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Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify <jats:italic>Sox5<\/jats:italic> as a regulator of the module. <jats:italic>Sox5<\/jats:italic> knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca<jats:sup>2+<\/jats:sup>-influx and \u03b2-cell exocytosis. <jats:italic>SOX5<\/jats:italic> overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key \u03b2-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight <jats:italic>SOX5<\/jats:italic> as a regulator of \u03b2-cell phenotype and function.<\/jats:p>","DOI":"10.1038\/ncomms15652","type":"journal-article","created":{"date-parts":[[2017,6,6]],"date-time":"2017-06-06T11:25:39Z","timestamp":1496748339000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes"],"prefix":"10.1038","volume":"8","author":[{"given":"A. S.","family":"Axelsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Mahdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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