Effect of in utero Metformin Exposure in Gestational Diabetes Mellitus on Infant Mesenchymal Stem Cell Metabolism.

Abstract

Offspring exposed to metformin treatment for gestational diabetes mellitus (GDM) experience altered growth patterns that increase the risk for developing cardiometabolic diseases later in life. The adaptive cellular mechanisms underlying these patterns remain unclear. Therefore, the objective of this study was to determine if chronic in utero metformin exposure associated with GDM treatment elicits infant cellular metabolic adaptations. In a cross-sectional design, 22 pregnant women diagnosed with GDM and treated exclusively with metformin (Met; n=12) or diet (A1DM; n=10) were compared. Umbilical cord derived mesenchymal stem cells (MSCs) were used as a model to study infant metabolism in vitro. OXPHOS and citrate synthase content were assessed by Western blot and intracellular lipid content was measured by Oil Red-O staining. Substrate oxidation and insulin action were measured with ¹⁴C radiolabeled glucose and oleate at baseline and following a 24-hour lipid challenge. Mitochondrial respiration was assessed by high-resolution respirometry. While no differences in infant birth measures were observed between groups, MSC outcomes revealed lower oleate oxidation rates (p=0.03) and lower mitochondrial capacity (p=0.009) among Met-MSCs. These findings suggest differences in energy metabolism may be present at birth among infants exposed to metformin in utero. Lower oleate oxidation and mitochondrial capacity in infant MSC may contribute to altered growth patterns that have been reported among offspring of metformin treated pregnant women with GDM.