Maternal hyperglycemia disrupts cardiomyocyte maturation via aberrant nucleotide metabolism and suppression of AMPK signaling

Glucose serves not only as an energy source but also as a signaling molecule for organ growth. Intrauterine hyperglycemia elevates the risk of congenital heart defects independently of genetic factors, although its underlying mechanisms remain unclear. In this study, we investigated the impact of maternal hyperglycemia on cardiac development using a diabetic pregnancy mouse model and pluripotent stem cell-derived cardiomyocytes. Multi-modal analysis revealed that hyperglycemia disrupts mitochondrial structure and function in fetal hearts even before overt malformations appear, indicating that mitochondrial immaturity is an early signature of diabetic embryopathy. Metabolomic profiling revealed nucleotide imbalance and subsequent AMP-activated protein kinase (AMPK) suppression-contrasting with reports of increased AMPK activity observed in hyperglycemic neural tube defects. Notably, pharmacological activation of AMPK restored cardiomyocyte and mitochondrial function under high-glucose conditions in vitro. Our findings demonstrate that high glucose inhibits cardiomyocyte maturation through dysregulated nucleotide metabolism and AMPK suppression, advancing understanding of hyperglycemia-induced cardiac developmental defects.