  PubMed  Google Scholar 

  21. Janciauskiene S, Eriksson S, Carlemalm E, Ahrén B. (1997) B cell granule peptides affect human islet amyloid polypeptide (IAPP) fibril formation in vitro. Biochem. Biophys. Res. Commun. 236: 580–585.

    Article  CAS  PubMed  Google Scholar 

  22. Gebre-Medhin S, Mulder H, Pekny M, et al. (1998) Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin). Biochem. Biophys. Res. Commun. 250: 271–277.

    Article  CAS  PubMed  Google Scholar 

  23. Westermark GT, Leckström A, Ma Z, Westermark P. (1998) Increased release of IAPP in response to long-term high fat intake in mice. Horm. Metab. Res. 30: 256–258.

    Article  CAS  PubMed  Google Scholar 

  24. Westermark GT, Johnson KH, Westermark P. (1999) Staining methods for identification of amyloid in tissue. Meth. Enzymol. 309: 3–25.

    Article  CAS  PubMed  Google Scholar 

  25. Ma Z, Westermark GT, Johnson KH, O’Brien TD, Westermark P. (1998) Quantitative immunohistochemical analysis of islet amyloid polypeptide (IAPP) in normal, impaired glucose tolerant, and diabetic cats. Amyloid 5: 255–261.

    Article  CAS  PubMed  Google Scholar 

  26. LeVine H III. (1999) Quantification of β-sheet amyloid fibrils structures with thioflavin T. Meth. Enzymol. 309: 274–284.

    Article  CAS  PubMed  Google Scholar 

  27. Wisniewski T, Frangione B. (1992) Apolipoprotein E a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett. 135: 235–238.

    Article  CAS  PubMed  Google Scholar 

  28. Young ID, Ailles L, Narindrasorasak S, Tan R, Kisilevsky R. (1992) Localization of the basement membrane heparan sulfate proteoglycan in islet amyloid deposits in type II diabetes mellitus. Arch. Pathol. Lab. Med. 116: 951–954.

    PubMed  CAS  Google Scholar 

  29. Ashburn TT, Lansbury PT. (1993) Interspecies sequence variation affects the kinetics and the thermodynamics of amyloid formation: peptide models of pancreatic amyloid. J. Am. Chem. Soc. 115: 11012–11013.

    Article  CAS  Google Scholar 

  30. Westermark P, Eizirik D, Pipeleers DG, Hellerström C, Andersson A. (1995) Rapid deposition of amyloid in human islets transplanted into nude mice. Diabetologia 38: 543–549.

    Article  CAS  PubMed  Google Scholar 

  31. Clark A, Charge SB, Badman MK, de Koning EJ. (1996) Islet amyloid in type 2 (non-insulin-dependent) diabetes. A.P.M.I.S. 104: 12–18.

    CAS  Google Scholar 

  32. Arnelo U, Permert J, Adrian TE, Larsson J, Westermark P, Reidelberger RD. (1996) Chronic infusion of islet amyloid polypeptide causes anorexia in rats. Am. J. Physiol. 271: R1654–1659.

    PubMed  CAS  Google Scholar 

  33. Arnelo U, Blevins JE, Larsson J, et al. (1996) Effects of acute and chronic infusion of islet amyloid polypeptide on food intake in rats. Scand. J. Gastroenterol. 31: 83–89.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Swedish Medical Research Council (project No 5941), the Research Fund of the Swedish Diabetes Association, and the Novo Nordisk Foundation.

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Authors and Affiliations

  1. Division of Medical Cell Biology, Department of Biomedicine and Surgery, Linköping University, University Hospital, S-581 85, Linköping, Sweden

    Gunilla T. Westermark

  2. Department of Physiological Sciences, Division of Molecular and Cellular Physiology, Lund University, Uppsala, Sweden

    Samuel Gebre-Medhin

  3. Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Per Westermark

  4. Department of Biochemistry and Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois, USA

    Donald F. Steiner

Authors
  1. Gunilla T. Westermark
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  2. Samuel Gebre-Medhin
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  3. Donald F. Steiner
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  4. Per Westermark
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Correspondence to Gunilla T. Westermark.

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Westermark, G.T., Gebre-Medhin, S., Steiner, D.F. et al. Islet Amyloid Development in a Mouse Strain Lacking Endogenous Islet Amyloid Polypeptide (IAPP) but Expressing Human IAPP. Mol Med 6, 998–1007 (2000). https://doi.org/10.1007/BF03402051

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