{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:16:11Z","timestamp":1788416171899,"version":"build-2803163510"},"reference-count":57,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2015,3,21]],"date-time":"2015-03-21T00:00:00Z","timestamp":1426896000000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Islet amyloid polypeptide (IAPP) is responsible for amyloid deposition in type 2 diabetes and plays an important role in the loss of \u03b2-cell mass associated with the disease and in the failure of islet transplants, but the mechanism of islet amyloid formation is not understood. The incorrect processing of proIAPP to produce partially processed forms of the peptide has been proposed to play a role in the initiation of islet amyloid in vivoby promoting interactions with proteoglycans of the extracellular matrix. Insulin is a potent inhibitor of the formation of amyloid by IAPP in vitro in a homogeneous solution; however, its ability to inhibit IAPP in the presence of proteoglycans has not been tested, nor has its effect on the formation of amyloid by proIAPP processing intermediates been examined. Here we show that insulin is a much less effective amyloid inhibitor of both IAPP and proIAPP processing intermediates in vitro in the presence of model glycosaminoglycans, but does inhibit the formation of amyloid by proIAPP processing intermediates in a homogeneous solution. This highlights another mechanism by which sulfated proteoglycans could enhance islet amyloid formation in vivo. Interactions with sulfated proteoglycans can directly promote amyloid formation and can also significantly reduce the effectiveness of natural inhibitors.<\/jats:p>","DOI":"10.1021\/bi4015488","type":"journal-article","created":{"date-parts":[[2014,3,21]],"date-time":"2014-03-21T15:07:07Z","timestamp":1395414427000},"page":"2605-2614","source":"Crossref","is-referenced-by-count":23,"title":["The Ability of Insulin To Inhibit the Formation of\nAmyloid by Pro-Islet Amyloid Polypeptide Processing Intermediates\nIs Significantly Reduced in the Presence of Sulfated Glycosaminoglycans"],"prefix":"10.1021","volume":"53","author":[{"given":"Hui","family":"Wang","sequence":"first","affiliation":[{"name":"State University of New York at Stony Brook , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Raleigh","sequence":"additional","affiliation":[{"name":"State University of New York at Stony Brook , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]},{"name":"State University of New York at Stony Brook , , , ,","place":["Stony Brook, New York, United States, 11794"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,3,21]]},"reference":[{"key":"2026090301455469500_cit1","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3109\/10408369409084679","article-title":"Amyloidosis","volume":"31","author":"Sipe","year":"1994","journal-title":"Crit. 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Pathol."},{"key":"2026090301455469500_cit5","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev.biophys.050708.133622","article-title":"The interplay of catalysis and toxicity\nby amyloid\nintermediates on lipid bilayers: Insights from type II diabetes","volume":"38","author":"Hebda","year":"2009","journal-title":"Annu. Rev. Biophys."},{"key":"2026090301455469500_cit6","doi-asserted-by":"crossref","first-page":"5035","DOI":"10.1210\/endo.142.11.8593","article-title":"Inhibition of central Amylin signaling\nincreases food intake and body adiposity in rats","volume":"142","author":"Rushing","year":"2001","journal-title":"Endocrinology"},{"key":"2026090301455469500_cit7","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/BF01925572","article-title":"Amylin given by central or peripheral\nroutes decreases gastric emptying and intestinal transit in the rat","volume":"52","author":"Clementi","year":"1996","journal-title":"Experientia"},{"key":"2026090301455469500_cit8","first-page":"151","article-title":"Islet amyloid, increased A-cells, reduced B-cells and\nexocrine fibrosis: Quantitative changes in the pancreas in type 2\ndiabetes","volume":"9","author":"Clark","year":"1988","journal-title":"Diabetes Res. Clin. Pract."},{"key":"2026090301455469500_cit9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2337\/diabetes.48.2.241","article-title":"Islet amyloid: A long-recognized\nbut underappreciated pathological feature of type 2 diabetes","volume":"48","author":"Kahn","year":"1999","journal-title":"Diabetes"},{"key":"2026090301455469500_cit10","doi-asserted-by":"crossref","first-page":"562985","DOI":"10.1155\/2008\/562985","article-title":"Amyloid deposition in transplanted\nhuman pancreatic islets: A conceivable cause of their long-term failure","volume":"2008","author":"Andersson","year":"2008","journal-title":"Exp. Diabetes Res."},{"key":"2026090301455469500_cit11","doi-asserted-by":"crossref","first-page":"4305","DOI":"10.1073\/pnas.0909024107","article-title":"Islet amyloid deposition\nlimits the viability of human islet grafts but not porcine islet grafts","volume":"107","author":"Potter","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090301455469500_cit12","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1042\/bj20030852","article-title":"Pancreatic \u03b2-cell granule peptides\nform heteromolecular complexes which inhibit islet amyloid polypeptide\nfibril formation","volume":"377","author":"Jaikaran","year":"2004","journal-title":"Biochem. J."},{"key":"2026090301455469500_cit13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.jmb.2003.10.045","article-title":"The mechanism of\ninsulin action on islet amyloid polypeptide\nfiber formation","volume":"335","author":"Larson","year":"2004","journal-title":"J. Mol. 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Chem."},{"key":"2026090301455469500_cit20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2337\/diabetes.53.1.141","article-title":"Role of \u03b2-cell prohormone convertase\n(PC) 1\/3 in processing of pro-islet amyloid polypeptide","volume":"53","author":"Marzban","year":"2004","journal-title":"Diabetes"},{"key":"2026090301455469500_cit21","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1210\/en.2004-1175","article-title":"Role of carboxypeptidase E in processing\nof pro-islet amyloid polypeptide in \u03b2-cells","volume":"146","author":"Marzban","year":"2005","journal-title":"Endocrinology"},{"key":"2026090301455469500_cit22","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0014-5793(95)01460-8","article-title":"Processing\nof pro-islet amyloid polypeptide (proIAPP) by the prohormone convertase\nPC2","volume":"378","author":"Badman","year":"1996","journal-title":"FEBS Lett."},{"key":"2026090301455469500_cit23","doi-asserted-by":"crossref","first-page":"9662","DOI":"10.1073\/pnas.86.24.9662","article-title":"Molecular and functional characterization of amylin,\na peptide associated with type 2 diabetes mellitus","volume":"86","author":"Roberts","year":"1989","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090301455469500_cit24","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1007\/BF00296991","article-title":"Disproportionate elevation of immunoreactive proinsulin in type-2\n(non-insulin-dependent) diabetes-mellitus and in experimental insulin\nresistance","volume":"30","author":"Ward","year":"1987","journal-title":"Diabetologia"},{"key":"2026090301455469500_cit25","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s00592-010-0201-9","article-title":"Serum levels\nof proamylin and amylin in normal subjects and patients with impaired\nglucose regulation and type 2 diabetes mellitus","volume":"47","author":"Zheng","year":"2010","journal-title":"Acta Diabetol."},{"key":"2026090301455469500_cit26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1517\/03009734000000057","article-title":"Pro islet\namyloid polypeptide (ProIAPP) immunoreactivity in the islets of langerhans","volume":"105","author":"Westermark","year":"2000","journal-title":"Upsala J. Med. Sci."},{"key":"2026090301455469500_cit27","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0168-8227(89)90008-9","article-title":"Islet amyloid polypeptide (Iapp) and pro-Iapp immunoreactivity\nin human islets of Langerhans","volume":"7","author":"Westermark","year":"1989","journal-title":"Diabetes Res.\nClin. Pract."},{"key":"2026090301455469500_cit28","doi-asserted-by":"crossref","first-page":"16611","DOI":"10.1074\/jbc.M008423200","article-title":"Identification of\na heparin binding domain in the N-terminal\ncleavage site of pro-islet amyloid polypeptide: Implications for islet\namyloid formation","volume":"276","author":"Park","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2026090301455469500_cit29","first-page":"951","article-title":"Localization\nof the basement membrane heparan sulfate proteoglycan in islet amyloid\ndeposits in type II diabetes mellitus","volume":"116","author":"Young","year":"1992","journal-title":"Arch.\nPathol. Lab. Med."},{"key":"2026090301455469500_cit30","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3109\/13506120309041728","article-title":"Amyloidogenesis:\nHistorical and modern observations point to heparan sulfate proteoglycans\nas a major culprit","volume":"10","author":"Ancsin","year":"2003","journal-title":"Amyloid"},{"key":"2026090301455469500_cit31","doi-asserted-by":"crossref","first-page":"31617","DOI":"10.1074\/jbc.272.50.31617","article-title":"Heparin-binding properties of the\namyloidogenic peptides A\u03b2 and amylin: Dependence on aggregation\nstate and inhibition by Congo red","volume":"272","author":"Watson","year":"1997","journal-title":"J. Biol.\nChem."},{"key":"2026090301455469500_cit32","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/0197-4580(89)90108-5","article-title":"Proteoglycans in\nthe pathogenesis of Alzheimers-disease\nand other amyloidoses","volume":"10","author":"Snow","year":"1989","journal-title":"Neurobiol. Aging"},{"key":"2026090301455469500_cit33","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1046\/j.1471-4159.1997.69062452.x","article-title":"Perlecan binds to\nthe \u03b2-amyloid proteins (A\u03b2) of Alzheimer\u2019s disease,\naccelerates A\u03b2 fibril formation, and maintains A\u03b2\nfibril stability","volume":"69","author":"Castillo","year":"1997","journal-title":"J. Neurochem."},{"key":"2026090301455469500_cit34","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0074-7696(01)10005-7","article-title":"Basement membrane\nand \u03b2 amyloid fibrillogenesis in Alzheimer\u2019s disease","volume":"210","author":"Inoue","year":"2001","journal-title":"Int. Rev. Cytol."},{"key":"2026090301455469500_cit35","doi-asserted-by":"crossref","first-page":"612","DOI":"10.2337\/diabetes.47.4.612","article-title":"Sulfate content\nand specific glycosaminoglycan backbone of perlecan are critical for\nperlecan\u2019s\nenhancement of islet amyloid polypeptide (amylin) fibril formation","volume":"47","author":"Castillo","year":"1998","journal-title":"Diabetes"},{"key":"2026090301455469500_cit36","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/S0003-9861(03)00116-4","article-title":"Proteoglycans\nsynthesized and secreted by pancreatic islet \u03b2-cells bind amylin","volume":"413","author":"Potter-Perigo","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"2026090301455469500_cit37","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1097\/01.ASN.0000103228.81623.C7","article-title":"Glycosaminoglycans enhance the trifluoroethanol-induced\nextension of \u03b2(2)-microglobulin-related amyloid fibrils at a\nneutral pH","volume":"15","author":"Yamamoto","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"2026090301455469500_cit38","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1021\/bi0519295","article-title":"Heparin\naccelerates gelsolin amyloidogenesis","volume":"45","author":"Suk","year":"2006","journal-title":"Biochemistry"},{"key":"2026090301455469500_cit39","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1146\/annurev-biochem-072611-130030","article-title":"Systemic Amyloidoses","volume":"82","author":"Blancas-Meji\u0301a","year":"2013","journal-title":"Annu. Rev.\nBiochem."},{"key":"2026090301455469500_cit40","doi-asserted-by":"crossref","first-page":"12091","DOI":"10.1021\/bi7004834","article-title":"Amyloid formation\nby pro-islet amyloid polypeptide processing intermediates: Examination\nof the role of protein heparan sulfate interactions and implications\nfor islet amyloid formation in type 2 diabetes","volume":"46","author":"Meng","year":"2007","journal-title":"Biochemistry"},{"key":"2026090301455469500_cit41","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1152\/physrev.00042.2009","article-title":"Islet amyloid polypeptide, islet\namyloid, and diabetes mellitus","volume":"91","author":"Westermark","year":"2011","journal-title":"Physiol. Rev."},{"key":"2026090301455469500_cit42","doi-asserted-by":"crossref","first-page":"861","DOI":"10.2353\/ajpath.2010.090532","article-title":"Evidence for proteotoxicity\nin \u03b2\ncells in type 2 diabetes toxic islet amyloid polypeptide oligomers\nform intracellularly in the secretory pathway","volume":"176","author":"Gurlo","year":"2010","journal-title":"Am. J. Pathol."},{"key":"2026090301455469500_cit43","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1007\/s00125-011-2143-3","article-title":"Exendin-4 increases islet amyloid\ndeposition but offsets the resultant \u03b2 cell toxicity in human\nislet amyloid polypeptide transgenic mouse islets","volume":"54","author":"Aston-Mourney","year":"2011","journal-title":"Diabetologia"},{"key":"2026090301455469500_cit44","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1021\/ol047480+","article-title":"Incorporation of pseudoproline derivatives allows the\nfacile synthesis of human IAPP, a highly amyloidogenic and aggregation-prone\npolypeptide","volume":"7","author":"Abedini","year":"2005","journal-title":"Org. Lett."},{"key":"2026090301455469500_cit45","doi-asserted-by":"crossref","first-page":"4848","DOI":"10.1021\/ol101981b","article-title":"Efficient\nmicrowave-assisted synthesis of human islet amyloid polypeptide designed\nto facilitate the specific incorporation of labeled amino acids","volume":"12","author":"Marek","year":"2010","journal-title":"Org. Lett."},{"key":"2026090301455469500_cit46","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ab.2005.11.029","article-title":"Recovery and purification of highly\naggregation-prone disulfide-containing peptides: Application to islet\namyloid polypeptide","volume":"351","author":"Abedini","year":"2006","journal-title":"Anal. Biochem."},{"key":"2026090301455469500_cit47","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.jmb.2012.11.003","article-title":"Amyloid\nformation in heterogeneous environments: Islet\namyloid polypeptide glycosaminoglycan interactions","volume":"425","author":"Wang","year":"2013","journal-title":"J. Mol. Biol."},{"key":"2026090301455469500_cit48","doi-asserted-by":"crossref","first-page":"16284","DOI":"10.1021\/bi051432v","article-title":"The role of His-18 in amyloid formation by human islet\namyloid polypeptide","volume":"44","author":"Abedini","year":"2005","journal-title":"Biochemistry"},{"key":"2026090301455469500_cit49","doi-asserted-by":"crossref","first-page":"4694","DOI":"10.1021\/bi0160462","article-title":"Islet amyloid: Phase\npartitioning and secondary nucleation\nare central to the mechanism of fibrillogenesis","volume":"41","author":"Padrick","year":"2002","journal-title":"Biochemistry"},{"key":"2026090301455469500_cit50","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1110\/ps.036350.108","article-title":"Interaction of membrane-bound islet\namyloid polypeptide with soluble and crystalline insulin","volume":"17","author":"Knight","year":"2008","journal-title":"Protein Sci."},{"key":"2026090301455469500_cit51","doi-asserted-by":"crossref","first-page":"6476","DOI":"10.1002\/anie.200602034","article-title":"Molecular mapping of the recognition\ninterface between the islet amyloid polypeptide and insulin","volume":"45","author":"Gilead","year":"2006","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090301455469500_cit52","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/pro.145","article-title":"Atomic structures\nof IAPP (amylin) fusions suggest a mechanism for fibrillation and\nthe role of insulin in the process","volume":"18","author":"Wiltzius","year":"2009","journal-title":"Protein\nSci."},{"key":"2026090301455469500_cit53","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1093\/protein\/gzp036","article-title":"A critical assessment\nof the role of helical intermediates\nin amyloid formation by natively unfolded proteins and polypeptides","volume":"22","author":"Abedini","year":"2009","journal-title":"Protein Eng., Des. Sel."},{"key":"2026090301455469500_cit54","doi-asserted-by":"crossref","first-page":"015005","DOI":"10.1088\/1478-3975\/6\/1\/015005","article-title":"A role for helical intermediates in amyloid formation\nby natively unfolded polypeptides?","volume":"6","author":"Abedini","year":"2009","journal-title":"Phys. Biol."},{"key":"2026090301455469500_cit55","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1110\/ps.062486907","article-title":"Direct detection of transient \u03b1-helical\nstates\nin islet amyloid polypeptide","volume":"16","author":"Williamson","year":"2007","journal-title":"Protein Sci."},{"key":"2026090301455469500_cit56","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.bpc.2010.01.006","article-title":"Suppression of IAPP\nfibrillation at anionic lipid membranes via IAPP-derived amyloid inhibitors\nand insulin","volume":"150","author":"Sellin","year":"2010","journal-title":"Biophys. Chem."},{"key":"2026090301455469500_cit57","doi-asserted-by":"crossref","first-page":"22894","DOI":"10.1074\/jbc.M110.215814","article-title":"Mechanism of amylin fibrillization enhancement by heparin","volume":"286","author":"Jha","year":"2011","journal-title":"J. Biol. Chem."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi4015488","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/16\/2605\/7872768\/bi4015488.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/16\/2605\/7872768\/bi4015488.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:46:05Z","timestamp":1788414365000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/53\/16\/2605\/772802\/The-Ability-of-Insulin-To-Inhibit-the-Formation-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,21]]},"references-count":57,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2014,3,21]]},"published-print":{"date-parts":[[2014,4,29]]}},"URL":"https:\/\/doi.org\/10.1021\/bi4015488","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,21]]}}}