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Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes. Proinsulin-Cys(B19) and Cys(A20) are necessary and sufficient for the formation of proinsulin disulfide-linked complexes; indeed, proinsulin Cys(B19)-Cys(B19) covalent homodimers resist reductive dissociation, highlighting a structural basis for aberrant proinsulin complex formation. We conclude that increased proinsulin misfolding via disulfide-linked complexes is an early event associated with prediabetes that worsens with \u00df-cell dysfunction in type two diabetes.<\/jats:p>","DOI":"10.7554\/elife.44532","type":"journal-article","created":{"date-parts":[[2019,6,10]],"date-time":"2019-06-10T20:00:26Z","timestamp":1560196826000},"source":"Crossref","is-referenced-by-count":147,"title":["Proinsulin misfolding is an early event in the progression to type 2 diabetes"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-1860","authenticated-orcid":true,"given":"Anoop","family":"Arunagiri","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Haataja","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, 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