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Several factors contribute to \u03b2\u2010cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain \u03b1\u2010sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic \u03b1\u2010sheet compounds designed to be nontoxic and complementary to the \u03b1\u2010sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer\u2010mediated cytotoxicity in cell\u2010based assays. In vivo administration of an \u03b1\u2010sheet design to mice for 4\u2009weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the \u03b1\u2010sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid\u2010associated \u03b2\u2010cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of \u03b1\u2010sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid\u2010associated \u03b2\u2010cell loss.<\/jats:p>","DOI":"10.1002\/pro.4854","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T09:04:12Z","timestamp":1702026252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Human islet amyloid polypeptide\u2010induced \u03b2\u2010cell cytotoxicity is linked to formation of \u03b1\u2010sheet structure"],"prefix":"10.1002","volume":"33","author":[{"given":"Cheng\u2010Chieh","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of Washington  Seattle Washington USA"},{"name":"Molecular Engineering Program University of Washington  Seattle Washington 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