{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T18:29:29Z","timestamp":1782584969675,"version":"3.54.5"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001381","name":"National Research Foundation Singapore","doi-asserted-by":"publisher","award":["NRF2020-THE003-0006"],"award-info":[{"award-number":["NRF2020-THE003-0006"]}],"id":[{"id":"10.13039\/501100001381","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education Singapore","award":["2019-T1-001-059"],"award-info":[{"award-number":["2019-T1-001-059"]}]},{"name":"Ministry of Education Singapore","award":["MOE-T2EP30221-0003"],"award-info":[{"award-number":["MOE-T2EP30221-0003"]}]},{"name":"Ministry of Education Singapore","award":["RG30\/23"],"award-info":[{"award-number":["RG30\/23"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2025,12]]},"DOI":"10.1007\/s00125-025-06541-0","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T07:41:10Z","timestamp":1758872470000},"page":"2767-2780","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["I-BET151 modulates glucokinase gene expression and beta cell function in part through changes in FOXO1 expression"],"prefix":"10.1007","volume":"68","author":[{"given":"Qing Wei Calvin","family":"Ho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Gunaseelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosi","family":"Chelliah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemapriya Jayaranga","family":"Babu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Yan","family":"Chew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surabhi","family":"Devaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Shiyun","family":"Tay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewei","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne Yuanling","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Rutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernett","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian Kee Keong","family":"Teo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuf","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"6541_CR1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.neulet.2015.10.015","volume":"625","author":"A Ntranos","year":"2016","unstructured":"Ntranos A, Casaccia P (2016) Bromodomains: translating the words of lysine acetylation into myelin injury and repair. Neurosci Lett 625:4\u201310. https:\/\/doi.org\/10.1016\/j.neulet.2015.10.015","journal-title":"Neurosci Lett"},{"issue":"11","key":"6541_CR2","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.3390\/ijms17111849","volume":"17","author":"Y Taniguchi","year":"2016","unstructured":"Taniguchi Y (2016) The Bromodomain and Extra-Terminal domain (BET) family: functional anatomy of BET paralogous proteins. Int J Mol Sci 17(11):1849. https:\/\/doi.org\/10.3390\/ijms17111849","journal-title":"Int J Mol Sci"},{"issue":"12","key":"6541_CR3","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.18632\/oncotarget.1572","volume":"4","author":"A Wyce","year":"2013","unstructured":"Wyce A, Degenhardt Y, Bai Y et al (2013) Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4(12):2419\u20132429","journal-title":"Oncotarget"},{"key":"6541_CR4","doi-asserted-by":"publisher","first-page":"e04631","DOI":"10.7554\/eLife.04631","volume":"3","author":"W Fu","year":"2014","unstructured":"Fu W, Farache J, Clardy SM et al (2014) Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and \u03b2 cells. eLife 3:e04631. https:\/\/doi.org\/10.7554\/eLife.04631","journal-title":"eLife"},{"key":"6541_CR5","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/nature10509","volume":"478","author":"MA Dawson","year":"2011","unstructured":"Dawson MA, Prinjha RK, Dittmann A et al (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478:529. https:\/\/doi.org\/10.1038\/nature10509","journal-title":"Nature"},{"issue":"7327","key":"6541_CR6","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1038\/nature09504","volume":"468","author":"P Filippakopoulos","year":"2010","unstructured":"Filippakopoulos P, Qi J, Picaud S et al (2010) Selective inhibition of BET bromodomains. Nature 468(7327):1067\u20131073. https:\/\/doi.org\/10.1038\/nature09504","journal-title":"Nature"},{"key":"6541_CR7","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1038\/nature09589","volume":"468","author":"E Nicodeme","year":"2010","unstructured":"Nicodeme E, Jeffrey KL, Schaefer U et al (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468:1119. https:\/\/doi.org\/10.1038\/nature09589","journal-title":"Nature"},{"key":"6541_CR8","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ddtec.2016.06.004","volume":"19","author":"G Andrieu","year":"2016","unstructured":"Andrieu G, Belkina AC, Denis GV (2016) Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol 19:45\u201350. https:\/\/doi.org\/10.1016\/j.ddtec.2016.06.004","journal-title":"Drug Discov Today Technol"},{"issue":"3","key":"6541_CR9","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1177\/2040620715576662","volume":"6","author":"A Chaidos","year":"2015","unstructured":"Chaidos A, Caputo V, Karadimitris A (2015) Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence. Ther Adv Hematol 6(3):128\u2013141. https:\/\/doi.org\/10.1177\/2040620715576662","journal-title":"Ther Adv Hematol"},{"issue":"40","key":"6541_CR10","doi-asserted-by":"publisher","first-page":"16669","DOI":"10.1073\/pnas.1108190108","volume":"108","author":"JA Mertz","year":"2011","unstructured":"Mertz JA, Conery AR, Bryant BM et al (2011) Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A 108(40):16669\u201316674. https:\/\/doi.org\/10.1073\/pnas.1108190108","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"6541_CR11","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1038\/nm.3952","volume":"21","author":"PK Mazur","year":"2015","unstructured":"Mazur PK, Herner A, Mello SS et al (2015) Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med 21(10):1163\u20131171. https:\/\/doi.org\/10.1038\/nm.3952","journal-title":"Nat Med"},{"key":"6541_CR12","doi-asserted-by":"publisher","first-page":"D849","DOI":"10.2741\/denis","volume":"6","author":"GV Denis","year":"2001","unstructured":"Denis GV (2001) Duality in bromodomain-containing protein complexes. Front Biosci 6:D849-852. https:\/\/doi.org\/10.2741\/denis","journal-title":"Front Biosci"},{"issue":"11","key":"6541_CR13","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.1073\/pnas.1615601114","volume":"114","author":"K Cheung","year":"2017","unstructured":"Cheung K, Lu G, Sharma R et al (2017) BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. Proc Natl Acad Sci U S A 114(11):2952\u20132957. https:\/\/doi.org\/10.1073\/pnas.1615601114","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"6541_CR14","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1038\/s41419-022-05344-0","volume":"13","author":"M Yang","year":"2022","unstructured":"Yang M, Liu K, Chen P, Zhu H, Wang J, Huang J (2022) Bromodomain-containing protein 4 (BRD4) as an epigenetic regulator of fatty acid metabolism genes and ferroptosis. Cell Death Dis 13(10):912. https:\/\/doi.org\/10.1038\/s41419-022-05344-0","journal-title":"Cell Death Dis"},{"issue":"8","key":"6541_CR15","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1056\/NEJMcibr1414708","volume":"372","author":"A Lehuen","year":"2015","unstructured":"Lehuen A (2015) A double-edged sword against type 1 diabetes. N Engl J Med 372(8):778\u2013780. https:\/\/doi.org\/10.1056\/NEJMcibr1414708","journal-title":"N Engl J Med"},{"issue":"19","key":"6541_CR16","doi-asserted-by":"publisher","first-page":"4776","DOI":"10.3390\/ijms20194776","volume":"20","author":"PJ Thompson","year":"2019","unstructured":"Thompson PJ, Shah A, Apostolopolou H, Bhushan A (2019) BET proteins are required for transcriptional activation of the senescent islet cell secretome in type 1 diabetes. Int J Mol Sci 20(19):4776. https:\/\/doi.org\/10.3390\/ijms20194776","journal-title":"Int J Mol Sci"},{"issue":"4","key":"6541_CR17","doi-asserted-by":"publisher","first-page":"761","DOI":"10.2337\/db18-0224","volume":"68","author":"L Huijbregts","year":"2019","unstructured":"Huijbregts L, Petersen MBK, Berthault C et al (2019) Bromodomain and extra terminal protein inhibitors promote pancreatic endocrine cell fate. Diabetes 68(4):761\u2013773. https:\/\/doi.org\/10.2337\/db18-0224","journal-title":"Diabetes"},{"issue":"8","key":"6541_CR18","doi-asserted-by":"publisher","first-page":"e23610","DOI":"10.1096\/fj.202301700RR","volume":"38","author":"M Hu","year":"2024","unstructured":"Hu M, Kim I, Moran I et al (2024) Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic beta-cell survival and function. FASEB J 38(8):e23610. https:\/\/doi.org\/10.1096\/fj.202301700RR","journal-title":"FASEB J"},{"issue":"3","key":"6541_CR19","doi-asserted-by":"publisher","first-page":"e0151329","DOI":"10.1371\/journal.pone.0151329","volume":"11","author":"JT Deeney","year":"2016","unstructured":"Deeney JT, Belkina AC, Shirihai OS, Corkey BE, Denis GV (2016) BET bromodomain proteins Brd2, Brd3 and Brd4 selectively regulate metabolic pathways in the pancreatic beta-cell. PLoS One 11(3):e0151329. https:\/\/doi.org\/10.1371\/journal.pone.0151329","journal-title":"PLoS One"},{"issue":"2","key":"6541_CR20","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1210\/en.2003-1099","volume":"145","author":"A Merglen","year":"2004","unstructured":"Merglen A, Theander S, Rubi B, Chaffard G, Wollheim CB, Maechler P (2004) Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells. Endocrinology 145(2):667\u2013678. https:\/\/doi.org\/10.1210\/en.2003-1099","journal-title":"Endocrinology"},{"issue":"11","key":"6541_CR21","doi-asserted-by":"publisher","first-page":"e2113074119","DOI":"10.1073\/pnas.2113074119","volume":"119","author":"X Zheng","year":"2022","unstructured":"Zheng X, Ho QWC, Chua M et al (2022) Destabilization of beta Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes. Proc Natl Acad Sci U S A 119(11):e2113074119. https:\/\/doi.org\/10.1073\/pnas.2113074119","journal-title":"Proc Natl Acad Sci U S A"},{"key":"6541_CR22","unstructured":"Andrews S (2010) FastQC: a quality control tool for high throughput sequence data. Available from: https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/. Accessed\u00a08 Dec 2024"},{"issue":"19","key":"6541_CR23","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","volume":"32","author":"P Ewels","year":"2016","unstructured":"Ewels P, Magnusson M, Lundin S, Kaller M (2016) MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics 32(19):3047\u20133048. https:\/\/doi.org\/10.1093\/bioinformatics\/btw354","journal-title":"Bioinformatics"},{"issue":"1","key":"6541_CR24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin A, Davis CA, Schlesinger F et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1):15\u201321. https:\/\/doi.org\/10.1093\/bioinformatics\/bts635","journal-title":"Bioinformatics"},{"issue":"D1","key":"6541_CR25","doi-asserted-by":"publisher","first-page":"D766","DOI":"10.1093\/nar\/gky955","volume":"47","author":"A Frankish","year":"2019","unstructured":"Frankish A, Diekhans M, Ferreira AM et al (2019) GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res 47(D1):D766\u2013D773. https:\/\/doi.org\/10.1093\/nar\/gky955","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"6541_CR26","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1):139\u2013140. https:\/\/doi.org\/10.1093\/bioinformatics\/btp616","journal-title":"Bioinformatics"},{"key":"6541_CR27","unstructured":"R Core Team (2022) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria"},{"issue":"11","key":"6541_CR28","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1002\/pro.3715","volume":"28","author":"M Kanehisa","year":"2019","unstructured":"Kanehisa M (2019) Toward understanding the origin and evolution of cellular organisms. Protein Sci 28(11):1947\u20131951. https:\/\/doi.org\/10.1002\/pro.3715","journal-title":"Protein Sci"},{"issue":"D1","key":"6541_CR29","doi-asserted-by":"publisher","first-page":"D587","DOI":"10.1093\/nar\/gkac963","volume":"51","author":"M Kanehisa","year":"2023","unstructured":"Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M (2023) KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res 51(D1):D587\u2013D592. https:\/\/doi.org\/10.1093\/nar\/gkac963","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"6541_CR30","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28(1):27\u201330. https:\/\/doi.org\/10.1093\/nar\/28.1.27","journal-title":"Nucleic Acids Res"},{"issue":"11","key":"6541_CR31","doi-asserted-by":"publisher","first-page":"105376","DOI":"10.1016\/j.isci.2022.105376","volume":"25","author":"X Yi","year":"2022","unstructured":"Yi X, Marmontel de Souza B, Sawatani T et al (2022) Mining the transcriptome of target tissues of autoimmune and degenerative pancreatic beta-cell and brain diseases to discover therapies. iScience 25(11):105376. https:\/\/doi.org\/10.1016\/j.isci.2022.105376","journal-title":"iScience"},{"issue":"5","key":"6541_CR32","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1182\/blood-2013-01-478420","volume":"123","author":"A Chaidos","year":"2014","unstructured":"Chaidos A, Caputo V, Gouvedenou K et al (2014) Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123(5):697\u2013705. https:\/\/doi.org\/10.1182\/blood-2013-01-478420","journal-title":"Blood"},{"issue":"6","key":"6541_CR33","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1007\/s00125-003-1115-7","volume":"46","author":"B Ritz-Laser","year":"2003","unstructured":"Ritz-Laser B, Gauthier BR, Estreicher A et al (2003) Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription. Diabetologia 46(6):810\u2013821. https:\/\/doi.org\/10.1007\/s00125-003-1115-7","journal-title":"Diabetologia"},{"issue":"6","key":"6541_CR34","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1016\/j.celrep.2013.08.010","volume":"4","author":"BL Taylor","year":"2013","unstructured":"Taylor BL, Liu FF, Sander M (2013) Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep 4(6):1262\u20131275. https:\/\/doi.org\/10.1016\/j.celrep.2013.08.010","journal-title":"Cell Rep"},{"issue":"2","key":"6541_CR35","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1007\/s00125-006-0490-2","volume":"50","author":"H Wang","year":"2007","unstructured":"Wang H, Brun T, Kataoka K, Sharma AJ, Wollheim CB (2007) MAFA controls genes implicated in insulin biosynthesis and secretion. Diabetologia 50(2):348\u2013358. https:\/\/doi.org\/10.1007\/s00125-006-0490-2","journal-title":"Diabetologia"},{"issue":"7","key":"6541_CR36","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.1073\/pnas.0510790103","volume":"103","author":"O Cabrera","year":"2006","unstructured":"Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A 103(7):2334\u20132339. https:\/\/doi.org\/10.1073\/pnas.0510790103","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"6541_CR37","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.7150\/ijbs.27173","volume":"14","author":"X Huang","year":"2018","unstructured":"Huang X, Liu G, Guo J, Su Z (2018) The PI3K\/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci 14(11):1483\u20131496. https:\/\/doi.org\/10.7150\/ijbs.27173","journal-title":"Int J Biol Sci"},{"issue":"7","key":"6541_CR38","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","volume":"129","author":"BD Manning","year":"2007","unstructured":"Manning BD, Cantley LC (2007) AKT\/PKB signaling: navigating downstream. Cell 129(7):1261\u20131274. https:\/\/doi.org\/10.1016\/j.cell.2007.06.009","journal-title":"Cell"},{"issue":"6","key":"6541_CR39","doi-asserted-by":"publisher","first-page":"2904","DOI":"10.1210\/en.2006-1149","volume":"148","author":"K Yoshida","year":"2007","unstructured":"Yoshida K, Murao K, Imachi H et al (2007) Pancreatic glucokinase is activated by insulin-like growth factor-I. Endocrinology 148(6):2904\u20132913. https:\/\/doi.org\/10.1210\/en.2006-1149","journal-title":"Endocrinology"},{"key":"6541_CR40","doi-asserted-by":"publisher","first-page":"118145","DOI":"10.1016\/j.lfs.2020.118145","volume":"258","author":"B Zhang","year":"2020","unstructured":"Zhang B, Sun P, Shen C et al (2020) Role and mechanism of PI3K\/AKT\/FoxO1\/PDX-1 signaling pathway in functional changes of pancreatic islets in rats after severe burns. Life Sci 258:118145. https:\/\/doi.org\/10.1016\/j.lfs.2020.118145","journal-title":"Life Sci"},{"issue":"11","key":"6541_CR41","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1210\/mend.10.11.8923459","volume":"10","author":"G Waeber","year":"1996","unstructured":"Waeber G, Thompson N, Nicod P, Bonny C (1996) Transcriptional activation of the GLUT2 gene by the IPF-1\/STF-1\/IDX-1 homeobox factor. Mol Endocrinol 10(11):1327\u20131334. https:\/\/doi.org\/10.1210\/mend.10.11.8923459","journal-title":"Mol Endocrinol"},{"issue":"9","key":"6541_CR42","doi-asserted-by":"publisher","first-page":"4372","DOI":"10.1073\/pnas.94.9.4372","volume":"94","author":"H Wang","year":"1997","unstructured":"Wang H, Iynedjian PB (1997) Modulation of glucose responsiveness of insulinoma beta-cells by graded overexpression of glucokinase. Proc Natl Acad Sci U S A 94(9):4372\u20134377. https:\/\/doi.org\/10.1073\/pnas.94.9.4372","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"6541_CR43","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.cell.2017.09.045","volume":"171","author":"F Langlet","year":"2017","unstructured":"Langlet F, Haeusler RA, Linden D et al (2017) Selective inhibition of FOXO1 activator\/repressor balance modulates hepatic glucose handling. Cell 171(4):824\u2013835. https:\/\/doi.org\/10.1016\/j.cell.2017.09.045","journal-title":"Cell"},{"issue":"40","key":"6541_CR44","doi-asserted-by":"publisher","first-page":"20033","DOI":"10.1073\/pnas.1904311116","volume":"116","author":"T Kuo","year":"2019","unstructured":"Kuo T, Kraakman MJ, Damle M, Gill R, Lazar MA, Accili D (2019) Identification of C2CD4A as a human diabetes susceptibility gene with a role in beta cell insulin secretion. Proc Natl Acad Sci U S A 116(40):20033\u201320042. https:\/\/doi.org\/10.1073\/pnas.1904311116","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"6541_CR45","doi-asserted-by":"publisher","first-page":"13647","DOI":"10.1074\/jbc.M110.204248","volume":"286","author":"G Meur","year":"2011","unstructured":"Meur G, Qian Q, da Silva Xavier G et al (2011) Nucleo-cytosolic shuttling of FoxO1 directly regulates mouse Ins2 but not Ins1 gene expression in pancreatic beta cells (MIN6). J Biol Chem 286(15):13647\u201313656. https:\/\/doi.org\/10.1074\/jbc.M110.204248","journal-title":"J Biol Chem"},{"issue":"27","key":"6541_CR46","doi-asserted-by":"publisher","first-page":"2987","DOI":"10.2217\/fon-2022-0484","volume":"18","author":"CN Harrison","year":"2022","unstructured":"Harrison CN, Gupta VK, Gerds AT et al (2022) Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. Future Oncol 18(27):2987\u20132997. https:\/\/doi.org\/10.2217\/fon-2022-0484","journal-title":"Future Oncol"},{"issue":"17","key":"6541_CR47","doi-asserted-by":"publisher","first-page":"4079","DOI":"10.3390\/cancers14174079","volume":"14","author":"J Hilton","year":"2022","unstructured":"Hilton J, Cristea M, Postel-Vinay S et al (2022) BMS-986158, a small molecule inhibitor of the bromodomain and extraterminal domain proteins, in patients with selected advanced solid tumors: results from a phase 1\/2a trial. Cancers (Basel) 14(17):4079. https:\/\/doi.org\/10.3390\/cancers14174079","journal-title":"Cancers (Basel)"},{"issue":"20","key":"6541_CR48","doi-asserted-by":"publisher","first-page":"5338","DOI":"10.1158\/1078-0432.CCR-20-1707","volume":"26","author":"RR Aggarwal","year":"2020","unstructured":"Aggarwal RR, Schweizer MT, Nanus DM et al (2020) A phase Ib\/IIa study of the Pan-BET inhibitor ZEN-3694 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res 26(20):5338\u20135347. https:\/\/doi.org\/10.1158\/1078-0432.CCR-20-1707","journal-title":"Clin Cancer Res"},{"issue":"11","key":"6541_CR49","doi-asserted-by":"publisher","first-page":"2795","DOI":"10.1038\/jid.2014.243","volume":"134","author":"SJ Gallagher","year":"2014","unstructured":"Gallagher SJ, Mijatov B, Gunatilake D et al (2014) The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells. J Invest Dermatol 134(11):2795\u20132805. https:\/\/doi.org\/10.1038\/jid.2014.243","journal-title":"J Invest Dermatol"},{"issue":"7","key":"6541_CR50","doi-asserted-by":"publisher","first-page":"e143379","DOI":"10.1172\/jci.insight.143379","volume":"6","author":"X Hu","year":"2021","unstructured":"Hu X, Dong X, Li G et al (2021) Brd4 modulates diet-induced obesity via PPARgamma-dependent Gdf3 expression in adipose tissue macrophages. JCI Insight 6(7):e143379. https:\/\/doi.org\/10.1172\/jci.insight.143379","journal-title":"JCI Insight"},{"issue":"4","key":"6541_CR51","doi-asserted-by":"publisher","first-page":"966","DOI":"10.2337\/diabetes.51.4.966","volume":"51","author":"MK Lingohr","year":"2002","unstructured":"Lingohr MK, Dickson LM, McCuaig JF, Hugl SR, Twardzik DR, Rhodes CJ (2002) Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. Diabetes 51(4):966\u2013976. https:\/\/doi.org\/10.2337\/diabetes.51.4.966","journal-title":"Diabetes"},{"key":"6541_CR52","doi-asserted-by":"publisher","first-page":"113498","DOI":"10.1016\/j.ygcen.2020.113498","volume":"294","author":"PA Kolodziejski","year":"2020","unstructured":"Kolodziejski PA, Sassek M, Bien J et al (2020) FGF-1 modulates pancreatic beta-cell functions\/metabolism: an in vitro study. Gen Comp Endocrinol 294:113498. https:\/\/doi.org\/10.1016\/j.ygcen.2020.113498","journal-title":"Gen Comp Endocrinol"},{"issue":"10","key":"6541_CR53","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1007\/s00125-008-1087-8","volume":"51","author":"J Agudo","year":"2008","unstructured":"Agudo J, Ayuso E, Jimenez V et al (2008) IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice. Diabetologia 51(10):1862\u20131872. https:\/\/doi.org\/10.1007\/s00125-008-1087-8","journal-title":"Diabetologia"},{"issue":"7","key":"6541_CR54","doi-asserted-by":"publisher","first-page":"BSR20230501","DOI":"10.1042\/BSR20230501","volume":"43","author":"S Wan","year":"2023","unstructured":"Wan S, An Y, Fan W, Teng F, Jiang Z (2023) Comparative transcriptomic analysis reveals the underlying molecular mechanism in high-fat diet-induced islet dysfunction. Biosci Rep 43(7):BSR20230501. https:\/\/doi.org\/10.1042\/BSR20230501","journal-title":"Biosci Rep"},{"issue":"1","key":"6541_CR55","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1021\/bi901414g","volume":"49","author":"J Ai","year":"2010","unstructured":"Ai J, Duan J, Lv X et al (2010) Overexpression of FoxO1 causes proliferation of cultured pancreatic beta cells exposed to low nutrition. Biochemistry 49(1):218\u2013225. https:\/\/doi.org\/10.1021\/bi901414g","journal-title":"Biochemistry"},{"issue":"35","key":"6541_CR56","doi-asserted-by":"publisher","first-page":"25440","DOI":"10.1074\/jbc.M113.486852","volume":"288","author":"D Gupta","year":"2013","unstructured":"Gupta D, Leahy AA, Monga N, Peshavaria M, Jetton TL, Leahy JL (2013) Peroxisome proliferator-activated receptor gamma (PPARgamma) and its target genes are downstream effectors of FoxO1 protein in islet beta-cells: mechanism of beta-cell compensation and failure. J Biol Chem 288(35):25440\u201325449. https:\/\/doi.org\/10.1074\/jbc.M113.486852","journal-title":"J Biol Chem"},{"issue":"4","key":"6541_CR57","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1080\/15384047.2017.1294291","volume":"18","author":"L Wang","year":"2017","unstructured":"Wang L, Matkar S, Xie G et al (2017) BRD4 inhibitor IBET upregulates p27kip\/cip protein stability in neuroendocrine tumor cells. Cancer Biol Ther 18(4):229\u2013236. https:\/\/doi.org\/10.1080\/15384047.2017.1294291","journal-title":"Cancer Biol Ther"},{"issue":"6","key":"6541_CR58","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.3892\/ijo.2018.4577","volume":"53","author":"Y Tan","year":"2018","unstructured":"Tan Y, Wang L, Du Y et al (2018) Inhibition of BRD4 suppresses tumor growth in prostate cancer via the enhancement of FOXO1 expression. Int J Oncol 53(6):2503\u20132517. https:\/\/doi.org\/10.3892\/ijo.2018.4577","journal-title":"Int J Oncol"},{"issue":"9","key":"6541_CR59","doi-asserted-by":"publisher","first-page":"4065","DOI":"10.1210\/en.2009-0343","volume":"150","author":"X Zhang","year":"2009","unstructured":"Zhang X, Yong W, Lv J et al (2009) Inhibition of forkhead box O1 protects pancreatic beta-cells against dexamethasone-induced dysfunction. Endocrinology 150(9):4065\u20134073. https:\/\/doi.org\/10.1210\/en.2009-0343","journal-title":"Endocrinology"},{"key":"6541_CR60","doi-asserted-by":"publisher","first-page":"30321","DOI":"10.1038\/srep30321","volume":"6","author":"MY Song","year":"2016","unstructured":"Song MY, Wang J, Ka SO, Bae EJ, Park BH (2016) Insulin secretion impairment in Sirt6 knockout pancreatic beta cells is mediated by suppression of the FoxO1-Pdx1-Glut2 pathway. Sci Rep 6:30321. https:\/\/doi.org\/10.1038\/srep30321","journal-title":"Sci Rep"},{"issue":"6","key":"6541_CR61","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.2337\/db05-0678","volume":"55","author":"SC Martinez","year":"2006","unstructured":"Martinez SC, Cras-Meneur C, Bernal-Mizrachi E, Permutt MA (2006) Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet beta-cell. Diabetes 55(6):1581\u20131591. https:\/\/doi.org\/10.2337\/db05-0678","journal-title":"Diabetes"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06541-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-025-06541-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-025-06541-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T12:00:19Z","timestamp":1762516819000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-025-06541-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,26]]},"references-count":61,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["6541"],"URL":"https:\/\/doi.org\/10.1007\/s00125-025-06541-0","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,26]]},"assertion":[{"value":"29 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We thank C. Wollheim (Excellence of Diabetes Research in Sweden, Lund University, Sweden) for providing us the INS-1E cells. We also thank J. Feng (Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore) for helping with the experiments involving the overexpression constructs and gene expression.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Volcano plots of significant KEGG pathways listed in Fig.\n                      \n                      b can be found in the ESM. All other datasets are available from the corresponding author on request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"YA is supported by the Ministry of Education Singapore (MOE-T2EP30221-0003, 2019-T1-001-059, RG30\/23) and the National Research Foundation (NRF2020-THE003-0006). This work was also partly supported by the LKCMedicine Healthcare Research Fund (Diabetes Research), established through the generous support of alumni of Nanyang Technological University, Singapore. DK is supported by the NUS Research Scholarship for his PhD. AKKT is supported by IMCB, A*STAR, HLTRP\/2022\/NUS-IMCB-02, OFIRG21jun-0097, CSASI21jun-0006, MTCIRG21-0071, H22G0a0005, I22D1AG053, HLCA23Feb-0031, SC36\/19-000801-A044, H24G1a0015 and M24N2K0087. GAR is supported by a Wellcome Trust Investigator Award (WT212625\/Z\/18\/Z), MRC Programme grant (MR\/R022259\/1), Diabetes UK (BDA 16\/0005485) and NIH-NIDDK (R01DK135268) project grants, a CIHR-Breakthrough T1D (formerly known as JDRF) Team grant (CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N), CRCHUM start-up funds and an Innovation Canada John R. Evans Leader Award (CFI 42649).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"AKKT is a co-founder and shareholder of BetaLife Pte Ltd but is not employed by BetaLife Pte Ltd. GAR has received grant funding from, and is a consultant for, Sun Pharmaceuticals Inc. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"QWCH and YA designed the study and wrote the manuscript. GAR and AKKT provided input on the study design. QWHC, DG, RC, HJB, XYC, SD, VST, DK, XW and DYT performed the experiments. JAM and BL analysed and generated figures for the RNA-seq data. All authors reviewed and approved the final version of the manuscript. YA supervised the project and is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}