Fan Miaojuan, Pan Tongtong, Jin Wei, Sun Jian, Zhang Shujun, Du Yali, Chen Xinwei, Chen Qiong, Xu Wenxin, Choo Siew Woh, Zhu Guanghui, Chen Yongping, Zhou Jie
Department of Infectious Diseases & Zhejiang Provincial Key laboratory of Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Front Pharmacol. 2022 Mar 4;13:827617. doi: 10.3389/fphar.2022.827617. eCollection 2022.
Gestational diabetes mellitus (GDM) is associated with adverse maternal and neonatal outcomes, however the underlying mechanisms remain elusive. The aim of this study was to find efficient regulator of FGFs in response to the pathogenesis of GDM and explore the role of the FGFs in GDM. We performed a systematic screening of placental FGFs in GDM patients and further in two different GDM mouse models to investigate their expression changes. Significant changed FGF4 was selected, engineered, purified, and used to treat GDM mice in order to examine whether it can regulate the adverse metabolic phenotypes of the diabetic mice and protect their fetus. We found FGF4 expression was elevated in GDM patients and its level was positively correlated to blood glucose, indicating a physiological relevance of FGF4 with respect to the development of GDM. Recombinant FGF4 (rFGF4) treatment could effectively normalize the adverse metabolic phenotypes in high fat diet induced GDM mice but not in STZ induced GDM mice. However, rFGF4 was highly effective in reduce of neural tube defects (NTDs) of embryos in both the two GDM models. Mechanistically, rFGF4 treatment inhibits pro-inflammatory signaling cascades and neuroepithelial cell apoptosis of both GDM models, which was independent of glucose regulation. Our study provides novel insight into the important roles of placental FGF4 and suggests that it may serve as a promising diagnostic factor and therapeutic target for GDM.
妊娠期糖尿病（GDM）与不良的母婴结局相关，但其潜在机制仍不清楚。本研究的目的是寻找应对GDM发病机制的FGFs有效调节因子，并探讨FGFs在GDM中的作用。我们对GDM患者的胎盘FGFs进行了系统筛查，并在两种不同的GDM小鼠模型中进一步研究，以调查它们的表达变化。选择、改造、纯化了显著变化的FGF4，并将其用于治疗GDM小鼠，以检查它是否能调节糖尿病小鼠的不良代谢表型并保护其胎儿。我们发现GDM患者中FGF4表达升高，其水平与血糖呈正相关，表明FGF4与GDM的发生具有生理相关性。重组FGF4（rFGF4）治疗可有效使高脂饮食诱导的GDM小鼠的不良代谢表型恢复正常，但对链脲佐菌素诱导的GDM小鼠无效。然而，rFGF4在两种GDM模型中均能高效降低胚胎的神经管缺陷（NTDs）。从机制上讲，rFGF4治疗抑制了两种GDM模型的促炎信号级联反应和神经上皮细胞凋亡，这与葡萄糖调节无关。我们的研究为胎盘FGF4的重要作用提供了新的见解，并表明它可能作为GDM的一个有前景的诊断因子和治疗靶点。
