Abstract

In patients or animals affected by 2 type diabetes mellitus (diabetes mellitus type 2, DM2, non-insulin-dependent diabetes mellitus, NIDDM) or pancreatic tumor disease e.g., insulinoma, some pathological deposits, called amyloid, are observed among cells of islets of Langerhans. Among other constituents, pancreatic deposits consist of an insoluble, fibrillar form of peptide neurohormone termed amylin, produced by pancreatic beta cells. It is thought that formation of fibrillar deposits of misfolded and aggregated peptide is highly toxic to beta cells and leads to cell dysfunction, cell loss, pancreas destruction and progress of the disease.This relatively small, 37-amino acid peptide constitutes a serious scientific, research and to some extent a medical problem. This article presents amylin as a fibrillating molecule which participates in formation of amyloid deposits in human and animal pancreas, Langerhans islets as a microenvironment of pancreatic amyloid formation, occurrence of amylin and amyloid in animals and humans, and physico-chemical requirements to meet to name amylin deposit as amyloid.

References

• 1. Abedini A., Raleigh D.P.: Incorporation of pseudoproline derivativesallows the facile synthesis of human IAPP, a highly amyloidogenicand aggregation-prone polypeptide. Org. Lett., 2005; 7: 693-696 2 Andralojc K.M., Mercalli A., Nowak K.W., Albarello L., CalcagnoR., Luzi L., Bonifacio E., Doglioni C., Piemonti L.: Ghrelin-producingepsilon cells in the developing and adult human pancreas. Diabetologia,2009; 52: 486-493
  Google Scholar
• 2. diabetes. J. Pancreas, 2002, 2: 124-139
  Google Scholar
• 3. Barreto S.G., Carati C.J., Toouli J., Saccone G.T.: The islet-acinaraxis of the pancreas: more than just insulin. Am. J. Physiol. Gastrointest.Liver Physiol., 2010; 299: G10-G22
  Google Scholar
• 4. Betsholtz C., Christmansson L., Engström U., Rorsman F., SvenssonV., Johnson K.H., Westermark P.: Sequence divergence in a specific regionof islet amyloid polypeptide (IAPP) explains differences in isletamyloid formation between species. FEBS Lett., 1989; 251: 261-264
  Google Scholar
• 5. Brass B.J., Ablev Z., Liao E.P., Poretsky L.: Endocrine Pancreas.Chapter 3, W: Principles of Diabetes Mellitus. 2, red.: L. Poretsky.Springer Science+Business Media 2010, 37-55
  Google Scholar
• 6. Cabrera O., Berman D.M., Kenyon N.S., Ricordi C., Berggren P.O.,Caicedo A.: The unique cytoarchitecture of human pancreatic isletshas implications for islet cell function. Proc. Natl. Acad. Sci. USA,2006; 103: 2334-2339
  Google Scholar
• 7. Capella C., Solcia E., Frigerio B., Buffa R., Usellini L., Fontana P.:The endocrine cells of the pancreas and related tumours. Ultrastructuralstudy and classification. Virchows Arch. A Pathol. Anat.Histol., 1977; 373: 327-352
  Google Scholar
• 8. Carlotti F., Zaldumbide A., Loomans C.J., van Rossenberg E., EngelseM., de Koning E.J., Hoeben R.C.: Isolated human islets containa distinct population of mesenchymal stem cells. Islets, 2010; 2:164-173
  Google Scholar
• 9. Castillo G.M., Cummings J.A., Yang W., Judge M.E., SheardownM.J., Rimvall K., Hansen J.B., Snow A.D.: Sulfate content and specificglycosaminoglycan backbone of perlecan are critical for perlecan’senhancement of islet amyloid polypeptide (amylin) fibril formation.Diabetes, 1998; 47: 612-620
  Google Scholar
• 10. Cerf M.E.: Islet organogenesis, angiogenesis and innervation.Cell Biol. Int., 2011; 35: 1065-1078
  Google Scholar
• 11. Christmanson L., Betsholtz C., Leckström A., Engström U., CortieC., Johnson K.H., Adrian T.E., Westermark P.: Islet amyloid polypeptidein the rabbit and European hare: studies on its relationship toamyloidogenesis. Diabetologia, 1993; 36: 183-188
  Google Scholar
• 12. Christopher R.J., Takeuchi K., Lee B.: Rodent Models of Diabetes.W: Principles of Diabetes Mellitus, red.: L. Poretsky. SpringerScience+Business Media, 2010: 165-178
  Google Scholar
• 13. Clark A., Cooper G.J., Lewis C.E., Morris J.F., Willis A.C., Reid K.B.,Turner R.C.: Islet amyloid formed from diabetes-associated peptidemay be pathogenic in type-2 diabetes. Lancet, 1987; 2: 231-234
  Google Scholar
• 14. Clark A., Nilsson M.R.: Islet amyloid: a complication of islet dysfunctionor an aetiological factor in Type 2 diabetes? Diabetologia,2004; 47: 157-169
  Google Scholar
• 15. Clark A., Saad M.F., Nezzer T., Uren C., Knowler W.C., Bennett P.H.,Turner R.C.: Islet amyloid polypeptide in diabetic and non-diabeticPima Indians. Diabetologia, 1990; 33: 285-289
  Google Scholar
• 16. Cooper G.J., Leighton B., Dimitriadis G.D., Parry-Billings M., KowalchukJ.M., Howland K., Rothbard J.B., Willis A.C., Reid K.B.: Amylinfound in amyloid deposits in human type 2 diabetes mellitus may bea hormone that regulates glycogen metabolism in skeletal muscle.Proc. Natl. Acad. Sci. USA, 1988; 85: 7763-7766
  Google Scholar
• 17. Cooper G.J., Willis A.C., Clark A., Turner R.C., Sim R.B., Reid K.B.:Purifcation and characterisation of a peptide from amyloid-richpancreases of type 2 diabetic patients. Proc. Natl. Acad. Sci. USA,1987; 84: 8628-8632
  Google Scholar
• 18. Cooper G.J., Willis A.C., Reid K.B., Clark A., Baker C.A., TurnerR.C., Lewis C.E., Morris J.F., Howland K., Rothbard J.B.: Diabetesassociatedpeptide. Lancet, 1987; 2: 966
  Google Scholar
• 19. Czakó L., Hegyi P., Rakonczay Z. Jr., Wittmann T., Otsuki M.: Interactionsbetween the endocrine and exocrine pancreas and theirclinical relevance. Pancreatology, 2009; 9: 351-359
  Google Scholar
• 20. de Koning E.P.J., Morris E.R., Hofhuis F.M., Posthuma G., HöppenerJ.W., Morris J.F., Capel P.J., Clark A., Verbeek J.S.: Intra – andextracellular amyloid fibrils are formed in cultured pancreatic isletsof transgenic mice expressing human islet amyloid polypeptide.Proc. Natl. Acad. Sci. USA, 1994; 91: 8467-8471
  Google Scholar
• 21. Dumon K., Rosate E.F.: The Pancreas. W: The clinical review: anintegrated basic and clinical science study guide. Red.: P. Tluri, C.Karakousis, P.M. Porrett, L.R. Kaiser. Lippincott Williams &Wilkins,Philadelphia 2006, 480
  Google Scholar
• 22. Eanes E.D., Glenner G.G.: X-ray diffraction studies on amyloidfilaments. J. Histochem. Cytochem., 1968; 16: 673-677
  Google Scholar
• 23. Ehrlich J.C., Ratner I.M.: Amyloidosis of the islets of Langerhans. A restudy of islet hyalin in diabetic and non-diabetic individuals.Am. J. Pathol., 1961; 38: 49-59
  Google Scholar
• 24. Fendrich V., Langer P., Bartsch D.K.: Sporadic pancreatic endocrinetumors. W: Pancreatic Cancer, red.: J.P. Neoptolemo, R. Urrutia,J.L. Abbruzzese, M.W. Büchler. Springer Science + BusinessMedia, 2010: 201-227
  Google Scholar
• 25. Fonseca V., John-Kalarickal J.: Type 2 diabetes mellitus: epidemiology,genetics, pathogenesis, and clinical manifestations. W: Principlesof Diabetes Mellitus. red.: L. Poretsky. Springer Science+BusinessMedia, 2010: 203-220
  Google Scholar
• 26. Fritsch H.: Endocrine system:ancreatic islets. W: Color atlas ofhuman anatomy. Internal organs. Tom 2, red.: H. Fritsch. KuehnelGeorg Thieme Verlag, Stuttgart 2009, 354-355
  Google Scholar
• 27. Glenner G.G., Eanes D., Bladen H.A., Linke R.P., Termine J.D.:b-pleated sheet fibrils. A comparison of native amyloid with syntheticprotein fibrils. J. Histochem. Cytochem., 1974; 22: 1141-1158
  Google Scholar
• 28. Glenner G.G., Eanes E.D., Wiley C.A.: Amyloid fibrils formed froma segment of the pancreatic islet amyloid protein. Biochem. Biophys.Res. Commun., 1988; 155: 608-614
  Google Scholar
• 29. Groenning M.: Binding mode of thioflavin T and other molecularprobes in the context of amyloid fibrils – current status. J. Chem.Biol., 2010; 3: 1-18
  Google Scholar
• 30. Hayden M.R., Tyagi S.C.: “A” is for amylin and amyloid in type
  Google Scholar
• 31. Heller R.S.: The comparative anatomy of islets. Adv. Exp. Med.Biol., 2010; 654: 21-37
  Google Scholar
• 32. Heller R.S., Jenny M., Collombat P., Mansouri A., TomasettoC., Madsen O.D., Mellitzer G., Gradwohl G., Serup P.: Genetic determinantsof pancreatic ε-cell development. Dev. Biology, 2005;286: 217-224
  Google Scholar
• 33. Hellman U., Wernstedt C., Westermark P., O’Brien T.D., RathbunW.B., Johnson K.H.: Amino acid sequence from degu islet amyloidderivedinsulin shows unique sequence characteristics. Biochem.Biophys. Res. Commun., 1990; 169: 571-577
  Google Scholar
• 34. Higham C.E., Jaikaran E.T., Fraser P.E., Gross M., Clark A.: Preparationof synthetic human islet amyloid polypeptide (IAPP) in a stableconformation to enable study of conversion to amyloid-like fibrils.FEBS Lett., 2000; 470: 55-60
  Google Scholar
• 35. Hoenig M., Hall G., Ferguson D., Jordan K., Henson M., JohnsonK., O’Brien T.: A feline model of experimentally induced islet amyloidosis.Am. J. Pathol., 2000; 157: 2143-2150
  Google Scholar
• 36. Howard C.F.Jr.: Diabetes in Macaca nigra: metabolic and histologicchanges. Diabetologia, 1974; 10: 671-677
  Google Scholar
• 37. Howard C.F.Jr., Van Bueren A.: Changes in islet cell compositionduring development of diabetes in Macaca nigra. Diabetes, 1986;35: 165-171
  Google Scholar
• 38. Hubbard J.A., Martin S.R., Chaplin L.C., Bose C., Kelly S.M., PriceN.C.: Solution structures of calcitonin-gene-related-peptide analoguesof calcitonin-gene-related peptide and amylin. Biochem. J.,1991; 275: 785-788
  Google Scholar
• 39. In’t Veld P., Marichal M.: Microscopic anatomy of the humanislets of Langerhans. Adv. Exp. Med. Biol., 2010; 654: 1-19
  Google Scholar
• 40. Jaikaran E.T., Higham C.E., Serpell L.C., Zurdo J., Gross M., ClarkA., Fraser P.E.: Identification of a novel human islet amyloid polypeptideβ-sheet domain and factors influencing fibrillogenesis. J.Mol. Biol., 2001; 308: 515-525
  Google Scholar
• 41. Johnson K.H., Stevens J.B: Light and electron microscopic studiesof islet amyloid in diabetic cats. Diabetes, 1973; 22: 81-90 43 Johnson K.H., Wernstedt C., O’Brien T.D., Westermark P.: Amyloidin the pancreatic islets of the cougar (Felis concolor) is derivedfrom islet amyloid polypeptide (IAPP). Comp. Biochem. Physiol. B,1991; 98: 115-119
  Google Scholar
• 42. Jordan K., Murtaugh M.P., O’Brien T.D., Westermark P., BetsholtzC., Johnson K.H.: Canine IAPP cDNA sequence provides importantclues regarding diabetogenesis and amyloidogenesis in type 2 diabetes.Biochem. Biophys. Res. Commun., 1990; 169: 502-508 44 Kelenyi G.: On the histochemistry of azo group-free thiazoledyes. J. Histochem. Cytochem., 1967; 15: 172-180 45 Kos-Kudła B., Bolanowski M., Hubalewska-Dydejczyk A., KrzakowskiM., Marek B., Nasierowska-Guttmejer A., Lampe P., SworczakK.: Guzy endokrynne trzustki (zasady postępowania rekomendowaneprzez Polską Sieć Guzów Neuroendokrynnych). Endokrynol.Pol., 2008; 59: 68-86 46 Krumbhaar E.B.: Spontaneous diabetes in a dog. J. Exp. Med.,1916; 24: 361-366 47 Larsson L.I., Rehfeld J.F., Sundler F., Hakanson R.: Pancreatic gastrinin foetal and neonatal rats. Nature, 1976; 262: 609-610 48 Lauwers G.Y., Mino-Kenduson M., Rubin R.: The Pancreas. W:Rubin’s Pathology. Clinicopathologic Foundations in Medicine. red.:R. Rubin, D.S. Strayer. Lippincott Williams &Wilkins,Wolters Kluver2008, 675-691 49 Leffert J.D., Newgard C.B., Okamoto H., Milburn J.L., Luskey K.L.:Rat amylin: cloning and tissue-specific expression in pancreatic islets.Proc. Natl. Acad. Sci. USA, 1989; 86: 3127-3130 50 LeVine H.3rd.: Quantification of β-sheet amyloid fibril, structureswith thioflavin T. Methods Enzymol., 1999; 309: 274-284 51 Li D.: Diabetes and pancreatic cancer. Mol. Carcinogenesis, 2012;51: 64-74 52 Makin O.S., Serpell L.C.: Structural characterisation of islet amyloidpolypepide fibrils. J. Mol. Biol., 2004; 335: 1279-1288 53 Małecki M.T., Klupa T.: Rola komórki beta trzustki w patogeneziecukrzycy typu 2. Diabetologia Praktyczna, 2007; 8 (Suppl. B): B1-B10 54 Mazor Y., Gilead S., Benhar I., Gazit E.: Identification and characterizationof a novel molecular-recognition and self-assemblydomain within the islet amyloid polypeptide. J. Mol. Biol., 2002;322: 1013-1024 55 Mianownictwo histologiczne i cytofizjologiczne polskie angielskiełacińskie. Red.: W. Sawicki, PZWL, Warszawa 1998 56 Moriarty D.F., Raleigh D.P.: Effects of sequential proline substitutionson amyloid formation by human amylin20-29. Biochemistry,1999; 38: 1811-1818 57 Moskalewski S.: Trzustka. W: Histologia. Red.: K. Ostrowski,PZWL, Warszawa 1988, 52 58 Nasierowska-Guttmejer A., Malinowska M.: Guzy neuroendokrynneukładu pokarmowego (GEP NET) – dyskusja wokół nazewnictwai klasyfikacji. Przegl. Gastroenterol., 2006; 1: 16-21 59 Nelson R., Sawaya M.R., Balbirnie M., Madsen A.O., Riekel C.,Grothe R., Eisenberg D.: Structure of the cross-β spine of amyloidlikefibrils. Nature, 2005; 435: 773-778 60 Nicolls M.R.: The clinical and biological relationship betweentype II diabetes mellitus and Alzheimer’s disease. Curr. AlzheimerRes., 2004; 1: 47-54 61 Nilsson M.R., Driscoll M., Raleigh D.P.: Low levels of asparaginedeamidation can have a dramatic effect on aggregation of amyloidogenicpeptides: implications for the study of amyloid formation.Protein Sci., 2002; 11: 342-349 62 Nilsson M.R., Raleigh D.P.: Analysis of amylin cleavage productsprovides new insights into the amyloidogenic region of human amylin.J. Mol. Biol., 1999; 294: 1375-1385 63 Nishi M., Chan S.J., Nagamatsu S., Bell G.I., Steiner D.F.: Conservationof the sequence of islet amyloid polypeptide in five mammalsis consistent with its putative role as an islet hormone. Proc. Natl.Acad. Sci. USA, 1989; 86: 5738-5742 64 Nishi M., Steiner D.F.: Cloning of complementary DNAs encodingislet amyloid polypeptide, insulin, and glucagon precursors froma New World rodent, the degu, Octodon degus. Mol. Endocrinol., 1990;4: 1192-1198 65 O’Brien T.D., Hellman U., Westermark P., Wernstedt C., RathbunW.B., Johnson K.H.: Pancreatic islet amyloid in the degu is derivedfrom insulin. W: Amyloid and Amyloidosis 1990, red.: J.B. Natvig O.Forre, G. Husby, A. Husebekk, B. Skogen, K. Sletten, P Westermark.Kluwer Academic Publishers Dordrecht The Netherlands 1991, 462-465 66 O’Grady H.L., Conlon K.C.: Pancreatic neuroendocrine tumors.Eur. J. Surg. Oncol., 2008; 34: 324-332 67 Opie E.L.: Pathological changes affecting the islands of Langerhansof the pancreas. J. Boston Soc. Med. Sci., 1900; 4: 251-260 68 Opie E.L.: The relation of diabetes mellitus to lesions of thepancreas. Hyaline degeneration of the islands of Langerhans. J. Exp.Med., 1901; 5: 527-540 69 Page K., Hood C.A., Patel H., Fuentes G., Menakuru M., Park J.H.:Fast Fmoc synthesis of hAmylin1-37 with pseudoproline assisted onresindisulfide formation. J. Pept. Sci., 2007; 13: 833-838 70 Palotay J.L., Howard C.F.Jr.: Insular amyloidosis in spontaneouslydiabetic nonhuman primates. Vet. Pathol. Suppl., 1982; 19(Suppl. 7): 181-192 71 Paulsson J.F., Andersson A., Westermark P., Westermark G.T.:Intracellular amyloid-like deposits contain unprocessed pro-isletamyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressingthe gene for human IAPP and transplanted human islets.Diabetologia, 2006; 49: 1237-1246 72 Prado C.L., Pugh-Bernard A.E., Elghazi L., Sosa-Pineda B., SusselL.: Ghrelin cells replace insulin-producing β cells in two mousemodels of pancreas development. Proc. Natl. Acad. Sci. USA, 2004;101: 2924-2929 73 Rhoades E., Agarwal J., Gafni A.: Aggregation of an amyloidogenicfragment of human islet amyloid polypeptide. Biochim. Biophys.Acta, 2000; 1476: 230-238 74 Sawaya M.R., Sambashivan S., Nelson R., Ivanova M.I., SieversS.A., Apostol M.I., Thompson M.J., Balbirnie M., Wiltzius J.J., McFarlaneH.T., Madsen A.O., Riekel C., Eisenberg D.: Atomic structures ofamyloid cross-b spines reveal varied steric zippers. Nature, 2007;447: 453-457 75 Scharfmann R., Xiao X., Heimberg H., Mallet J., Ravassard P.: Betacells within single human islets originate from multiple progenitors.PloS One, 2008; 3: e3559 76 Szczeblowska D., Grys I.: Zaburzenia wewnątrzwydzielniczew przebiegu chorób trzustki. Pol. Merkur. Lekarski, 2009; 26: 542-544 77 Tenidis K., Waldner M., Bernhagen J., Fischle W., Bergmann M.,Weber M., Merkle M., Voelter W., Brunner H., Kapurniotu A.: Identificationof a penta – and hexapeptide of islet amyloid polypeptide(IAPP) with amyloidogenic and cytotoxic properties. J. Mol. Biol.,2000; 295: 1055-1071 78 van Hulst K.L., Oosterwijk C., Born W., Vroom T.M., NieuwenhuisM.G., Blankenstein M.A., Lips C.J., Fischer J.A., Höppener J.W.: Isletamyloid polypeptide/amylin messenger RNA and protein expressionin human insulinomas in relation to amyloid formation. Eur. J.Endocrinol., 1999; 140: 69-78 79 Wang X., Meloche M., Verchere C.B., Ou D., Mui A., WarnockG.L.: Improving islet engraftment by gene therapy. J. Transplant.,2011; 2011: 594851 80 Westermark P., Johnson K.H.: The polypeptide hormone-derivedamyloid forms: nonspecific alterations or signs of abnormal peptideprocessing?APMIS, 1988; 96: 475-483 81 Westermark P., Wernstedt C., O’Brien T.D., Hayden D.W., JohnsonK.H.: Islet amyloid in type 2 human diabetes mellitus and adultdiabetic cats contains a novel putative polypeptide hormone. Am.J. Pathol., 1987; 127: 414-417 82 Westermark P., Wernstedt C., Wilander E., Hayden D.W., O’BrienT.D., Johnson K.H.: Amyloid fibrils in human insulinoma and isletsof Langerhans of the diabetic cat are derived from a neuropeptidelikeprotein also present in normal islet cells. Proc. Natl. Acad. Sci.USA, 1987; 84: 3881-3885 83 Westermark P., Wernstedt C., Wilander E., Sletten K.: A novelpeptide in the calcitonin gene related peptide family as an amyloidfibril protein in the endocrine pancreas. Biochem. Biophys. Res.Commun., 1986; 140: 827-831 84 Wierup N., Svensson H., Mulder H., Sundler F.: The ghrelin cell:a novel developmentally regulated islet cell in the human pancreas.Regul. Pept., 2002; 107: 63-69 85 Wilander E.: Diagnostic pathology of gastrointestinal and pancreaticneuroendocrine tumours. Acta Oncol., 1989; 28: 363-369 86 Wiltzius J.J., Sievers S.A., Sawaya M.R., Cascio D., Popov D., RiekelC., Eisenberg D.: Atomic structure of the cross-β spine of islet amyloidpolypeptide (amylin). Protein Sci., 2008; 17: 1467-1474 87 Yano B.L., Hayden D.W., Johnson K.H.: Feline insular amyloid:incidence in adult cats with no clinicopathologic evidence of overtdiabetes mellitus. Vet. Pathol., 1981; 18: 310-315 88 Zhang X., Cheng B., Gong H., Li C., Chen H., Zheng L., Huang K.:Porcine islet amyloid polypeptide fragments are refractory to amyloidformation. FEBS Lett., 2011; 585: 71-77
  Google Scholar

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