{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:40:43Z","timestamp":1790365243708,"version":"4.1.0"},"reference-count":66,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Fetal growth restriction\u00a0increases the risk of metabolic conditions such as gestational diabetes mellitus (GDM). One\u2010carbon metabolite and nutrient concentrations are dysregulated in GDM and influenced by antihyperglycaemic medications. However, it remains unclear whether disrupted one\u2010carbon metabolism contributes to GDM onset in growth restricted offspring and whether antihyperglycaemic medications exacerbate this dysregulation. We investigated the effects of growth restriction and antihyperglycaemic treatment on one\u2010carbon metabolism in pregnant rats and their fetuses. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was performed on embryonic day (E)18 in Wistar\u2013Kyoto rats. Female F1 offspring were mated and Restricted dams received daily metformin, insulin or vehicle from E13. Although restricted dams did not develop metabolic dysfunction during pregnancy, they exhibited reduced one\u2010carbon metabolism and a lower <jats:italic>S<\/jats:italic>\u2010adenosylmethionine:<jats:italic>S<\/jats:italic>\u2010adenosylhomocysteine (SAM:SAH)\u00a0ratio, indicating reduced methylation capacity. These changes were exacerbated by both metformin and insulin. In F2 fetuses, plasma one\u2010carbon metabolites were unaffected despite changes in expression of genes involved in one\u2010carbon metabolism and DNA methylation in the placenta and fetal liver. F2 fetuses displayed an elevated pancreatic \u03b2\u2010cell:islet ratio. Antihyperglycaemic medications altered the expression of multiple one\u2010carbon metabolising enzymes in the maternal liver, the placenta junctional zone and the fetal liver. Metformin also increased pancreatic \u03b1\u2010cell area. This study suggests disrupted one\u2010carbon metabolism may underly programmed metabolic dysfunction and highlights the need for monitoring females born small. Both metformin and insulin induced similar physiological changes indicating that one is not safer than the other. Treatment decisions should consider potential impacts on long\u2010term health.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70071-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Being born growth restricted predisposes females to develop gestational diabetes (GDM) contributing to intergenerational transmission of disease. GDM is often treated with metformin or insulin. Disruptions to one\u2010carbon metabolism caused by growth restriction, insulin or metformin may explain transmission of disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This study investigated the effects of growth restriction, metformin and insulin on one\u2010carbon metabolism and subsequent fetal outcomes in rats.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Growth restriction impaired one\u2010carbon metabolism in mothers resulting in a reduced <jats:italic>S<\/jats:italic>\u2010adenosylmethionine:<jats:italic>S<\/jats:italic>\u2010adenosylhomocysteine ratio, changes to expression of associated enzymes in the placenta and fetal liver and an increase in the fetal \u03b2\u2010cell: pancreatic islet ratio.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin and insulin exacerbated deficits in one\u2010carbon metabolism in growth restricted dams and their fetuses, whereas metformin also increased pancreatic \u03b1\u2010cell area.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This study demonstrates one\u2010carbon metabolism as a key regulator of programmed metabolic disease in pregnancy and informs about the appropriate treatment of GDM in women born growth restricted.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp289453","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T04:29:12Z","timestamp":1756268952000},"page":"5751-5775","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Metformin and insulin exacerbate one\u2010carbon metabolism deficits in pregnant growth restricted rats and impacts the placenta, fetal liver and pancreas"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7631-9531","authenticated-orcid":false,"given":"Dayna A.","family":"Zimmerman","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences The University of Queensland  St Lucia QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica F.","family":"Briffa","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology The University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewei","family":"Kong","sequence":"additional","affiliation":[{"name":"Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research  Singapore Singapore"},{"name":"Dean's Office, Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sogand","family":"Gravina","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology The University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0805-5148","authenticated-orcid":false,"given":"Dara","family":"Daygon","sequence":"additional","affiliation":[{"name":"Queensland Metabolomics and Proteomics Facility The University of Queensland  St Lucia QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7263-9917","authenticated-orcid":false,"given":"Vinod","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Queensland  St Lucia QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8085-0034","authenticated-orcid":false,"given":"Karen M.","family":"Moritz","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Queensland  St Lucia QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian Y.","family":"Lim","sequence":"additional","affiliation":[{"name":"Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian K. 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