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How these factors are integrated to regulate beta cells remains largely unclear. Based on our previous findings that the family of myelin transcription factors (MYT TFs; including MYT1, MYT1L and ST18) prevents mouse beta cell failure by repressing the overactivation of stress response, their regulation by obesity-related nutrition signals in human beta cells and their association with type 2 diabetes, we postulate that these factors prevent human beta cell failure under normal physiological conditions and obesity-related stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>MYT1<\/jats:italic>\n                      or\n                      <jats:italic>ST18<\/jats:italic>\n                      were knocked down in primary human beta cells using shRNA. Beta cell survival, secretory function and gene expression were examined after islet cells were cultured in vitro or xenotransplanted into mice under normal conditions or obesity-related stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In culture,\n                      <jats:italic>MYT1-<\/jats:italic>\n                      knockdown (KD) caused beta cell death, while\n                      <jats:italic>ST18-<\/jats:italic>\n                      KD compromised glucose-stimulated insulin secretion. Under obesity-induced stress as xenotransplants,\n                      <jats:italic>ST18-<\/jats:italic>\n                      KD also caused beta cell death. Accordingly,\n                      <jats:italic>MYT1-<\/jats:italic>\n                      KD deregulated several genes and gene sets related to cell death and cellular stress response, while\n                      <jats:italic>ST18<\/jats:italic>\n                      -KD deregulated those regulating stress response, mitochondria and ion channels. Corresponding to these gene expression changes,\n                      <jats:italic>ST18<\/jats:italic>\n                      -KD reduced glucose-stimulated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx in beta cells. In addition, the\n                      <jats:italic>MYT1-<\/jats:italic>\n                      and\n                      <jats:italic>ST18<\/jats:italic>\n                      -regulated genes were enriched for type-2-diabetes-associated loci, with an enrichment of 2.05-fold relative to the random distribution of beta cell-expressed genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      The MYT TFs complement each other to integrate genetic and environmental factors to prevent beta cell failure and type 2 diabetes, with their major effects exerted on beta cell viability and\/or Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06757-8","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T12:24:39Z","timestamp":1780662279000},"page":"2554-2568","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diabetes-associated MYT1 and ST18 genes regulate human beta cell insulin secretion and survival via other diabetes risk genes"],"prefix":"10.1007","volume":"69","author":[{"given":"Ruiying","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nala","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahircan","family":"Yagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanna K.","family":"Dadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Harmelink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teri D.","family":"Doss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J.","family":"Simmons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken S.","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Appakalai N.","family":"Balamurugan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Kaverina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie C.","family":"Coate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0772-9139","authenticated-orcid":false,"given":"Guoqiang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"issue":"8003","key":"6757_CR1","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","volume":"627","author":"K Suzuki","year":"2024","unstructured":"Suzuki K, Hatzikotoulas K, Southam L et al (2024) Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. 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Such necessary research as this would not be possible without this selfless gift of hope. Thanks to the efforts of IIDP and Network for Hope (Louisville and Cincinnati) and Lifeline of Ohio, Columbus, for supporting these special families and providing human research pancreases to A. N. Balamurugan\u2019s islet laboratory. We also thank members of A. N. Balamurugan\u2019s islet laboratory for their contributions to islet research and transplant.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The RNA-seq data were deposited in the Gene Expression Omnibus (GEO) (GSE307815 for scRNA-seq and GSE307751 for bulk RNA-seq). They are now freely available from the following sites:\n                      \n                      ; and\n                      \n                      . GG is the guarantor of the data, and he will fulfil reasonable resource and reagent requests.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This study is supported by NIH grants (DK125696 and DK128710 for GG, DK103831 and CA274367 for KSL, YX and AJS). The imaging facility used is funded by grants CA68485, DK20593, DK58404, DK59637 and EY08126.","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"RH, MY, XT and GG designed and performed human PSI production, GSIS, immunofluorescence assays and imaging. NH performed the type 2 diabetes association studies and beta cell immunofluorescence imaging. RH performed ITT and TD designed and performed PSI transplantation. JL and CH helped with viral production and PSI growth. YW and QL critically analysed scRNA-seq data to help with hypothesis generation. YX, AJS and KSL designed and performed scRNA-seq using InDrop. PD and DJ designed and did Ca\n                      2+\n                      recording. AB performed human islet isolation. RS, IK, AB, QL, KC and GG conceptualised the overall study. All authors participated in manuscript writing\/proofing, and approved the submission. GG is the guarantor of this work.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}