Metformin and insulin exacerbate one-carbon metabolism deficits in pregnant growth restricted rats and impacts the placenta, fetal liver and pancreas
Abstract
Fetal growth restriction increases the risk of metabolic conditions such as gestational diabetes mellitus (GDM). One-carbon metabolite and nutrient concentrations are dysregulated in GDM and influenced by antihyperglycaemic medications. However, it remains unclear whether disrupted one-carbon 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-carbon metabolism in pregnant rats and their fetuses. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was performed on embryonic day (E)18 in Wistar-Kyoto 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-carbon metabolism and a lower S-adenosylmethionine:S-adenosylhomocysteine (SAM:SAH) ratio, indicating reduced methylation capacity. These changes were exacerbated by both metformin and insulin. In F2 fetuses, plasma one-carbon metabolites were unaffected despite changes in expression of genes involved in one-carbon metabolism and DNA methylation in the placenta and fetal liver. F2 fetuses displayed an elevated pancreatic β-cell:islet ratio. Antihyperglycaemic medications altered the expression of multiple one-carbon metabolising enzymes in the maternal liver, the placenta…
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