{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:43:02Z","timestamp":1790700182932,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: The classification of patients with diabetes into phenotypes with distinct risks and therapeutic needs is crucial for individualized care. We recently introduced a clustering model for gestational diabetes mellitus (GDM). This study aims to further characterize the proposed clusters and to identify cluster-specific differences in glucometabolic parameters during early pregnancy in an independent cohort. The metabolic profiles and dietary habits of GDM clusters will be compared with those of a normal glucose-tolerant (NGT) control group. Methods: 1088 women (195 who developed GDM and 893 who remained NGT) underwent a broad risk evaluation at early pregnancy. GDM patients were further categorized into the three proposed GDM subtypes (CL1 to CL3). Results: Among GDM patients, 7.7% were classified as CL1, 35.9% as CL2, and 56.4% as CL3. CL1 showed higher age, pregestational BMI, and increased glucose concentrations both at fasting and during the diagnostic oral glucose tolerance test. CL2 was characterized by elevated BMI and fasting glucose, while CL3 showed higher glucose concentrations after the oral glucose load, with BMI levels comparable to NGT mothers. Women in the CL1 group exhibited impaired insulin sensitivity and \u03b2-cell function at early pregnancy and showed elevated lipid levels. Compared to NGT women, a positive family history of diabetes was more prevalent in CL1 and CL3, but not in CL2. Dietary patterns were similar across all groups. Conclusions: Our study showed distinct alterations in glucometabolic parameters already at early pregnancy among GDM subtypes. Patients in CL1 exhibited the most unfavorable risk constellation and could benefit from lifestyle changes and nutrition therapy in early pregnancy, despite showing similar dietary patterns as the NGT group.<\/jats:p>","DOI":"10.3390\/nu17203252","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T16:33:22Z","timestamp":1760632402000},"page":"3252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Gestational Diabetes Mellitus Subtypes Derived by Clustering Analysis Show Heterogeneity in Glucometabolic Parameters Already at Early Pregnancy"],"prefix":"10.3390","volume":"17","author":[{"given":"Grammata","family":"Kotzaeridi","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4878-8699","authenticated-orcid":false,"given":"Benedetta","family":"Salvatori","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1921-838X","authenticated-orcid":false,"given":"Agnese","family":"Piersanti","sequence":"additional","affiliation":[{"name":"National Research Council (CNR) Institute of Neuroscience, 35127 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0523-5696","authenticated-orcid":false,"given":"Florian","family":"Heinzl","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9696-1428","authenticated-orcid":false,"given":"Sophie","family":"Zarotti","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Kiss","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Wegener","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9448-475X","authenticated-orcid":false,"given":"Iris","family":"Dressler-Steinbach","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Henrich","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8327-8379","authenticated-orcid":false,"given":"Micaela","family":"Morettini","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, Universit\u00e0 Politecnica delle Marche, 60131 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3466-5900","authenticated-orcid":false,"given":"Andrea","family":"Tura","sequence":"additional","affiliation":[{"name":"National Research Council (CNR) Institute of Neuroscience, 35127 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian S.","family":"G\u00f6bl","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.2337\/dc15-2672","article-title":"Heterogeneous Contribution of Insulin Sensitivity and Secretion Defects to Gestational Diabetes Mellitus","volume":"39","author":"Powe","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.2337\/dbi20-0004","article-title":"Defining Heterogeneity Among Women with Gestational Diabetes Mellitus","volume":"69","author":"Powe","year":"2020","journal-title":"Diabetes"},{"key":"ref_3","first-page":"118","article-title":"Non-insulin-dependent diabetes mellitus: A clinical strategy","volume":"7","author":"Skyler","year":"1984","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1038\/s41588-018-0241-6","article-title":"Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps","volume":"50","author":"Mahajan","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1007\/s00125-024-06184-7","article-title":"Identification and validation of gestational diabetes subgroups by data-driven cluster analysis","volume":"67","author":"Salvatori","year":"2024","journal-title":"Diabetologia"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"HAPO Study Cooperative Research Group, Metzger, B.E., Lowe, L.P., Dyer, A.R., Trimble, E.R., Chaovarindr, U., Coustan, D.R., Hadden, D.R., McCance, D.R., and Hod, M. (2008). Hyperglycemia and Adverse Pregnancy Outcomes. N. Engl. J. Med., 358, 1991\u20132002.","DOI":"10.1056\/NEJMoa0707943"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1001\/jama.2018.11628","article-title":"Association of Gestational Diabetes with Maternal Disorders of Glucose Metabolism and Childhood Adiposity","volume":"320","author":"Lowe","year":"2018","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"i4694","DOI":"10.1136\/bmj.i4694","article-title":"Hyperglycaemia and risk of adverse perinatal outcomes: Systematic review and meta-analysis","volume":"354","author":"Farrar","year":"2016","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"j1","DOI":"10.1136\/bmj.j1","article-title":"Obesity and pregnancy: Mechanisms of short term and long term adverse consequences for mother and child","volume":"356","author":"Catalano","year":"2017","journal-title":"BMJ"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"780","DOI":"10.2337\/dc11-1790","article-title":"The Hyperglycemia and Adverse Pregnancy Outcome Study","volume":"35","author":"Catalano","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1097\/AOG.0000000000002726","article-title":"Research Gaps in Gestational Diabetes Mellitus","volume":"132","author":"Wexler","year":"2018","journal-title":"Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Linder, T., Eder, A., Monod, C., Rosicky, I., Eppel, D., Redling, K., Geissler, F., Huhn, E.A., H\u00f6sli, I., and G\u00f6bl, C.S. (2022). Impact of Prepregnancy Overweight and Obesity on Treatment Modality and Pregnancy Outcome in Women with Gestational Diabetes Mellitus. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.799625"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1016\/j.ajog.2004.12.049","article-title":"Overweight and obese in gestational diabetes: The impact on pregnancy outcome","volume":"192","author":"Langer","year":"2005","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"56","DOI":"10.2337\/dc12-0741","article-title":"The Relative Contribution of Prepregnancy Overweight and Obesity, Gestational Weight Gain, and IADPSG-Defined Gestational Diabetes Mellitus to Fetal Overgrowth","volume":"36","author":"Black","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mecacci, F., Lisi, F., Vannuccini, S., Ottanelli, S., Rambaldi, M.P., Serena, C., Simeone, S., and Petraglia, F. (2021). Different Gestational Diabetes Phenotypes: Which Insulin Regimen Fits Better?. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.630903"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110913","DOI":"10.1016\/j.diabres.2023.110913","article-title":"Pregnancy outcomes in the different phenotypes of gestational diabetes mellitus based on the oral glucose tolerance test. A systematic review and meta-analysis","volume":"204","author":"Chatzakis","year":"2023","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e13628","DOI":"10.1111\/eci.13628","article-title":"Characteristics of gestational diabetes subtypes classified by oral glucose tolerance test values","volume":"51","author":"Kotzaeridi","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2264","DOI":"10.1210\/clinem\/dgae754","article-title":"Heterogeneity of Gestational Diabetes and Risk for Adverse Pregnancy Outcome: A Cohort Study","volume":"110","author":"Gong","year":"2025","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s12020-025-04329-1","article-title":"Gestational diabetes mellitus subtypes according to oral glucose tolerance test and pregnancy outcomes","volume":"90","author":"Athanasiadou","year":"2025","journal-title":"Endocrine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1186\/s12967-018-1666-5","article-title":"Heterogeneity of insulin resistance and beta cell dysfunction in gestational diabetes mellitus: A prospective cohort study of perinatal outcomes","volume":"16","author":"Liu","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1515\/jpm-2023-0170","article-title":"Advanced maternal age (AMA) and 75 g oGTT glucose levels are pedictors for insulin therapy in women with gestational diabetes (GDM)","volume":"51","author":"Koenigbauer","year":"2023","journal-title":"J. Perinat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e13630","DOI":"10.1111\/eci.13630","article-title":"Performance of early risk assessment tools to predict the later development of gestational diabetes","volume":"51","author":"Kotzaeridi","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1475-2891-9-36","article-title":"Relative validation of a food frequency questionnaire for national health and nutrition monitoring","volume":"9","author":"Haftenberger","year":"2010","journal-title":"Nutr. J."},{"key":"ref_24","unstructured":"World Health Organization (2024, May 30). Diagnostic Criteria and Classification of Hyperglycaemia First Detected in Pregnancy. Available online: https:\/\/www.who.int\/publications\/i\/item\/WHO-NMH-MND-13.2."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S0140-6736(14)60932-6","article-title":"International standards for newborn weight, length, and head circumference by gestational age and sex: The Newborn Cross-Sectional Study of the INTERGROWTH-21st Project","volume":"384","author":"Villar","year":"2014","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1210\/jcem.85.7.6661","article-title":"Quantitative Insulin Sensitivity Check Index: A Simple, Accurate Method for Assessing Insulin Sensitivity in Humans","volume":"85","author":"Katz","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1186\/s12933-022-01649-8","article-title":"TyGIS: Improved triglyceride-glucose index for the assessment of insulin sensitivity during pregnancy","volume":"21","author":"Salvatori","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.diabres.2005.10.005","article-title":"Insulinogenic indices from insulin and C-peptide: Comparison of beta-cell function from OGTT and IVGTT","volume":"72","author":"Tura","year":"2006","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1111\/j.1464-5491.2009.02841.x","article-title":"Evaluation of proposed oral disposition index measures in relation to the actual disposition index","volume":"26","author":"Retnakaran","year":"2009","journal-title":"Diabet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1530\/eje.0.1500097","article-title":"Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies","volume":"150","author":"Ahren","year":"2004","journal-title":"Eur. J. Endocrinol."},{"key":"ref_31","unstructured":"Salvatori, B. (2024, October 31). Compute Subgroup for Patients with Gestational Diabetes Mellitus (GDM). Available online: https:\/\/clugdm.shinyapps.io\/clugdm\/."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v064.i09","article-title":"nparcomp: An R Software Package for Nonparametric Multiple Comparisons and Simultaneous Confidence Intervals","volume":"64","author":"Konietschke","year":"2015","journal-title":"J. Stat. Softw."},{"key":"ref_33","unstructured":"R Core Team (2022). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e14413","DOI":"10.1111\/dme.14413","article-title":"Metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes","volume":"38","author":"Immanuel","year":"2021","journal-title":"Diabet. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1007\/s00125-019-4961-7","article-title":"Characteristics and pregnancy outcomes across gestational diabetes mellitus subtypes based on insulin resistance","volume":"62","author":"Benhalima","year":"2019","journal-title":"Diabetologia"},{"key":"ref_36","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_37","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00592-020-01644-z","article-title":"Association between maternal triglycerides and disturbed glucose metabolism in pregnancy","volume":"58","author":"Eppel","year":"2021","journal-title":"Acta Diabetol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1159\/000535490","article-title":"Glucometabolic Alterations in Pregnant Women with Overweight or Obesity but without Gestational Diabetes Mellitus: An Observational Study","volume":"17","author":"Linder","year":"2024","journal-title":"Obes. Facts"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s43856-024-00491-1","article-title":"Effective interventions in preventing gestational diabetes mellitus: A systematic review and meta-analysis","volume":"4","author":"Takele","year":"2024","journal-title":"Commun. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.2337\/db12-1692","article-title":"Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies","volume":"62","author":"Hayes","year":"2013","journal-title":"Diabetes"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1007\/s00125-024-06110-x","article-title":"Metabolomic and genetic architecture of gestational diabetes subtypes","volume":"67","author":"Lee","year":"2024","journal-title":"Diabetologia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41588-023-01607-4","article-title":"Distinct and shared genetic architectures of gestational diabetes mellitus and type 2 diabetes","volume":"56","author":"Elliott","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"268","DOI":"10.2337\/db20-0772","article-title":"Genetic Loci and Physiologic Pathways Involved in Gestational Diabetes Mellitus Implicated Through Clustering","volume":"70","author":"Powe","year":"2021","journal-title":"Diabetes"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/20\/3252\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T16:39:05Z","timestamp":1760632745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/20\/3252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":43,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["nu17203252"],"URL":"https:\/\/doi.org\/10.3390\/nu17203252","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]}}}