Endocrine Abstracts

Metformin is a first-line therapy for type-2 diabetes mellitus and gestational diabetes mellitus (GDM) which shows significant benefits for maternal health. However, offspring exposed to metformin in-utero have an increased risk of being born small for gestational age and developing cardiometabolic complications in adulthood. The mechanisms responsible are unknown. As fetal growth is dependent on optimal placental function, we assessed whether metformin exposure alters fetal growth by impacting placental development and function. Publicly available microarray data (ArrayExpress: E-MTAB-6418) from term placentae of obese women with GDM, treated with metformin (n=12) or placebo (n=8) from 12 16 weeks’ gestation, was used to assess the impact of in-utero¬ metformin exposure on birthweight and the placental transcriptome. Offspring exposed to metformin were born 375g lighter (P=0.35) and 46 significant DEGs (P<0.01; -0.58≥Log₂FoldChange≥0.58; FDR<0.05) were identified in placentae of metformin treated women. Functional enrichment and Ingenuity Pathway analyses were performed to predict functional impact of differentially expressed genes (DEGs). DEGs were enriched in pathways associated with placental metabolism, development, nutrient transport and mitochondrial dysfunction. To investigate if these functional effects were a direct consequence of metformin, term human placental villous explants from uncomplicated pregnancies (n=5) were exposed to metformin (40μM-1 mm) for up to 72 hours. Total and activated (phosphorylated; p) AMPK levels were assessed by western blotting. Metformin (100μM-1 mm) induced pAMPK expression in explants after 24 hours. QPCR analysis revealed metformin did not directly affect genes associated with placental development or nutrient transport. However, following 72 hour treatment, metformin (100μM) altered the expression of genes associated with mitochondrial activity (PINK1, PARKIN, LC3, BCL2). These results demonstrate in-utero metformin exposure alters genes associated with placental development, metabolism, nutrient transport and mitochondrial activity. However, data from ex-vivo placental tissue treated with metformin suggests metformin may have both direct and indirect actions on the placenta.