33 Effect of metformin use during pregnancy on fetal skeletal muscle growth and metabolism in rhesus macaques

Abstract Abstract: Introduction Metformin use in pregnancy is increasingly common, even beyond treatment of diabetes. Metformin crosses the placenta and bioaccumulates at equimolar concentrations near maternal circulation. Concerningly, metformin can suppress mitochondrial complex I activity in adults, limiting oxidative metabolism and ATP production. Objective Examine the effect of metformin on fetal growth and muscle metabolism in Rhesus macaques. Methods Twice-daily metformin (MET, 10 mg/kg) or placebo was given at 30 days of pregnancy with a chow (mCD) or Western diet (mWD). Fetal (n = 25F/17M) muscle was collected at g145 (of g164). Respiration was measured with carbohydrate or lipid substrates in permeabilized fiber bundles (PFB) from gastrocnemius and soleus or isolated mitochondria (mitos) from rectus femoris. Results Female mCD+MET offspring had reduced weight compared to mWD+MET (p = 0.02), with no differences in males. Muscle cross-sectional area was reduced with MET, independent of diet, in gastrocnemius but not soleus, suggesting fiber type-specific effects. In mCD, MET decreased CI reliance (p = 0.03) in gastrocnemius and soleus PFB. Increased fat oxidation and respiratory capacity in mWD was blunted by MET in PFB. Lipid oxidation (p = 0.03) was lower in mWD+MET mitos concomitant with reduced ATP production. CI and CI+II carbohydrate-respiration was higher in mCD+MET vs. mCD mitos (p = 0.04) but without greater ATP production. Conclusion Metformin resulted in subtle changes in fetal weight and was principally associated with reduced glycolytic muscle fiber size, mitochondrial respiration and ATP generation. As muscle mass correlates with functional capacity and insulin sensitivity throughout life, caution is warranted in using metformin during pregnancy. (Supported by NIH DK128187)