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The aggregation of hIAPP plays a role in the progression of type 2 diabetes and contributes to the failure of islet cell grafts. Despite considerable effort, little is known about the mode of action of IAPP amyloid inhibitors, and this has limited rational drug design. Insulin is one of the most potent inhibitors of hIAPP fibril formation, but its inhibition mechanism is not understood. In this study, the aggregation of mixtures of hIAPP with insulin, as well as with the separate A and B chains of insulin, were characterized using ion mobility spectrometry-based mass spectrometry and atomic force microscopy. Insulin and the insulin B chain target the hIAPP monomer in its compact isoform and shift the equilibrium away from its extended isoform, an aggregation-prone conformation, and thus inhibit hIAPP from forming \u03b2-sheets and subsequently amyloid fibrils. All-atom molecular modeling supports these conclusions.<\/jats:p>","DOI":"10.1021\/ja504031d","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T15:43:59Z","timestamp":1408635839000},"page":"12912-12919","source":"Crossref","is-referenced-by-count":77,"title":["Defining\nthe Molecular Basis of Amyloid Inhibitors:\nHuman Islet Amyloid Polypeptide\u2013Insulin Interactions"],"prefix":"10.1021","volume":"136","author":[{"given":"Anna C.","family":"Susa","sequence":"first","affiliation":[{"name":"University of California , , , ,","place":["Santa Barbara, California, United States, 93106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Wu","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Santa Barbara, California, United States, 93106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Summer L.","family":"Bernstein","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Santa Barbara, California, United States, 93106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas F.","family":"Dupuis","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Santa Barbara, California, United States, 93106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Raleigh","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan-Emma","family":"Shea","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Santa Barbara, California, United States, 93106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Bowers","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Santa Barbara, California, United States, 93106"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,8,21]]},"reference":[{"key":"2026090217144287200_cit1","volume-title":"National\nDiabetes Fact Sheet: National Estimates and General Information on\nDiabetes and Prediabetes in the United States","year":"2011"},{"issue":"3","key":"2026090217144287200_cit2","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2337\/diabetes.48.3.491","volume":"48","author":"Janson","year":"1999","journal-title":"Diabetes"},{"issue":"5","key":"2026090217144287200_cit3","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.2337\/db06-1579","volume":"56","author":"Lin","year":"2007","journal-title":"Diabetes"},{"issue":"3","key":"2026090217144287200_cit4","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1210\/er.2007-0037","volume":"29","author":"Haataja","year":"2008","journal-title":"Endocr. 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