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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:p>\n                    Fine mapping and validation of genes causing \u03b2 cell failure from susceptibility loci identified in type 2 diabetes genome-wide association studies (GWAS) poses a significant challenge. The\n                    <jats:italic>VPS13C-C2CD4A-C2CD4B<\/jats:italic>\n                    locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1 is involved in the pathogenesis of \u03b2 cell dysfunction, but its link to human diabetes GWAS has not been explored. Here we generated a genome-wide map of FoxO1 superenhancers in chemically identified \u03b2 cells using 2-photon live-cell imaging to monitor FoxO1 localization. When parsed against human superenhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved superenhancer in\n                    <jats:italic>C2CD4A<\/jats:italic>\n                    , a gene encoding a \u03b2 cell\/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in \u03b2 cells of mice phenocopied the metabolic abnormalities of human carriers of\n                    <jats:italic>C2CD4A<\/jats:italic>\n                    -linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2CD4A regulates glycolytic genes, and notably represses key \u03b2 cell \u201cdisallowed\u201d genes, such as\n                    <jats:italic>lactate dehydrogenase A<\/jats:italic>\n                    . We propose that\n                    <jats:italic>C2CD4A<\/jats:italic>\n                    is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1904311116","type":"journal-article","created":{"date-parts":[[2019,9,16]],"date-time":"2019-09-16T20:34:31Z","timestamp":1568666071000},"page":"20033-20042","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":57,"title":["Identification of\n                    <i>C2CD4A<\/i>\n                    as a human diabetes susceptibility gene with a role in \u03b2 cell insulin secretion"],"prefix":"10.1073","volume":"116","author":[{"given":"Taiyi","family":"Kuo","sequence":"first","affiliation":[{"name":"Department of Medicine, Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Kraakman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manashree","family":"Damle","sequence":"additional","affiliation":[{"name":"The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;"},{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Medicine, Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 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