{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T19:17:47Z","timestamp":1769023067396,"version":"3.49.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T00:00:00Z","timestamp":1597017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/BD\/136887\/2018; PTDC\/BIM-MET\/2115\/2014; PTDC\/BIM-MET\/4265\/2014; iNOVA4Health (UIDB\/Multi\/04462\/2020"],"award-info":[{"award-number":["PD\/BD\/136887\/2018; PTDC\/BIM-MET\/2115\/2014; PTDC\/BIM-MET\/4265\/2014; iNOVA4Health (UIDB\/Multi\/04462\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["grant agreements no. 722619 and no. 734719"],"award-info":[{"award-number":["grant agreements no. 722619 and no. 734719"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Portuguese Diabetology Society","award":["2014"],"award-info":[{"award-number":["2014"]}]},{"name":"Portuguese Directorate General Health","award":["2014"],"award-info":[{"award-number":["2014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Type 2 diabetes (T2D) heterogeneity is a major determinant of complications risk and treatment response. Using cluster analysis, we aimed to stratify glycemia within metabolic multidimensionality and extract pathophysiological insights out of metabolic profiling. We performed a cluster analysis to stratify 974 subjects (PREVADIAB2 cohort) with normoglycemia, prediabetes, or non-treated diabetes. The algorithm was informed by age, anthropometry, and metabolic milieu (glucose, insulin, C-peptide, and free fatty acid (FFA) levels during the oral glucose tolerance test OGTT). For cluster profiling, we additionally used indexes of metabolism mechanisms (e.g., tissue-specific insulin resistance, insulin clearance, and insulin secretion), non-alcoholic fatty liver disease (NAFLD), and glomerular filtration rate (GFR). We found prominent heterogeneity within two optimal clusters, mainly representing normometabolism (Cluster-I) or insulin resistance and NAFLD (Cluster-II), at higher granularity. This was illustrated by sub-clusters showing similar NAFLD prevalence but differentiated by glycemia, FFA, and GFR (Cluster-II). Sub-clusters with similar glycemia and FFA showed dissimilar insulin clearance and secretion (Cluster-I). This work reveals that T2D heterogeneity can be captured by a thorough metabolic milieu and mechanisms profiling\u2014metabolic footprint. It is expected that deeper phenotyping and increased pathophysiology knowledge will allow to identify subject\u2019s multidimensional profile, predict their progression, and treat them towards precision medicine.<\/jats:p>","DOI":"10.3390\/jcm9082588","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T09:04:16Z","timestamp":1597050256000},"page":"2588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Metabolic Footprint, towards Understanding Type 2 Diabetes beyond Glycemia"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8135-7420","authenticated-orcid":false,"given":"Ana F.","family":"Pina","sequence":"first","affiliation":[{"name":"CEDOC-Centro de Estudos de Doen\u00e7as Cr\u00f3nicas, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal"},{"name":"ProRegem-ProRegeM PhD Programme, NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-2917","authenticated-orcid":false,"given":"Rita S.","family":"Patarr\u00e3o","sequence":"additional","affiliation":[{"name":"CEDOC-Centro de Estudos de Doen\u00e7as Cr\u00f3nicas, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal"},{"name":"IGC-Instituto de Gulbenkian e Ci\u00eancia, 1150-082 Lisbon, Portugal"}]},{"given":"Rog\u00e9rio T.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Portuguese Diabetes Association-Education and Research Center (APDP-ERC), 1150-082 Lisbon, Portugal"}]},{"given":"Carlos","family":"Penha-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"IGC-Instituto de Gulbenkian e Ci\u00eancia, 1150-082 Lisbon, Portugal"}]},{"given":"Jo\u00e3o F.","family":"Raposo","sequence":"additional","affiliation":[{"name":"CEDOC-Centro de Estudos de Doen\u00e7as Cr\u00f3nicas, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal"},{"name":"Portuguese Diabetes Association-Education and Research Center (APDP-ERC), 1150-082 Lisbon, Portugal"},{"name":"SPD-Sociedade Portuguesa de Diabetologia, 1150-082 Lisbon, Portugal"}]},{"given":"Lu\u00eds","family":"Gardete-Correia","sequence":"additional","affiliation":[{"name":"Portuguese Diabetes Association-Education and Research Center (APDP-ERC), 1150-082 Lisbon, Portugal"}]},{"given":"Rui","family":"Duarte","sequence":"additional","affiliation":[{"name":"Portuguese Diabetes Association-Education and Research Center (APDP-ERC), 1150-082 Lisbon, Portugal"},{"name":"SPD-Sociedade Portuguesa de Diabetologia, 1150-082 Lisbon, Portugal"}]},{"given":"Jos\u00e9","family":"M. Boavida","sequence":"additional","affiliation":[{"name":"Portuguese Diabetes Association-Education and Research Center (APDP-ERC), 1150-082 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7229-9679","authenticated-orcid":false,"given":"Jos\u00e9","family":"L. Medina","sequence":"additional","affiliation":[{"name":"SPD-Sociedade Portuguesa de Diabetologia, 1150-082 Lisbon, Portugal"}]},{"given":"Roberto","family":"Henriques","sequence":"additional","affiliation":[{"name":"NovaIMS-Nova Information Management School, 1150-082 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2549-0275","authenticated-orcid":false,"given":"Maria P.","family":"Macedo","sequence":"additional","affiliation":[{"name":"CEDOC-Centro de Estudos de Doen\u00e7as Cr\u00f3nicas, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal"},{"name":"Portuguese Diabetes Association-Education and Research Center (APDP-ERC), 1150-082 Lisbon, Portugal"},{"name":"SPD-Sociedade Portuguesa de Diabetologia, 1150-082 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/S0140-6736(13)62219-9","article-title":"The many faces of diabetes: A disease with increasing heterogeneity","volume":"383","author":"Tuomi","year":"2014","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.diabres.2010.01.026","article-title":"Global healthcare expenditure on diabetes for 2010 and 2030","volume":"87","author":"Zhang","year":"2010","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"963","DOI":"10.2337\/dc17-1962","article-title":"Global economic burden of diabetes in adults: Projections from 2015 to 2030","volume":"41","author":"Bommer","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_4","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":"ref_5","doi-asserted-by":"crossref","unstructured":"Matthiesen, R. (2020). Clustering clinical data in R. Mass Spectrometry Data Analysis in Proteomics, Springer.","DOI":"10.1007\/978-1-4939-9744-2"},{"key":"ref_6","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":"ref_7","first-page":"1","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":"8587","author":"Dennis","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_8","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":"ref_9","unstructured":"World Health Organization (1965). Diabetes Mellitus: Report of a WHO Expert Committee, World Health Organization."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"773","DOI":"10.2337\/db09-9028","article-title":"From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus","volume":"58","author":"DeFronzo","year":"2009","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s00125-017-4210-x","article-title":"Painting a new picture of personalised medicine for diabetes","volume":"60","author":"McCarthy","year":"2017","journal-title":"Diabetologia"},{"key":"ref_12","first-page":"2279","article-title":"Prediabetes: A high-risk state for developing diabetes Progression from prediabetes to diabetes Reversion to normoglycaemia Risk prediction","volume":"379","author":"Herder","year":"2014","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1111\/j.1464-5491.2010.03017.x","article-title":"Original Article: Epidemiology First diabetes prevalence study in Portugal: PREVADIAB study","volume":"27","author":"Boavida","year":"2010","journal-title":"Diabet. Med."},{"key":"ref_14","unstructured":"WHO, and IDF (2006). Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia, WHO Press."},{"key":"ref_15","unstructured":"International Diabetes Federation (2017). IDF Clinical Practice Recommendations for managing Type 2 Diabetes in Primary Care, International Diabetes Federation."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1464-5491.2006.01858.x","article-title":"Metabolic syndrome\u2014A new world-wide definition. A consensus statement from the International Diabetes Federation","volume":"23","author":"Alberti","year":"2006","journal-title":"Diabet. Med."},{"key":"ref_17","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":"ref_18","doi-asserted-by":"crossref","unstructured":"Herzberg-Sch\u00e4fer, S.A., Staiger, H., Heni, M., Ketterer, C., Guthoff, M., Kantartzis, K., Machicao, F., Stefan, N., H\u00e4ring, H.U., and Fritsche, A. (2010). Evaluation of fasting state-\/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired \u03b2-cell function. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0014194"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.2337\/diacare.22.9.1462","article-title":"Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic insulin clamp","volume":"22","author":"Matsuda","year":"1999","journal-title":"Diabetes Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1007\/s00125-010-1966-7","article-title":"A novel surrogate index for hepatic insulin resistance","volume":"54","author":"Vangipurapu","year":"2011","journal-title":"Diabetologia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2337\/dc06-1519","article-title":"Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test","volume":"30","author":"Matsuda","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1002\/hep.23116","article-title":"Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis","volume":"50","author":"Gastaldelli","year":"2009","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1006\/mgme.1997.2658","article-title":"Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels","volume":"63","author":"Belfiore","year":"1998","journal-title":"Mol. Genet. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kahl, S., Stra\u00dfburger, K., Nowotny, B., Livingstone, R., Kl\u00fcppelholz, B., Ke\u00dfel, K., Hwang, J.H., Giani, G., Hoffmann, B., and Pacini, G. (2014). Comparison of liver fat indices for the diagnosis of hepatic steatosis and insulin resistance. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094059"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Balkau, B., Lange, C., Vol, S., Fumeron, F., and Bonnet, F. (2010). Nine-year incident diabetes is predicted by fatty liver indices: The French D.E.S.I.R. study. BMC Gastroenterol., 10.","DOI":"10.1186\/1471-230X-10-56"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-230X-6-33","article-title":"The fatty liver index: A simple and accurate predictor of hepatic steatosis in the general population","volume":"6","author":"Bedogni","year":"2006","journal-title":"BMC Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Levey, A.S., Stevens, L.A., Schmid, C.H., Zhang, Y.L., Iii, A.F.C., Feldman, H.I., Kusek, J.W., Eggers, P., Van Lente, F., and Greene, T. (2012). Article annals of internal medicine a new equation to estimate glomerular filtration rate. S. Afr. J. Sci., 604\u2013612.","DOI":"10.7326\/0003-4819-150-9-200905050-00006"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1109\/72.846731","article-title":"Clustering of the self-organizing map","volume":"11","author":"Vesanto","year":"2000","journal-title":"IEEE Trans. Neural Netw."},{"key":"ref_29","unstructured":"Toppila, I. (2016). Identifying Novel Phenotype Profiles of Diabetic Complications and Their Genetic Components Using Machine Learning Approaches. [Master\u2019s Thesis, Aalto University]."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.18637\/jss.v087.i07","article-title":"Flexible self-organizing maps in kohonen 3.0","volume":"87","author":"Wehrens","year":"2018","journal-title":"J. Stat. Softw."},{"key":"ref_31","unstructured":"(2018). R Core Team R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_32","unstructured":"Kassambara, A., and Mundt, F. (2020, August 08). Factoextra: Extract and Visualize the Results of Multivariate Data Analyses. R Package Version 1.0.5. Available online: https:\/\/CRAN.R-project.org\/package=factoextra."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.csda.2006.11.025","article-title":"Cluster-wise assessment of cluster stability","volume":"52","author":"Hennig","year":"2007","journal-title":"Comput. Stat. Data Anal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12933-018-0762-4","article-title":"Association between insulin resistance and the development of cardiovascular disease","volume":"17","author":"Ormazabal","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.2337\/diacare.25.7.1135","article-title":"HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: Prospective data from the Verona Diabetes Complications Study","volume":"25","author":"Bonora","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"396","DOI":"10.4239\/wjd.v7.i17.396","article-title":"Evidence for current diagnostic criteria of diabetes mellitus","volume":"7","author":"Kumar","year":"2016","journal-title":"World J. Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/ng.257","article-title":"Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease","volume":"40","author":"Romeo","year":"2008","journal-title":"Nat. Genet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/8\/2588\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:58:48Z","timestamp":1760176728000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/8\/2588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,10]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["jcm9082588"],"URL":"https:\/\/doi.org\/10.3390\/jcm9082588","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,10]]}}}