Schoonejans Josca M, Wilsmore Phoebe, Mennitti Lais V, Wong Kwun K, Ashmore Thomas J, Garrud Tessa A C, Blackmore Heather L, Patey Olga V, Fernandez-Twinn Denise S, Giussani Dino A, Ozanne Susan E
Institute of Metabolic Science-Metabolic Research Laboratories and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, UK.
Institute of Reproductive Biology, Department of Metabolism, Digestion and Reproduction, Imperial College, London, UK.
J Physiol. 2025 Sep;603(17):4747-4764. doi: 10.1113/JP288696. Epub 2025 Jun 19.
Metformin is increasingly used to treat diabetes in pregnancy, but the effects on adult offspring health remain under-explored. The present study investigated the long-term cardiovascular effects in male and female offspring of maternal metformin treatment using a well-established mouse model of obese glucose intolerant pregnancy. Female mice were given chow, or an obesogenic diet with/without 300 mg kg day oral metformin during gestation. At 3, 6 and 12 months of age, male and female offspring were studied longitudinally with tail-cuff plethysmography and echocardiography. At 12 months, tissues were collected for wire myography, histology and molecular analyses. Female offspring of obese dams had elevated blood pressure throughout life, cardiac diastolic dysfunction at 3 months, and increased femoral vasoconstrictor reactivity and aortic wall remodelling at 12 months. Metformin treatment did not ameliorate these effects and led to obesity-induced hypertension at 12 months. Irrespective of metformin, male offspring of obese pregnancy had cardiac diastolic dysfunction from 6 months without changes in blood pressure. Male metformin-exposed offspring also showed cardiomegaly, increased cardiac collagen and vascular sympathetic hyperreactivity, suggesting metformin exposure worsened the cardiovascular phenotype. These findings show that maternal obesity caused sex-specific cardiovascular aberrations in aged offspring. Maternal metformin was not corrective and introduced further sex-dependent cardiovascular alterations. Further long-term offspring follow up of both sexes is needed for informed decisions about metformin during pregnancy. KEY POINTS: The oral medication metformin is increasingly used to treat diabetes in pregnancy. Metformin readily crosses the placenta, and long-term effects on offspring cardiovascular health remain unexplored in human and animal studies. In a mouse model of maternal diet-induced obesity with impaired glucose tolerance, female and male offspring developed hypertension and diastolic cardiac dysfunction, respectively, by 12 months of age (equivalent to middle age in humans). Maternal metformin treatment worsened the cardiovascular phenotype and introduced further sex-dependent cardiovascular alterations in both male (cardiac stiffening, vascular dysfunction) and female (obesity-induced hypertension) offspring. This work highlights that long-term cardiovascular follow up in offspring of both sexes from human pregnancies treated with metformin is crucial to make more informed decisions about metformin use in diabetic pregnancy.
二甲双胍越来越多地用于治疗妊娠期糖尿病，但其对成年子代健康的影响仍有待深入研究。本研究使用一种成熟的肥胖糖耐量不耐受妊娠小鼠模型，调查了母体使用二甲双胍治疗对雄性和雌性子代心血管系统的长期影响。雌性小鼠在妊娠期被给予普通饲料，或给予致肥胖饮食，并分别添加或不添加300mg/kg/天的口服二甲双胍。在子代3、6和12月龄时，使用尾套体积描记法和超声心动图对雄性和雌性子代进行纵向研究。在12月龄时，收集组织进行钢丝肌动描记法、组织学和分子分析。肥胖母鼠的雌性子代一生血压都升高，3月龄时出现心脏舒张功能障碍，12月龄时股动脉血管收缩反应性增加，主动脉壁重塑。二甲双胍治疗并未改善这些影响，反而在12月龄时导致肥胖诱导的高血压。无论是否使用二甲双胍，肥胖妊娠的雄性子代从6月龄起就出现心脏舒张功能障碍，但血压无变化。暴露于二甲双胍的雄性子代还表现出心脏肥大、心脏胶原蛋白增加和血管交感神经反应性增强，表明暴露于二甲双胍会使心血管表型恶化。这些发现表明，母体肥胖会导致老年子代出现性别特异性的心血管异常。母体使用二甲双胍并无纠正作用，反而会导致进一步的性别依赖性心血管改变。为了在妊娠期就二甲双胍的使用做出明智决策，需要对两性子代进行进一步的长期随访。要点：口服药物二甲双胍越来越多地用于治疗妊娠期糖尿病。二甲双胍很容易穿过胎盘，其对后代心血管健康的长期影响在人类和动物研究中仍未得到探索。在母体饮食诱导肥胖且糖耐量受损的小鼠模型中，雌性和雄性子代分别在12月龄（相当于人类中年）时出现高血压和心脏舒张功能障碍。母体使用二甲双胍治疗会使心血管表型恶化，并在雄性（心脏僵硬、血管功能障碍）和雌性（肥胖诱导的高血压）子代中导致进一步的性别依赖性心血管改变。这项研究强调，对接受二甲双胍治疗的人类妊娠子代进行长期心血管随访，对于就二甲双胍在糖尿病妊娠中的使用做出更明智的决策至关重要。
