Diabetes in pregnancy can have detrimental effects on placental mitochondrial function and development, leading to adverse fetal outcomes. Metformin is a popular anti-diabetic medication outside of pregnancy, however exact mechanisms of action are still poorly understood. This understandably causes hesitation around its use during pregnancy, where protecting fetal development is of utmost importance. This study investigated the impact of chronic maternal metformin treatment on placental mitochondrial function, in mice with and without diabetes in pregnancy and evaluated the subsequent fetal outcomes.
Four-week-old C57BL/6J female mice consumed either a control or high fat diet (HFD; 60% calories from fat) for five weeks to induce glucose intolerance. Mice were treated with metformin (300mg/kg/day) or sterile water via oral gavage for two weeks prior to mating and throughout pregnancy. Mice were culled on embryonic day 18.5. To observe chronic effects of metformin treatment, daily dose was not delivered on cull day. Placental mitochondrial respiration was measured using an Oxygraph-2k respirometer (Oroboros Instruments, Austria). Fetal and placental growth was assessed at cull.
Maternal glucose intolerance decreased fetal growth by 8%, in females only. Metformin did not rescue female fetal growth. Chronic metformin treatment increased placental weight in both sexes, but in HFD mice only. Metformin decreased female fetal-placental ratio, suggestive of reduced placental efficiency. Maternal glucose intolerance and metformin treatment decreased oxidative phosphorylation capacity through complex I (CI) in female placenta only. Metformin also decreased mitochondrial spare capacity in both control and HFD mice, indicating that the mitochondria are operating near their limit. LEAK, OXPHOS CI + CII, CIV and ETS were unaffected by either treatment.
In our model of diabetes during pregnancy, chronic metformin treatment significantly increased placental growth, but reduced female placental mitochondrial function. Despite these changes, metformin failed to prevent growth restriction in the female fetuses in our diabetic-like mice.