{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:51:53Z","timestamp":1793299913087,"version":"4.5.0"},"reference-count":39,"publisher":"American Diabetes Association","issue":"7","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,7,7]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>Type 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6\u20136.1 per 1-SD increase, P &amp;lt; 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P &amp;lt; 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4\u20131.9 per 1-SD increase, P &amp;lt; 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>We identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/dc21-2489","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T02:38:37Z","timestamp":1653359917000},"page":"1621-1630","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":56,"title":["Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns That Associate With Future Diabetic Complications"],"prefix":"10.2337","volume":"45","author":[{"given":"Silja","family":"Schrader","sequence":"first","affiliation":[{"name":"1Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Perfilyev","sequence":"additional","affiliation":[{"name":"1Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6513-2384","authenticated-orcid":false,"given":"Emma","family":"Ahlqvist","sequence":"additional","affiliation":[{"name":"2Genomics, Diabetes and Endocrinology Unit, Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leif","family":"Groop","sequence":"additional","affiliation":[{"name":"2Genomics, Diabetes and Endocrinology Unit, Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan","family":"Vaag","sequence":"additional","affiliation":[{"name":"3Type 2 Diabetes Biology Research, Steno Diabetes Center, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Martinell","sequence":"additional","affiliation":[{"name":"4Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden"},{"name":"5Academic Primary Care Centre, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1249-4795","authenticated-orcid":false,"given":"Sonia","family":"Garc\u00eda-Calz\u00f3n","sequence":"additional","affiliation":[{"name":"1Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malm\u00f6, Sweden"},{"name":"6Department of Food Science and Physiology, University of Navarra, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0587-7154","authenticated-orcid":false,"given":"Charlotte","family":"Ling","sequence":"additional","affiliation":[{"name":"1Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"2023053114511815000_B1","unstructured":"World Health Organization Newsroom Fact Sheet\n          . World Health Organization 2021. Available from https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/diabetes"},{"key":"2023053114511815000_B2","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.cmet.2019.03.009","article-title":"Epigenetics in human obesity and type 2 diabetes","volume":"29","author":"Ling","year":"2019","journal-title":"Cell Metab"},{"key":"2023053114511815000_B3","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S2213-8587(18)30052-4","article-title":"Precision medicine in the management of type 2 diabetes","volume":"6","author":"Gloyn","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023053114511815000_B4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S2213-8587(18)30051-2","article-title":"Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables","volume":"6","author":"Ahlqvist","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023053114511815000_B5","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/S2213-8587(19)30087-7","article-title":"Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared with models based on simple clinical features: an analysis using clinical trial data","volume":"7","author":"Dennis","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023053114511815000_B6","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S2213-8587(19)30187-1","article-title":"Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study","volume":"7","author":"Zaharia","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023053114511815000_B7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S2213-8587(18)30316-4","article-title":"Novel subgroups of patients with adult-onset diabetes in Chinese and US populations","volume":"7","author":"Zou","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023053114511815000_B8","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s00125-021-05567-4","article-title":"Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial","volume":"65","author":"Pigeyre","year":"2022","journal-title":"Diabetologia"},{"key":"2023053114511815000_B9","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1007\/s00125-021-05490-8","article-title":"Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study","volume":"64","author":"Slieker","year":"2021","journal-title":"Diabetologia"},{"key":"2023053114511815000_B10","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1038\/s41588-021-00948-2","article-title":"Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes","volume":"53","author":"Mansour Aly","year":"2021","journal-title":"Nat Genet"},{"key":"2023053114511815000_B11","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.2337\/db20-1281","article-title":"Distinct molecular signatures of clinical clusters in people with type 2 diabetes: an IMI-RHAPSODY study","volume":"70","author":"Slieker","year":"2021","journal-title":"Diabetes"},{"key":"2023053114511815000_B12","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/S2213-8587(15)00127-8","article-title":"Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study","volume":"3","author":"Chambers","year":"2015","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023053114511815000_B13","doi-asserted-by":"crossref","first-page":"e1004160","DOI":"10.1371\/journal.pgen.1004160","article-title":"Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion","volume":"10","author":"Dayeh","year":"2014","journal-title":"PLoS Genet"},{"key":"2023053114511815000_B14","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.2337\/db13-1459","article-title":"Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes","volume":"63","author":"Nilsson","year":"2014","journal-title":"Diabetes"},{"key":"2023053114511815000_B15","doi-asserted-by":"crossref","first-page":"E1491","DOI":"10.1210\/jc.2015-3204","article-title":"Epigenetic alterations in human liver from subjects with type 2 diabetes in parallel with reduced folate levels","volume":"100","author":"Nilsson","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"2023053114511815000_B16","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.2337\/db16-0996","article-title":"Whole-genome bisulfite sequencing of human pancreatic islets reveals novel differentially methylated regions in type 2 diabetes pathogenesis","volume":"66","author":"Volkov","year":"2017","journal-title":"Diabetes"},{"key":"2023053114511815000_B17","doi-asserted-by":"crossref","first-page":"11089","DOI":"10.1038\/ncomms11089","article-title":"Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes","volume":"7","author":"Bacos","year":"2016","journal-title":"Nat Commun"},{"key":"2023053114511815000_B18","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1080\/15592294.2016.1178418","article-title":"DNA methylation of loci within ABCG1 and PHOSPHO1 in blood DNA is associated with future type 2 diabetes risk","volume":"11","author":"Dayeh","year":"2016","journal-title":"Epigenetics"},{"key":"2023053114511815000_B19","doi-asserted-by":"crossref","first-page":"eaaz1802","DOI":"10.1126\/scitranslmed.aaz1803","article-title":"Epigenetic markers associated with metformin response and intolerance in drug-na\u00efve patients with type 2 diabetes","volume":"12","author":"Garc\u00eda-Calz\u00f3n","year":"2020","journal-title":"Sci Transl Med"},{"key":"2023053114511815000_B20","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.2337\/diacare.21.12.2191","article-title":"Correct homeostasis model assessment (HOMA) evaluation uses the computer program","volume":"21","author":"Levy","year":"1998","journal-title":"Diabetes Care"},{"key":"2023053114511815000_B21","doi-asserted-by":"crossref","first-page":"247","DOI":"10.7326\/0003-4819-145-4-200608150-00004","article-title":"Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate","volume":"145","author":"Levey","year":"2006","journal-title":"Ann Intern Med"},{"key":"2023053114511815000_B22","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nature20784","article-title":"Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity","volume":"541","author":"Wahl","year":"2017","journal-title":"Nature"},{"key":"2023053114511815000_B23","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13059-018-1448-7","article-title":"An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray","volume":"19","author":"Salas","year":"2018","journal-title":"Genome Biol"},{"key":"2023053114511815000_B24","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1093\/hmg\/ddv493","article-title":"Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia","volume":"25","author":"Soriano-T\u00e1rraga","year":"2016","journal-title":"Hum Mol Genet"},{"key":"2023053114511815000_B25","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1530\/JOE-20-0109","article-title":"GABA requires GLP-1R to exert its pancreatic function during STZ challenge","volume":"246","author":"Shao","year":"2020","journal-title":"J Endocrinol"},{"key":"2023053114511815000_B26","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.2337\/db20-0204","article-title":"Epigenetic changes in islets of Langerhans preceding the onset of diabetes","volume":"69","author":"Ouni","year":"2020","journal-title":"Diabetes"},{"key":"2023053114511815000_B27","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.2337\/db20-1108","article-title":"FOXO1-mediated downregulation of RAB27B leads to decreased exosome secretion in diabetic kidneys","volume":"70","author":"Zeng","year":"2021","journal-title":"Diabetes"},{"key":"2023053114511815000_B28","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/s41366-018-0254-3","article-title":"Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood","volume":"43","author":"Lillycrop","year":"2019","journal-title":"Int J Obes"},{"key":"2023053114511815000_B29","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/s42255-021-00368-w","article-title":"TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response","volume":"3","author":"Kim","year":"2021","journal-title":"Nat Metab"},{"key":"2023053114511815000_B30","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41366-020-00662-9","article-title":"Influence of genetic variants in FADS2 and ELOVL2 genes on BMI and PUFAs homeostasis in children and adolescents with obesity","volume":"45","author":"Maguolo","year":"2021","journal-title":"Int J Obes"},{"key":"2023053114511815000_B31","first-page":"3792","article-title":"Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood","volume":"24","author":"R\u00f6nn","year":"2015","journal-title":"Hum Mol Genet"},{"key":"2023053114511815000_B32","first-page":"1068","article-title":"Surfactant protein D is associated with 3-month mortality of anti-MDA5 antibody-interstitial lung disease","volume":"38","author":"Lyu","year":"2020","journal-title":"Clin Exp Rheumatol"},{"key":"2023053114511815000_B33","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1097\/GME.0000000000001367","article-title":"Genetic associations with age of menopause in familial longevity","volume":"26","author":"Bae","year":"2019","journal-title":"Menopause"},{"key":"2023053114511815000_B34","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1038\/s41467-017-02332-3","article-title":"Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan","volume":"8","author":"Wang","year":"2017","journal-title":"Nat Commun"},{"key":"2023053114511815000_B35","doi-asserted-by":"crossref","first-page":"110267","DOI":"10.1016\/j.forsciint.2020.110267","article-title":"DNA methylation age estimation in blood samples of living and deceased individuals using a multiplex SNaPshot assay","volume":"311","author":"Dias","year":"2020","journal-title":"Forensic Sci Int"},{"key":"2023053114511815000_B36","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1267\/ahc.18030","article-title":"Collapsin response mediator protein 1, a novel marker protein for differentiated odontoblasts","volume":"51","author":"Miyazaki","year":"2018","journal-title":"Acta Histochem Cytochem"},{"key":"2023053114511815000_B37","doi-asserted-by":"crossref","first-page":"7196","DOI":"10.1093\/hmg\/ddv417","article-title":"Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia","volume":"24","author":"Kim","year":"2015","journal-title":"Hum Mol Genet"},{"key":"2023053114511815000_B38","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Zheng","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"2023053114511815000_B39","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13059-016-1131-9","article-title":"Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution","volume":"18","author":"van Iterson","year":"2017","journal-title":"Genome Biol"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/7\/1621\/715997\/dc212489.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/7\/1621\/715997\/dc212489.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T10:51:52Z","timestamp":1685530312000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/45\/7\/1621\/146986\/Novel-Subgroups-of-Type-2-Diabetes-Display"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,24]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,5,24]]},"published-print":{"date-parts":[[2022,7,7]]}},"URL":"https:\/\/doi.org\/10.2337\/dc21-2489","relation":{},"ISSN":["0149-5992"],"issn-type":[{"value":"0149-5992","type":"print"}],"subject":[],"published":{"date-parts":[[2022,5,24]]}}}