Metformin use during pregnancy for treatment of diabetes mellitus (DM) remains controversial despite its popularity outside of pregnancy. DM can induce placental mitochondrial dysfunction and excessive ROS production and inflammation (1). Given that metformin reduces the placental dysfunction implicated in preeclampsia (2), it is possible that by restoring mitochondrial function, metformin can improve placental function in DM and therefore fetal outcomes. Therefore, this study aimed to investigate the impact of maternal metformin treatment on placental mitochondrial function, in mice with and without diabetes in pregnancy.
Four-week-old C57BL/6J female mice were placed on either a control diet or a high fat diet (60% calories from fat) for five weeks to induce glucose intolerance. Mice then received either a daily dose of metformin (300mg/kg/day) or sterile water via oral gavage for two weeks prior to mating and throughout pregnant. Mice were culled on embryonic day 18.5 (E18.5) and placental mitochondrial respiration was measured using an Oxygraph-2k respirometer (Oroboros Instruments, Austria).
Maternal HFD reduced fetal weight by 8.5%, though brain weight was maintained. Metformin was unable to restore these changes. Metformin did increase in placental weight, however this also occurred in the LFD fed mice. Oxidative phosphorylation capacity through complex I (CI) was significantly decreased by both diet and metformin. LEAK, OXPHOS CI + CII, CIV and ETS were not affected by either treatment.
HFD lowered placental CI, which has been previously demonstrated in skeletal muscle to be linked to ROS production (3). Metformin has been shown to directly inhibit complex I activity (4), which we found to also occur in the placenta. It is possible that with reduced mitochondrial respiration, placental glucose will accumulate. Future work will investigate if the increased placental weight is driven by glycogen deposition. This study demonstrated that HFD and metformin have independent effects on placental physiology.