Nutr Diabetes. 2026 Jul 11. doi: 10.1038/s41387-026-00453-7. Online ahead of print.
ABSTRACT
BACKGROUND: Gestational diabetes mellitus (GDM), a prevalent prenatal metabolic disorder characterized by hyperglycemia occurring in approximately 9.2% of pregnancies globally, imposes significant cardiovascular risks on offspring, including developmental cardiac hypertrophy and long-term functional impairment. Despite its clinical importance, the molecular mechanisms governing GDM-induced cardiac malformations remain elusive.
AIMS: This study aimed to delineate the regulatory role of the Wnt/β-catenin/Tcf7l2 signaling pathway in mediating pathological cardiac remodeling in GDM-exposed offspring through experimental manipulation using a clinically relevant murine model.
METHODS: We established a clinically relevant GDM mouse model exhibiting key metabolic features including hyperinsulinemia and impaired glucose tolerance, which faithfully recapitulates human GDM pathology. Cardiomyocyte-specific β-catenin knockout and cardiomyocyte-specific overexpression of constitutively active β-catenin were employed for genetic manipulation. Pharmacological intervention was performed using saxagliptin, a clinically approved DPP-4 inhibitor. Cardiac phenotypes were evaluated by histopathological analysis, echocardiography, and molecular assessments of Wnt/β-catenin pathway activity and hypertrophic markers.
RESULTS: Histopathological and echocardiographic analyses revealed pronounced cardiac hypertrophy in GDM-exposed offspring, concomitant with activation of the Wnt/β-catenin/Tcf7l2 pathway in myocardial tissues. Functional studies demonstrated that cardiomyocyte-specific β-catenin ablation attenuated GDM-induced hypertrophic remodeling, whereas constitutive β-catenin overexpression exacerbated cardiac dysfunction. Importantly, pharmacological intervention with saxagliptin significantly ameliorated cardiac hypertrophy in GDM-offspring. This therapeutic effect was paralleled by marked suppression of Wnt/β-catenin signaling activity and reduced expression of ANP.
CONCLUSION: Collectively, these findings provide compelling evidence that dysregulation of the Wnt/β-catenin/Tcf7l2 pathway constitutes a critical mediator in GDM-induced cardiac hypertrophy, and highlight saxagliptin as a potential therapeutic strategy to mitigate adverse cardiac outcomes in GDM offspring.
PMID:42436144 | DOI:10.1038/s41387-026-00453-7