Skip to main content
SpringerLink
Log in

Islet Amyloid Polypeptide: Aggregation and Fibrillogenesisin vitroand Its Inhibition

  • Chapter
  • First Online:
Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease

Part of the book series: Subcellular Biochemistry ((SCBI,volume 65))

Abstract

The development of type 2 diabetes mellitus is associated with the dysfunction of b-cells which is correlated to the formation of deposits consisting of the islet amyloid polypeptide (IAPP). The process of human IAPP (hIAPP) self-association, the intermediate structures formed as well as the interaction of hIAPP with membrane systems seem to be responsible for the cytotoxicity. For monomeric hIAPP, a natively random coil conformation with transient a-helical parts could be determined in bulk solution, which rapidly converts to an amyloid structure consisting of cross b-sheets. By comparing the amyloidogenic propensities of hIAPP in the bulk and in the presence of various neutral and charged lipid bilayer systems as well as biological membranes, an enhancing effect of anionic and heterogeneous membranes to hIAPP fibril formation has been found. We also discuss the cross-interaction of hIAPP with other amyloidogenic peptides (e.g., insulin and Ab) and present first small-molecule inhibitors of the fibrillation process of hIAPP.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Andrews MN, Winter R (2011) Comparing the structural properties of human and rat islet amyloid polypeptide by MD computer simulations. Biophys Chem 156:43–50

    Article  PubMed  CAS  Google Scholar 

  • Brittes J, Lúcio M, Nunes C, Lima JLFC, Reis S (2010) Effects of resveratrol on membrane biophysical properties: relevance for its pharmacological effects. Chem Phys Lipids 163:747–754

    Article  PubMed  CAS  Google Scholar 

  • Bulic B, Pickhardt M, Khlistunova I, Biernat J, Mandelkow EM, Mandelkow E, Waldmann H (2007) Rhodanine-based tau aggregation inhibitors in cell models of tauopathy. Angew Chem Int Ed 46:9215–9219

    Article  Google Scholar 

  • Butterfield SM, Lashuel HA (2010) Amyloidogenic protein-membrane interactions: mechanistic insight from model systems. Angew Chem Int Ed 49:5628–5654

    Article  CAS  Google Scholar 

  • Clark A, Lewis CE, Willis AC, Cooper GJS, Morris JF, Reid KBM, Turner RC (1987) Islet amyloid formed from diabetes-associated peptide may be pathogenic in type-2 diabetes. Lancet 330:231–234

    Article  Google Scholar 

  • Clément L, Kim-Sohn KA, Magnan C, Kassis N, Adnot P, Kergoat M, Assimacopoulos-Jeannet F, Pénicaud L, Hsu FF, Turk J, Ktorza A (2002) Pancreatic β-Cell α2A Adrenoceptor and Phospholipid Changes in Hyperlipidemic Rats. Lipids 37:501–506

    Article  PubMed  Google Scholar 

  • Cooper GJS, Willis AC, Clark A, Turner RC, Sim RB, Reid KBM (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci U S A 84:8628–8632

    Article  PubMed  CAS  Google Scholar 

  • Cooper GJS, Leighton B, Dimitriadis GD, Parry-Billings M, Kowalchuk JM, Howland K, Rothbard JB, Willis AC, Reid KBM (1988) Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle. Proc Natl Acad Sci U S A 85:7763–7766

    Article  PubMed  CAS  Google Scholar 

  • Engel MFM, Khemtémourian L, Kleijer CC, Meeldijk HJ, Jacobs J, Verkleij AJ, de Kruijff B, Killian JA, Höppener JW (2008) Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane. Proc Natl Acad Sci U S A 105:6033–6038

    Article  PubMed  CAS  Google Scholar 

  • Evers F, Jeworrek C, Tiemeyer S, Weise K, Sellin D, Paulus M, Struth B, Tolan M, Winter R (2009) Elucidating the mechanism of lipid membrane-induced IAPP fibrillogenesis and its inhibition by the red wine compound resveratrol: a synchrotron X-ray reflectivity study. J Am Chem Soc 131:9516–9521

    Article  PubMed  CAS  Google Scholar 

  • Goldsbury C, Goldie K, Pellaud J, Seelig J, Frey P, Müller SA, Kistler J, Cooper GJ, Aebi U (2000) Amyloid fibril formation from full-length and fragments of amylin. J Struct Biol 130:352–362

    Article  PubMed  CAS  Google Scholar 

  • Gurlo T, Ryazantsev S, Huang CJ, Yeh MW, Reber HA, Hines OJ, O’Brien TD, Glabe CG, Butler PC (2010) Evidence for proteotoxicity in beta cells in type 2 diabetes: toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway. Am J Pathol 176:861–869

    Article  PubMed  CAS  Google Scholar 

  • Hebda JA, Miranker AD (2009) The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes. Annu Rev Biophys 38:125–152

    Article  PubMed  CAS  Google Scholar 

  • Hull RL, Westermark GT, Westermark P, Kahn SE (2004) Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab 89:3629–3643

    Article  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Jayasinghe SA, Langen R (2007) Membrane interaction of islet amyloid polypeptide. Biochim Biophys Acta Biomembr 1768:2002–2009

    Article  CAS  Google Scholar 

  • Jha S, Sellin D, Seidel R, Winter R (2009) Amyloidogenic propensities and conformational properties of proIAPP and IAPP in the presence of lipid bilayer membranes. J Mol Biol 389:907–920

    Article  PubMed  CAS  Google Scholar 

  • Jiang P, Li W, Shea JE, Mu Y (2011) Resveratrol inhibits the formation of multiple-layered sheet oligomers of the human islet amyloid polypeptide segment 22–27. Biophys J 100:1550–1558

    Article  Google Scholar 

  • Johnson KH, O’Brien TD, Betsholtz C, Westermark P (1992) Islet amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus. Lab Invest 66:522–535

    PubMed  CAS  Google Scholar 

  • Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K (2002) Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 41:7385–7390

    Article  PubMed  CAS  Google Scholar 

  • Kapoor S, Werkmüller A, Denter C, Zhai Y, Markgraf J, Weise K, Opitz N, Winter R (2011) Temperature-pressure phase diagram of a heterogeneous anionic model biomembrane system: results from a combined calorimetry, spectroscopy and microscopy study. Biochim Biophys Acta Biomembr 1808:1187–1195

    Article  CAS  Google Scholar 

  • Kayed R, Bernhagen J, Greenfield N, Sweimeh K, Brunner H, Voelter W, Kapurniotu A (1999) Conformational transitions of islet amyloid polypeptide (IAPP) in amyloid formation in vitro. J Mol Biol 287:781–796

    Article  PubMed  CAS  Google Scholar 

  • Knight JD, Miranker AD (2004) Phospholipid catalysis of diabetic amyloid assembly. J Mol Biol 341:1175–1187

    Article  PubMed  CAS  Google Scholar 

  • Leighton B, Cooper GJS (1988) Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 335:632–635

    Article  PubMed  CAS  Google Scholar 

  • Lopes DHJ, Meister A, Gohlke A, Hauser A, Blume A, Winter R (2007) Mechanism of islet amyloid polypeptide fibrillation at lipid interfaces studied by infrared reflection absorption spectroscopy. Biophys J 93:3132–3141

    Article  PubMed  CAS  Google Scholar 

  • Marzban L, Soukhatcheva G, Verchere CB (2005) Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in β-cells. Endocrinology 146:1808–1817

    Article  PubMed  CAS  Google Scholar 

  • Merglen A, Theander S, Rubi B, Chaffard G, Wollheim CB, Maechler P (2004) Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells. Endocrinology 145:667–678

    Article  PubMed  CAS  Google Scholar 

  • Mirzabekov TA, Lin MC, Kagan BL (1996) Pore formation by the cytotoxic islet amyloid peptide amylin. J Biol Chem 271:1988–1992

    Article  PubMed  CAS  Google Scholar 

  • Mishra R, Bulic B, Sellin D, Jha S, Waldmann H, Winter R (2008) Small-molecule inhibitors of islet amyloid polypeptide fibril formation. Angew Chem Int Ed 47:4679–4682

    Article  CAS  Google Scholar 

  • Mishra R, Geyer M, Winter R (2009a) NMR spectroscopic investigation of early events in IAPP amyloid fibril formation. ChemBioChem 10:1769–1772

    Article  CAS  Google Scholar 

  • Mishra R, Sellin D, Radovan D, Gohlke A, Winter R (2009b) Inhibiting islet amyloid polypeptide fibril formation by the red wine compound resveratrol. ChemBioChem 10:445–449

    Article  CAS  Google Scholar 

  • Naiki H, Higuchi K, Hosokawa M, Takeda T (1989) Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavine T. Anal Biochem 177:244–249

    Article  PubMed  CAS  Google Scholar 

  • Nishi M, Sanke T, Nagamatsu S, Bell GI, Steiner DF (1990) Islet amyloid polypeptide—a new β- cell secretory product related to islet amyloid deposits. J Biol Chem 265:4173–4176

    PubMed  CAS  Google Scholar 

  • Opie EL (1901) The relation of diabetes mellitus to lesions of the pancreas: hyaline degeneration of the islets of Langerhans. J Exp Med 5:527–540

    Article  PubMed  CAS  Google Scholar 

  • Porat Y, Kolusheva S, Jelinek R, Gazit E (2003) The human islet amyloid polypeptide forms transient membrane-active prefibrillar assemblies. Biochemistry 42:10971–10977

    Article  PubMed  CAS  Google Scholar 

  • Porat Y, Abramowitz A, Gazit E (2006) Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 67:27–37

    Article  PubMed  CAS  Google Scholar 

  • Radovan D, Opitz N, Winter R (2009) Fluorescence microscopy studies on islet amyloid polypeptide fibrillation at heterogeneous and cellular membrane interfaces and its inhibition by resveratrol. FEBS Lett 583:1439–1445

    Article  PubMed  CAS  Google Scholar 

  • Rauch S, Fackler OT (2007) Viruses, lipid rafts and signal transduction. Signal Transduction 7:53–63

    Article  CAS  Google Scholar 

  • Sanke T, Bell GI, Sample C, Rubenstein AH, Steiner DF (1988) An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing. J Biol Chem 263:17243–17246

    PubMed  CAS  Google Scholar 

  • Seeliger J, Evers F, Jeworrek C, Kapoor S, Weise K, Andreetto E, Tolan M, Kapurniotu A, Winter R (2012a) Cross-amyloid interaction of Aβ and IAPP at lipid membranes. Angew Chem Int Ed 51:679–683

    Google Scholar 

  • Seeliger J, Weise K, Opitz N, Winter R (2012b) The effect of Aβ on IAPP aggregation in the presence of an isolated β-cell membrane. J Mol Biol 421:348–363

    Google Scholar 

  • Sellin D, Yan LM, Kapurniotu A, Winter R (2010) Suppression of IAPP fibrillation at anionic lipid membranes via IAPP-derived amyloid inhibitors and insulin. Biophys Chem 150:73–79

    Article  PubMed  CAS  Google Scholar 

  • Staubach S, Hanisch FG (2011) Lipid rafts: signaling and sorting platforms of cells and their roles in cancer. Expert Rev Proteomics 8:263–277

    Article  PubMed  CAS  Google Scholar 

  • Turk J, Wolf BA, Lefkowith JB, Stump WT, McDaniel ML (1986) Glucose-induced phospholipid hydrolysis in isolated pancreatic islets: quantitative effects on the phospholipid content of arachidonate and other fatty acids. Biochim Biophys Acta Lipids Lipid Metab 879:399–409

    Article  CAS  Google Scholar 

  • Wakabayashi M, Matsuzaki K (2007) Formation of amyloids by Abeta-(1–42) on NGF-differentiated PC12 cells: roles of gangliosides and cholesterol. J Mol Biol 371:924–933

    Article  PubMed  CAS  Google Scholar 

  • Weichselbaum A, Stangl E (1901) Zur Kenntnis der feineren Veränderungen des Pankreas bei Diabetes mellitus. Wien Klein Wochenschr 14:968–972

    Google Scholar 

  • Weise K, Radovan D, Gohlke A, Opitz N, Winter R (2010a) Interaction of hIAPP with model raft membranes and pancreatic β-cells: cytotoxicity of hIAPP oligomers. ChemBioChem 11:1280–1290

    Article  CAS  Google Scholar 

  • Weise K, Triola G, Janosch S, Waldmann H, Winter R (2010b) Visualizing association of lipidated signaling proteins in heterogeneous membranes—partitioning into subdomains, lipid sorting, interfacial adsorption, and protein association. Biochim Biophys Acta Biomembr 1798:1409–1417

    Article  CAS  Google Scholar 

  • Westermark P (1973) Fine structure of islets of Langerhans in insular amyloidosis. Virchows Arch A Pathol Anat 359:1–18

    Article  PubMed  CAS  Google Scholar 

  • Westermark P (2011) Amyloid in the islets of Langerhans: thoughts and some historical aspects. Upsala J Med Sci 116:81–89

    Article  PubMed  Google Scholar 

  • Westermark P, Wernstedt C, Wilander E, Hayden DW, O’Brien TD, Johnson KH (1987) 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 84:3881–3885

    Article  PubMed  CAS  Google Scholar 

  • Westermark G, Westermark P, Eizirik DL, Hellerström C, Fox N, Steiner DF, Andersson A (1999) Differences in amyloid deposition in islets of transgenic mice expressing human islet amyloid polypeptide versus human islets implanted into nude mice. Metabolism 48:448–454

    Article  PubMed  CAS  Google Scholar 

  • Yan LM, Velkova A, Tatarek-Nossol M, Andreetto E, Kapurniotu A (2007) IAPP mimic blocks Ab cytotoxic self-assembly: cross-suppression of amyloid toxicity of Aβ and IAPP suggests a molecular link between Alzheimer’s disease and type II diabetes. Angew Chem Int Ed 46:1246–1252

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Financial support from the DFG, the BMBF, the country Northrhine Westfalia, and the European Union (Europäischer Fonds für regionale Entwicklung), is gratefully acknowledged. We thank our collaboration partners Prof. Dr. A. Kapurniotu and Prof. Dr. A. Blume for many helpful discussions. INS-1E cell line was a gift from Dr. Pierre Maechler (University Hospital, Geneva, Switzerland).

Author information

Authors and Affiliations

  1. Faculty of Chemistry, Physical Chemistry I-Biophysical Chemistry, TU Dortmund University, Otto-Hahn Str. 6, 44227, Dortmund, Germany

    Janine Seeliger & Roland Winter

Authors
  1. Janine Seeliger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roland Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roland Winter .

Editor information

Editors and Affiliations

  1. Inst. of Zoology, University of Mainz, Becherweg 6, Mainz, 55099, Germany

    J. Robin Harris

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Seeliger, J., Winter, R. (2012). Islet Amyloid Polypeptide: Aggregation and Fibrillogenesisin vitroand Its Inhibition. In: Harris, J. (eds) Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease. Subcellular Biochemistry, vol 65. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5416-4_8

Download citation

Publish with us

Policies and ethics

Search

Navigation