Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Metformin and insulin exacerbate one-carbon metabolism deficits in pregnant growth restricted rats and impacts the placenta, fetal liver and pancreas (128619)

Dayna A Zimmerman 1 , Jessica F Briffa 2 , Dewei Kong 3 , Sogand Gravina 2 , Dara Daygon 4 , Vinod Kumar 1 , Karen M Moritz 1 , Lillian Y Lim 5 , Adrian KK Teo 5 , Shiao-Yng Chan 6 , Mary E Wlodek 2 6 , James SM Cuffe 1
  1. School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
  2. Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
  3. Stem Cells and Diabetes Laboratory, Agency for Science, Technology and Research (A∗STAR), Singapore
  4. Queensland Metabolomics and Proteomics Facility, The University of Queensland, St Lucia, Queensland, Australia
  5. Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, , Singapore
  6. Singapore Institute for Clinical Sciences (SICS), , Agency for Science, Technology and Research (A∗STAR), Singapore

Fetal growth restriction increases the risk of metabolic conditions such as gestational diabetes mellitus (GDM) (1). One-carbon metabolite concentrations are dysregulated in GDM and influenced by antihyperglycaemic medications (2-3). However, it remains unclear if disrupted one-carbon metabolism contributes to GDM onset in growth restricted offspring and if antihyperglycaemic medications exacerbate this dysregulation. We investigated the effects of growth restriction and antihyperglycaemic treatment on one-carbon metabolism in pregnant rats and their fetuses.

Uteroplacental insufficiency (Restricted) or sham (Control) surgery was performed on embryonic day 18 in Wistar-Kyoto rats. Female F1 offspring were mated and Restricted dams received daily metformin, insulin, or vehicle from E13. Maternal and fetal plasma concentrations of one-carbon metabolites were measured using liquid chromatography-mass spectrometry. Liver and placental gene expression of enzymes involved in one-carbon metabolism and associated processes were measured using real-time PCR. Immunofluorescence staining was used to quantify fetal pancreatic β-cell and α-cell area.

Although Restricted dams did not develop metabolic dysfunction during pregnancy, they exhibited reduced one-carbon metabolism with a 71% decrease om their SAM:SAH ratio, indicating reduced methylation capacity. These changes were exacerbated by both metformin and insulin, contributing to a further 41.04% and 79.78% reduction in methylation capacity. In Restricted F2 fetuses, plasma one-carbon metabolites were unaffected despite changes in expression of genes involved in one-carbon metabolism in the placenta and liver. F2 fetuses displayed an elevated pancreatic β-cell:islet ratio. Antihyperglycaemic medications altered expression of multiple one-carbon metabolising enzymes in the maternal liver, the placenta junctional zone and the fetal liver. Metformin also increased pancreatic α-cell area.

This study suggests disrupted one-carbon 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-term health.

  1. (1) Claesson R, Aberg A & Marsál K. (2007). Abnormal fetal growth is associated with gestational diabetes mellitus later in life: population-based register study. Acta Obstet Gynecol Scand 86, 652-656.
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  3. (3) Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, Bray GA, Schade DS, Temprosa MG & White NH. (2016). Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. The Journal of Clinical Endocrinology & Metabolism 101, 1754-1761.