Introduction and Objective: Metformin is an increasingly common medication used in pregnancy. However, metformin crosses the placenta raising concerns about unintended long-term effects to offspring health. This study examined whether metformin exposure during early development alters skeletal muscle metabolism in juvenile offspring and increases the risk of insulin resistance and obesity.Methods: Adult female Rhesus macaques were randomized to metformin (10 mg/kg BID) or placebo treats at 30 days of pregnancy and allocated to a chow (CD) or Western-style diet (WD). Treatment continued during lactation until 3 months postpartum with offspring remaining on diet to 24 months, yielding 4 groups: CD, MET/CD, WD, MET/WD. Mitochondrial respiration was measured in permeabilized gastrocnemius fiber bundles (n=24, 12F/12M) using high-resolution oxygraphy with glucose or lipid substrates. ATP and ROS production were measured using fluorescent probes. Data were analyzed with two-way ANOVA for diet and treatment or interaction.Results: Offspring body weight did not differ, but HbA1c was significantly elevated by diet (p=0.0001) with MET/WD exhibiting the highest values. Both ROS production and glucose-fueled respiration capacity increased in muscle of MET-exposed offspring (p=0.007; p=0.052), regardless of diet. ATP production and ATP/oxygen (P/O) ratio was higher in MET-exposed offspring (p=0.09; p=0.08). Although lipid-fueled respiration was unchanged, ATP production and P/O ratio with lipid increased in MET/WD (interaction: p=0.01; p=0.007), which was not observed in MET/CD, suggesting greater metabolic efficiency. Reserve capacity was also decreased in MET/WD vs. MET/CD or WD (interaction: p=0.03), indicating a limited ability to respond to energetic stress.Conclusion: Metformin exposure during pregnancy and lactation primes offspring muscle mitochondria to enhance metabolic efficiency, particularly when fed WD. Elevated ROS and reduced mitochondrial reserve capacity may increase offspring vulnerability to metabolic stress.
A. Gomez-Sharma: None. J. Truong: None. T. Dean: None. K. Aagaard-Tillery: None. M. Gannon: None. J. Friedman: None. S.R. Wesolowski: None. P. Kievit: Consultant; Current; Crinetics Pharmaceuticals, Inc. Research Support; Ended; Flagship Pioneering. Research Support; Current; Eli Lilly and Company, Novo Nordisk A/S. Consultant; Current; Merck & Co., Inc. C.E. McCurdy: None.
National Institutes of Health (R01-DK128187)
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