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Coffee intake by 156 overweight subjects (87% with Type-2-Diabetes, T2D) was assessed via a questionnaire, with 98 subjects (all T2D) also providing a 24 h urine sample for quantification of coffee metabolites by LC\u2013MS\/MS. NAFLD was characterized by the fatty liver index (FLI) and by Fibroscan\u00ae assessment of fibrosis. No associations were found between self-reported coffee intake and NAFLD parameters; however, total urine caffeine metabolites, defined as \u03a3caffeine (caffeine + paraxanthine + theophylline), and adjusted for fat-free body mass, were significantly higher for subjects with no liver fibrosis than for those with fibrosis. Total non-caffeine metabolites, defined as \u03a3ncm (trigonelline + caffeic acid + p-coumaric acid), showed a significant negative association with the FLI. Multiple regression analyses for overweight\/obese T2D subjects (n = 89) showed that both \u03a3caffeine and \u03a3ncm were negatively associated with the FLI, after adjusting for age, sex, HbA1c, ethanol intake and glomerular filtration rate. The theophylline fraction of \u03a3caffeine was significantly increased with both fibrosis and the FLI, possibly reflecting elevated CYP2E1 activity\u2014a hallmark of NAFLD worsening. Thus, for overweight\/obese T2D patients, higher intake of both caffeine and non-caffeine coffee components is associated with less severe NAFLD. Caffeine metabolites represent novel markers of NAFLD progression.<\/jats:p>","DOI":"10.3390\/nu15010004","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T04:45:53Z","timestamp":1671511553000},"page":"4","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Increased Intake of Both Caffeine and Non-Caffeine Coffee Components Is Associated with Reduced NAFLD Severity in Subjects with Type 2 Diabetes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0392-1118","authenticated-orcid":false,"given":"Margarida","family":"Coelho","sequence":"first","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal"},{"name":"III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-2917","authenticated-orcid":false,"given":"Rita S.","family":"Patarr\u00e3o","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School-Faculdade de Ci\u00eancias M\u00e9dicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal"}]},{"given":"In\u00eas","family":"Sousa-Lima","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School-Faculdade de Ci\u00eancias M\u00e9dicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal"}]},{"given":"Rog\u00e9rio T.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8236-5411","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Meneses","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School-Faculdade de Ci\u00eancias M\u00e9dicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal"}]},{"given":"Rita","family":"Andrade","sequence":"additional","affiliation":[{"name":"APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal"}]},{"given":"Vera M.","family":"Mendes","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal"},{"name":"III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-4042","authenticated-orcid":false,"given":"Bruno","family":"Manadas","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal"},{"name":"III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2589-7208","authenticated-orcid":false,"given":"Jo\u00e3o Filipe","family":"Raposo","sequence":"additional","affiliation":[{"name":"APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2549-0275","authenticated-orcid":false,"given":"M. Paula","family":"Macedo","sequence":"additional","affiliation":[{"name":"iNOVA4Health, NOVA Medical School-Faculdade de Ci\u00eancias M\u00e9dicas, NMS-FCM, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal"},{"name":"APDP-Diabetes Portugal, Education and Research Center, 1250-189 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3745-3885","authenticated-orcid":false,"given":"John G.","family":"Jones","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-531 Coimbra, Portugal"},{"name":"III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hodge, A., Lim, S., Goh, E., Wong, O., Marsh, P., Knight, V., Sievert, W., and de Courten, B. 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