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The objective of the study was to perform untargeted serum metabolomics and lipidomics analyses in 26 healthy, non-obese early-middle-aged LBW men, including five men with screen-detected and previously unrecognized non-alcoholic fatty liver disease (NAFLD), compared with 22 age- and BMI-matched NBW men (controls). While four metabolites (out of 65) and fifteen lipids (out of 279) differentiated the 26 LBW men from the 22 NBW controls (p \u2264 0.05), subgroup analyses of the LBW men with and without NAFLD revealed more pronounced differences, with 11 metabolites and 56 lipids differentiating (p \u2264 0.05) the groups. The differences in the LBW men with NAFLD included increased levels of ornithine and tyrosine (PFDR \u2264 0.1), as well as of triglycerides and phosphatidylcholines with shorter carbon-chain lengths and fewer double bonds. Pathway and network analyses demonstrated downregulation of transfer RNA (tRNA) charging, altered urea cycling, insulin resistance, and an increased risk of T2D in the LBW men with NAFLD. Our findings highlight the importance of increased liver fat in the pathogenesis of T2D in LBW individuals.<\/jats:p>","DOI":"10.3390\/nu15071590","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T01:38:36Z","timestamp":1679881116000},"page":"1590","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Circulating Metabolomic and Lipidomic Signatures Identify a Type 2 Diabetes Risk Profile in Low-Birth-Weight Men with Non-Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Line O.","family":"Elingaard-Larsen","sequence":"first","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9096-1555","authenticated-orcid":false,"given":"Sofie O.","family":"Villumsen","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise","family":"Justesen","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8639-9117","authenticated-orcid":false,"given":"Anne Cathrine B.","family":"Thuesen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9995-715X","authenticated-orcid":false,"given":"Mina","family":"Ali","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Else R.","family":"Danielsen","sequence":"additional","affiliation":[{"name":"Department of Radiology, Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Legido-Quigley","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerrit","family":"van Hall","sequence":"additional","affiliation":[{"name":"Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark"},{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Science, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Torben","family":"Hansen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7464-3354","authenticated-orcid":false,"given":"Tarunveer S.","family":"Ahluwalia","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"},{"name":"The Bioinformatics Center, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3690-2191","authenticated-orcid":false,"given":"Allan A.","family":"Vaag","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"},{"name":"Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, 214 28 Malm\u00f6, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Br\u00f8ns","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/BF00400248","article-title":"Type 2 (Non-Insulin-Dependent) Diabetes Mellitus: The Thrifty Phenotype Hypothesis","volume":"35","author":"Hales","year":"1992","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1093\/aje\/kwk071","article-title":"Birth Weight and Subsequent Risk of Type 2 Diabetes: A Meta-Analysis","volume":"165","author":"Harder","year":"2007","journal-title":"Am. 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