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The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI &lt;25 kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      ) and women with overweight (BMI \u226525 kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      ) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a nested case\u2013control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8\u201314 weeks\u2019 gestation. A 2 h 75 g OGTT was performed at 12\u201316 weeks\u2019 gestation (OGTT1), and women with normal results underwent repeat testing at 24\u201328 weeks\u2019 gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini\u2013Hochberg method.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the total cohort (\n                      <jats:italic>n<\/jats:italic>\n                      =419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and\/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and\/or fasting insulin and\n                      <jats:sc>l<\/jats:sc>\n                      -tyrosine, certain long-chain fatty acids and phospholipids (\n                      <jats:italic>q<\/jats:italic>\n                      &lt;0.001). Univariate analyses of GDM subtypes revealed significant differences (\n                      <jats:italic>q<\/jats:italic>\n                      &lt;0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4\/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0\/18:2 and 15:0\/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-024-06237-x","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T08:03:07Z","timestamp":1722412987000},"page":"2539-2554","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Analysis of early-pregnancy metabolome in early- and late-onset gestational diabetes reveals distinct associations with maternal overweight"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3078-0303","authenticated-orcid":false,"given":"Senja","family":"Masalin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Kl\u00e5vus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6344-1159","authenticated-orcid":false,"given":"Kristiina","family":"R\u00f6n\u00f6","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-070X","authenticated-orcid":false,"given":"Heikki A.","family":"Koistinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1587-8361","authenticated-orcid":false,"given":"Ville","family":"Koistinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0825-4956","authenticated-orcid":false,"given":"Olli","family":"K\u00e4rkk\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1202-0936","authenticated-orcid":false,"given":"Tiina J.","family":"J\u00e4\u00e4skel\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9038-130X","authenticated-orcid":false,"given":"Miira M.","family":"Klemetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"issue":"5","key":"6237_CR1","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1210\/endrev\/bnac003","volume":"43","author":"A Sweeting","year":"2022","unstructured":"Sweeting A, Wong J, Murphy HR, Ross GP (2022) A clinical update on gestational diabetes mellitus. 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The doctors Mervi Jokelainen, Beata Stach-Lempinen, Tero Tapiola, Antti Sotka, Ulla Pikarinen and Antti Valpas, in addition to Arja Nenonen, Arja Heikkinen, midwives and other personnel working at the South Karelia Central Hospital antenatal outpatient clinic, labour ward, operating theatres, laboratory and research administration, also provided crucial input and assistance in the implementation of this study. Data scientist Atte Lihtamo (Afekta Technologies Ltd) is thanked for his collaboration and contributions in the copy-editing phase.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data that support the findings of this study are not openly available for reasons of sensitivity, but may be available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital). This work was supported by the Research Foundation of South Karelia Central Hospital, the Viipuri Tuberculosis Foundation, Finnish State Funding for University-Level Health Research, the P\u00e4ivikki and Sakari Sohlberg Foundation, the Diabetes Research Foundation and the Juho Vainio Foundation. Additionally, individual researchers received grants from the Viipuri Tuberculosis Foundation (MMK and SM), the P\u00e4ivikki and Sakari Sohlberg Foundation (MMK and SM), South Karelia Medical Association (MMK), the Finnish Medical Foundation (MMK), the Maud Kuistila Memorial Foundation (MMK), the Research Foundation for Obstetrics and Gynecology (MMK), Biomedicum Helsinki Research Foundation (MMK), the Finnish Cultural Foundation (MMK), the Jalmari and Rauha Ahokas Foundation (MMK) and the Paulo Foundation (KR).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"MMK initiated the population-based EDDIE study. This nested case\u2013control study was planned by MMK, TJJ and KR. Metabolomics analyses were planned and implemented in collaboration with OK, AK and VK. KR was responsible for clinical data management and analysis. All authors participated in the planning of statistical analyses and interpretation of metabolomics data. SM and MMK wrote the manuscript. All authors contributed toward critically revising the paper, which was accepted by all authors. MMK is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}