Skip to main content
SpringerLink
Log in

Is aggregated IAPP a cause of beta-cell failure in transplanted human pancreatic islets?

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Aggregation of the â-cell product islet amyloid polypeptide (IAPP) is believed to be an important event in the development of the â-cell lesion in type 2 diabetes. Preamyloidotic oligomeric IAPP assemblies exert toxic effects on â cells that die, leading to reduced â-cell mass. Normal human islets, when isolated and cultured in vitro or transplanted into nude mice, also develop amyloid deposits, which are associated with increased â-cell death and reduced â-cell mass. The possible role of IAPP aggregation and amyloid formation in loss of islet transplant function should be taken into consideration and studied further.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Hull RL, Westermark GT, Westermark P, Kahn SE: Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab 2004, 89:3629–3643. State-of-the-art article on the importance of IAPP aggregation for the â-cell failure in type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  2. Rochet JC, Lansbury PTJ: Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 2000, 10:60–68.

    Article  PubMed  CAS  Google Scholar 

  3. Kayed R, Head E, Thompson JL, et al.: Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003, 300:486–489. For those who want to get information as to why proteins aggregate into amyloid and how aggregates exert their toxicity.

    Article  PubMed  CAS  Google Scholar 

  4. Kayed R, Sokolov Y, Edmonds B, et al.: Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 2004, 279:46363–46366.

    Article  PubMed  CAS  Google Scholar 

  5. Yuan J, Yankner BA: Apoptosis in the nervous system. Nature 2000, 407:802–809.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Westermark P, Wernstedt C, Wilander E, 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 U S A 1987, 84:3881–3885.

    Article  PubMed  CAS  Google Scholar 

  8. Cooper GJ, Willis AC, Clark A, et al.: Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci U S A 1987, 84:8628–8632.

    Article  PubMed  CAS  Google Scholar 

  9. Wang J, Xu J, Finnerty J, et al.: The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site. Diabetes 2001, 50:534–539.

    Article  PubMed  CAS  Google Scholar 

  10. Smeekens SP, Montag Ag, Thomas G, et al.: Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3. Proc Natl Acad Sci U S A 1992, 89:8822–8826.

    Article  PubMed  CAS  Google Scholar 

  11. Ward WK, LaCava EC, Paquette TL, et al.: Disproportionate elevation of immunoreactive proinsulin in type 2 (noninsulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 1987, 30:698–702.

    Article  PubMed  CAS  Google Scholar 

  12. Westermark P, Li ZC, Westermark GT, et al.: Effects of beta cell granule components on human islet amyloid polypeptide fibril formation. FEBS Lett 1996, 379:203–206.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Jaikaran ET, Clark A: Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology. Biochim Biophys Acta 2001, 1537:179–203.

    PubMed  CAS  Google Scholar 

  15. Westermark P: Amyloid and polypeptide hormones: what is their inter-relationship? Amyloid 1994, 1:47–60.

    Article  CAS  Google Scholar 

  16. Westermark P, Engström U, Johnson KH, et al.: Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci U S A 1990, 87:5036–5040.

    Article  PubMed  CAS  Google Scholar 

  17. Westermark P, Johnson KH, O'Brien TD, Betsholtz C: Islet amyloid polypeptide-a novel controversy in diabetes research. Diabetologia 1992, 35:297–303.

    Article  PubMed  CAS  Google Scholar 

  18. Westermark P, Grimelius L: The pancreatic islet cells in insular amyloidosis in human diabetic and non-diabetic adults. Acta Pathol Microbiol Scand [A] 1973, 81:291–300.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  20. Butler AE, Janson J, Bonner-Weir S, et al.: Beta-cell deficit and increase beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003, 52:102–110.

    Article  PubMed  CAS  Google Scholar 

  21. Howard CFJ: Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia 1986, 29:301–306.

    Article  PubMed  Google Scholar 

  22. Johnson KH, O'Brien TD, Betsholtz C, Westermark P: Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 1989, 321:513–518.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  24. Verchere CB, D'Alessio DA, Palmiter RD, 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 U S A 1996, 93:3492–3496.

    Article  PubMed  CAS  Google Scholar 

  25. Westermark GT, Gebre-Medhin S, Steiner DF, Westermark P: Islet amyloid development in a mouse strain lacking endogenous islet amyloid polypeptide (IAPP) but expressing human IAPP. Mol Med 2000, 6:998–1007.

    PubMed  CAS  Google Scholar 

  26. Butler AE, Janson J, Soeller WC, Butler PC: 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 2003, 52:2304–2314.

    Article  PubMed  CAS  Google Scholar 

  27. Butler AE, Jang J, Gurlo T, 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 2004, 53:1509–1516.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  29. Sakagashira S, Sanke T, Hanabusa T, et al.: Missense mutation of amylin gene (S20G) in Japanese NIDDM patients. Diabetes 1996, 45:1279–1281.

    Article  PubMed  CAS  Google Scholar 

  30. O'Brien TD, Butler AE, Roche PC, et al.: Islet amyloid polypeptide in human insulinomas. Evidence for intracellular amyloidogenesis. Diabetes 1994, 43:329–336.

    Article  PubMed  Google Scholar 

  31. Westermark GT, Steiner DF, Gebre-Medhin S, et al.: Pro islet amyloid polypeptide (proIAPP) immunoreactivity in amyloid formation in the islets of Langerhans. Upsala J Med Sci 2000, 105:97–106.

    PubMed  CAS  Google Scholar 

  32. Westermark P, Eizirik DL, Pipeleers DG, et al.: Rapid deposition of amyloid in human islets transplanted into nude mice. Diabetologia 1995, 38:543–549.

    PubMed  CAS  Google Scholar 

  33. Westermark GT, Westermark P, Eizirik D, et al.: Differences in amyloid deposition in islets of transgenic mice expressing human islet amyloid polypeptide versus human islets implanted into nude mice. Metabolism 1999, 48:448–454.

    Article  PubMed  CAS  Google Scholar 

  34. Shapiro AMJ, Lakey JRT, Ryan EA, et al.: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid free immunosuppressive regiment. N Engl J Med 2000, 343:230–238.

    Article  PubMed  CAS  Google Scholar 

  35. Ryan EA, Lakey JRT, Paty BW, et al.: Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 2002, 51:2148–2157.

    Article  PubMed  CAS  Google Scholar 

  36. Street CN, Lakey JRT, Shapiro AMJ, et al.: Islet graft assessment in the Edmonton Protocol. Implications for predicting long-term clinical outcome. Diabetes 2004, 53:3107–3114. Summarizes the present knowledge about clinical islet transplantation.

    Article  PubMed  CAS  Google Scholar 

  37. Eizirik DL, Pipeleers DG, Ling Z, et al.: Major species differences between man and rodents in the susceptibility to pancreatic beta-cell injury. Proc Natl Acad Sci U S A 1994, 91:9253–9256.

    Article  PubMed  CAS  Google Scholar 

  38. Westermark GT, Westermark P, Nordin A, et al.: Formation of amyloid in human pancreatic islets transplanted to the liver and spleen of nude mice. Upsala J Med Sci 2003, 108:193–204. One of few articles dealing with the putative role of IAPP aggregation for human islet transplant failure.

    Article  PubMed  Google Scholar 

  39. Kodama K, Hull RL, Wildbur S, et al.: Amyloid formation following islet transplantation is associated with increased beta-cell apoptosis, decreased beta-cell replication and reduced beta-cell volume [abstract]. Diabetes 2004, 53:A375-A376.

    Google Scholar 

  40. Westermark G, Benig Arora M, Fox N, et al.: 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 1995, 1:542–543.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedicine and Surgery, Cell Biology, Linköping University, 12, University Hospital, 581 85, Linköping, SE, Sweden

    Per Westermark MD,PhD

Authors
  1. Per Westermark MD,PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arne Andersson MD,PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gunilla T. Westermark PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Westermark, P., Andersson, A. & Westermark, G.T. Is aggregated IAPP a cause of beta-cell failure in transplanted human pancreatic islets?. Curr Diab Rep 5, 184–188 (2005). https://doi.org/10.1007/s11892-005-0007-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-005-0007-2

Keywords

Search

Navigation