{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:22:26Z","timestamp":1789525346179,"version":"build-2803163510"},"reference-count":34,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:00:00Z","timestamp":1647216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,5,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Obesity is a key risk factor for type 2 diabetes; however, up to 20% of patients are normal weight. Our aim was to identify metabolite patterns reproducibly predictive of BMI and subsequently to test whether lean individuals who carry an obese metabolome are at hidden high risk of obesity-related diseases, such as type 2 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>Levels of 108 metabolites were measured in plasma samples of 7,663 individuals from two Swedish and one Italian population-based cohort. Ridge regression was used to predict BMI using the metabolites. Individuals with a predicted BMI either &amp;gt;5 kg\/m2 higher (overestimated) or lower (underestimated) than their actual BMI were characterized as outliers and further investigated for obesity-related risk factors and future risk of type 2 diabetes and mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>The metabolome could predict BMI in all cohorts (r2 = 0.48, 0.26, and 0.19). The overestimated group had a BMI similar to individuals correctly predicted as normal weight, had a similar waist circumference, were not more likely to change weight over time, but had a two times higher risk of future type 2 diabetes and an 80% increased risk of all-cause mortality. These associations remained after adjustments for obesity-related risk factors and lifestyle parameters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>We found that lean individuals with an obesity-related metabolome have an increased risk for type 2 diabetes and all-cause mortality compared with lean individuals with a healthy metabolome. Metabolomics may be used to identify hidden high-risk individuals to initiate lifestyle and pharmacological interventions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc21-2402","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T17:48:35Z","timestamp":1647280115000},"page":"1260-1267","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":63,"title":["Metabolome-Defined Obesity and the Risk of Future Type 2 Diabetes and Mortality"],"prefix":"10.2337","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8312-3545","authenticated-orcid":false,"given":"Filip","family":"Ottosson","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"},{"name":"Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4150-2459","authenticated-orcid":false,"given":"Einar","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrika","family":"Ericson","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Brunkwall","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marju","family":"Orho-Melander","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Di Somma","sequence":"additional","affiliation":[{"name":"Department of Medical-Surgery Sciences and Translational Medicine, University of Rome Sapienza, Rome, Italy"},{"name":"GREAT Health Sciences, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Antonini","sequence":"additional","affiliation":[{"name":"GREAT Health Sciences, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-4982","authenticated-orcid":false,"given":"C\u00e9line","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olle","family":"Melander","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund University, Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,3,14]]},"reference":[{"key":"2022051317401755600_B1","unstructured":"World Health Organization\n          . Obesity. Accessed 30 August 2021. Available from https:\/\/www.who.int\/news-room\/facts-in-pictures\/detail\/6- facts-on-obesity"},{"key":"2022051317401755600_B2","first-page":"581","article-title":"Association of weight status with mortality in adults with incident diabetes","volume":"308","author":"Carnethon","year":"2012","journal-title":"JAMA"},{"key":"2022051317401755600_B3","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1161\/CIRCULATIONAHA.117.029617","article-title":"Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management","volume":"137","author":"Neeland","year":"2018","journal-title":"Circulation"},{"key":"2022051317401755600_B4","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s11154-013-9252-x","article-title":"Metabolically healthy obesity: definitions, determinants and clinical implications","volume":"14","author":"Phillips","year":"2013","journal-title":"Rev Endocr Metab Disord"},{"key":"2022051317401755600_B5","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nrm3314","article-title":"Innovation: metabolomics: the apogee of the omics trilogy","volume":"13","author":"Patti","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2022051317401755600_B6","doi-asserted-by":"crossref","first-page":"e0148361","DOI":"10.1371\/journal.pone.0148361","article-title":"metabolomic profiles of body mass index in the Framingham Heart Study reveal distinct cardiometabolic phenotypes","volume":"11","author":"Ho","year":"2016","journal-title":"PLoS One"},{"key":"2022051317401755600_B7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s12916-021-01970-1","article-title":"Metabolic signatures of greater body size and their associations with risk of colorectal and endometrial cancers in the European Prospective Investigation into Cancer and Nutrition","volume":"19","author":"Kliemann","year":"2021","journal-title":"BMC Med"},{"key":"2022051317401755600_B8","doi-asserted-by":"crossref","first-page":"366","DOI":"10.2337\/dc19-1199","article-title":"Plasma lipidome and prediction of type 2 diabetes in the population-based Malm\u00f6 Diet and Cancer Cohort","volume":"43","author":"Fernandez","year":"2020","journal-title":"Diabetes Care"},{"key":"2022051317401755600_B9","doi-asserted-by":"crossref","first-page":"e1002179","DOI":"10.1371\/journal.pmed.1002179","article-title":"Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a Mendelian randomisation analysis","volume":"13","author":"Lotta","year":"2016","journal-title":"PLoS Med"},{"key":"2022051317401755600_B10","doi-asserted-by":"crossref","first-page":"4921","DOI":"10.1210\/jc.2019-00822","article-title":"Purine metabolites and carnitine biosynthesis intermediates are biomarkers for incident type 2 diabetes","volume":"104","author":"Ottosson","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2022051317401755600_B11","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/nm.2307","article-title":"Metabolite profiles and the risk of developing diabetes","volume":"17","author":"Wang","year":"2011","journal-title":"Nat Med"},{"key":"2022051317401755600_B12","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.ijcard.2021.01.059","article-title":"A plasma lipid signature predicts incident coronary artery disease","volume":"331","author":"Ottosson","year":"2021","journal-title":"Int J Cardiol"},{"key":"2022051317401755600_B13","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1161\/CIRCULATIONAHA.114.013116","article-title":"Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts","volume":"131","author":"W\u00fcrtz","year":"2015","journal-title":"Circulation"},{"key":"2022051317401755600_B14","doi-asserted-by":"crossref","first-page":"e003755","DOI":"10.1161\/JAHA.116.003755","article-title":"Metabolites of glutamate metabolism are associated with incident cardiovascular events in the PREDIMED PREvenci\u00f3n con DIeta MEDiterr\u00e1nea (PREDIMED) trial","volume":"5","author":"Zheng","year":"2016","journal-title":"J Am Heart Assoc"},{"key":"2022051317401755600_B15","doi-asserted-by":"crossref","first-page":"6791","DOI":"10.1038\/ncomms7791","article-title":"Distinct metabolomic signatures are associated with longevity in humans","volume":"6","author":"Cheng","year":"2015","journal-title":"Nat Commun"},{"key":"2022051317401755600_B16","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1038\/s41467-019-11311-9","article-title":"A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals","volume":"10","author":"Deelen","year":"2019","journal-title":"Nat Commun"},{"key":"2022051317401755600_B17","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.cmet.2018.09.022","article-title":"Profound perturbation of the metabolome in obesity is associated with health risk","volume":"29","author":"Cirulli","year":"2019","journal-title":"Cell Metab"},{"key":"2022051317401755600_B18","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1111\/j.1365-2796.2005.01485.x","article-title":"Incident coronary events and case fatality in relation to common carotid intima-media thickness","volume":"257","author":"Rosvall","year":"2005","journal-title":"J Intern Med"},{"key":"2022051317401755600_B19","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s10654-020-00695-4","article-title":"The Malm\u00f6 Offspring Study (MOS): design, methods and first results","volume":"36","author":"Brunkwall","year":"2021","journal-title":"Eur J Epidemiol"},{"key":"2022051317401755600_B20","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1007\/s11739-020-02625-4","article-title":"Comparison of cardiovascular disease and cancer prevalence between Mediterranean and north European middle-aged populations (The Cilento on Ageing Outcomes Study and The Malm\u00f6 Offspring Study)","volume":"16","author":"Melander","year":"2021","journal-title":"Intern Emerg Med"},{"key":"2022051317401755600_B21","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1186\/1471-2458-11-450","article-title":"External review and validation of the Swedish National Inpatient Register","volume":"11","author":"Ludvigsson","year":"2011","journal-title":"BMC Public Health"},{"key":"2022051317401755600_B22","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1530\/EJE-15-0781","article-title":"Genetic vasopressin 1b receptor variance in overweight and diabetes mellitus","volume":"174","author":"Enh\u00f6rning","year":"2016","journal-title":"Eur J Endocrinol"},{"key":"2022051317401755600_B23","doi-asserted-by":"crossref","first-page":"8576730","DOI":"10.1155\/2016\/8576730","article-title":"Postprandial levels of branch chained and aromatic amino acids associate with fasting glycaemia","volume":"2016","author":"Ottosson","year":"2016","journal-title":"J Amino Acids"},{"key":"2022051317401755600_B24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization paths for generalized linear models via coordinate descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J Stat Softw"},{"key":"2022051317401755600_B25","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cmet.2009.02.002","article-title":"A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance","volume":"9","author":"Newgard","year":"2009","journal-title":"Cell Metab"},{"key":"2022051317401755600_B26","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1210\/jc.2017-02114","article-title":"Connection between BMI-related plasma metabolite profile and gut microbiota","volume":"103","author":"Ottosson","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"2022051317401755600_B27","doi-asserted-by":"crossref","first-page":"e012846","DOI":"10.1161\/JAHA.119.012846","article-title":"Dimethylguanidino valerate: a lifestyle-related metabolite associated with future coronary artery disease and cardiovascular mortality","volume":"8","author":"Ottosson","year":"2019","journal-title":"J Am Heart Assoc"},{"key":"2022051317401755600_B28","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1001\/jamacardio.2019.1573","article-title":"Association of dimethylguanidino valeric acid with partial resistance to metabolic health benefits of regular exercise","volume":"4","author":"Robbins","year":"2019","journal-title":"JAMA Cardiol"},{"key":"2022051317401755600_B29","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1161\/CIRCULATIONAHA.111.067827","article-title":"Metabolite profiling identifies pathways associated with metabolic risk in humans","volume":"125","author":"Cheng","year":"2012","journal-title":"Circulation"},{"key":"2022051317401755600_B30","doi-asserted-by":"crossref","first-page":"4394","DOI":"10.1172\/JCI95995","article-title":"Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes","volume":"127","author":"O\u2019Sullivan","year":"2017","journal-title":"J Clin Invest"},{"key":"2022051317401755600_B31","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1007\/s00125-017-4325-0","article-title":"Early metabolic markers identify potential targets for the prevention of type 2 diabetes","volume":"60","author":"Peddinti","year":"2017","journal-title":"Diabetologia"},{"key":"2022051317401755600_B32","doi-asserted-by":"crossref","first-page":"3060","DOI":"10.1210\/jc.2018-00546","article-title":"Altered asparagine and glutamate homeostasis precede coronary artery disease and type 2 diabetes","volume":"103","author":"Ottosson","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"2022051317401755600_B33","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.orcp.2019.10.002","article-title":"Metabolically healthy obesity (MHO) in the Malm\u00f6 diet cancer study - epidemiology and prospective risks","volume":"13","author":"Korduner","year":"2019","journal-title":"Obes Res Clin Pract"},{"key":"2022051317401755600_B34","doi-asserted-by":"crossref","first-page":"254","DOI":"10.15171\/jcvtr.2019.43","article-title":"Risk of type 2 diabetes in metabolically healthy people in different categories of body mass index: an updated network meta-analysis of prospective cohort studies","volume":"11","author":"Tajik","year":"2019","journal-title":"J Cardiovasc Thorac Res"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/5\/1260\/678603\/dc212402.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/5\/1260\/678603\/dc212402.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T13:40:59Z","timestamp":1652449259000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/45\/5\/1260\/144736\/Metabolome-Defined-Obesity-and-the-Risk-of-Future"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,14]]},"references-count":34,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3,14]]},"published-print":{"date-parts":[[2022,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc21-2402","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.19196900","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.19196900.v1","asserted-by":"object"},{"id-type":"doi","id":"10.1101\/2021.11.03.21265744","asserted-by":"object"}]},"ISSN":["0149-5992"],"issn-type":[{"value":"0149-5992","type":"print"}],"subject":[],"published":{"date-parts":[[2022,3,14]]}}}