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Understanding the molecular mechanisms that regulate beta cell function could pave the way for the development of more effective antidiabetic treatments. In this study, we identify the evolutionarily conserved transforming growth factor \u03b2\u20101 stimulated clone D1 (TSC22D1) protein as a previously unknown regulator of beta cell function. TSC22D1 depletion in INS\u20101E cells enhances the expression of key beta cell identity genes, including\n                    <jats:italic>Ins1<\/jats:italic>\n                    ,\n                    <jats:italic>Ins2<\/jats:italic>\n                    ,\n                    <jats:italic>Pdx1<\/jats:italic>\n                    ,\n                    <jats:italic>Slc2a2<\/jats:italic>\n                    , and\n                    <jats:italic>Nkx6.1<\/jats:italic>\n                    , and promotes glucose\u2010stimulated insulin secretion without altering intracellular insulin content. Mechanistically, TSC22D1 and Forkhead box protein O1 (FoxO1) interact and regulate each other in a reciprocal manner to control beta cell function. Our follow\u2010up interactome and RNA\u2010Seq analyses reveal that TSC22D1 is crucial for glucose\u2010responsive cellular processes in beta cells, including mRNA processing, ribonucleoprotein complex biogenesis, and Golgi vesicle transport. Overall, our findings indicate that TSC22D1 plays a significant role in regulating beta cell function at multiple levels, with potential implications for metabolic diseases, such as diabetes.\n                  <\/jats:p>","DOI":"10.1111\/febs.70194","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T16:50:22Z","timestamp":1752857422000},"page":"6307-6329","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>TSC22D1<\/scp>\n                    is a newly identified inhibitor of insulin secretion in pancreatic beta cells"],"prefix":"10.1111","volume":"292","author":[{"given":"S\u00fcmb\u00fcl","family":"Y\u0131ld\u0131r\u0131m","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Joint Heidelberg IDC Translational Diabetes Program Heidelberg University Hospital  Heidelberg Germany"},{"name":"Department of Genetics and Bioengineering Faculty of Engineering, Yeditepe University  Istanbul T\u00fcrkiye"},{"name":"Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center Munich  Neuherberg Germany"},{"name":"German Center for Diabetes Research (DZD)  Neuherberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Mhamane","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center Munich  Neuherberg Germany"},{"name":"German Center for Diabetes Research (DZD)  Neuherberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svenja","family":"L\u00f6sch","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Joint Heidelberg IDC Translational Diabetes Program Heidelberg University Hospital  Heidelberg Germany"},{"name":"Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center Munich  Neuherberg 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