Nutrition & diabetes · 2026
Reversal of canonical Wnt/β-catenin signaling pathway attenuates gestational diabetes mellitus-induced offspring cardiac hypertrophy: mechanistic insights into pathological remodeling.
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Yuan Xun, Jiao Yuejiang, Huang Zexin, Jiang Ruchao, Chen Yiling, Liu Ducai, Zhao Zexin, Zhu Qiulian, Qin Yuan, Zhang Guiping, Feng Zhimei, Yang Caixian, Hou Ning
Аннотация
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.
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.