Wentzel Parri, Xue Mingzhan, Rabbani Naila, Eriksson Ulf J, Thornalley Paul J
Department of Medical Cell Biology, Biomedical Center, Uppsala University, 75123 Uppsala, Sweden.
Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar.
Antioxidants (Basel). 2025 Aug 21;14(8):1022. doi: 10.3390/antiox14081022.
Hyperglycemia in early-stage embryogenesis is linked to diabetic embryopathy. High-glucose-concentration-induced accumulation of hexokinase-2 (HK2) may initiate metabolic dysfunction that contributes to diabetic embryopathy, including increased formation of methylglyoxal (MG). In this study, we evaluated changes in HK2 protein levels and embryo dysmorphogenesis in an experimental model of diabetic embryopathy. Rat embryos were cultured with high glucose concentrations, and the effects of glyoxalase 1 (Glo1) inducer, -resveratrol and hesperetin (tRES + HESP) were evaluated. Rat embryos, on gestational day 9, were cultured for 48 h in low and high glucose concentrations with or without tRES + HESP. Embryo crown-rump length, somite number, malformation score, concentrations of HK2 and Glo1 protein, rates of glucose consumption, and MG formation were assessed. Under low-glucose conditions, embryos exhibited normal morphogenesis. In contrast, high-glucose conditions led to reduced crown-rump length and somite number, and an increased malformation score. The addition of 10 μM tRES + HESP reversed these high glucose-induced changes by 60%, 49%, and 47%, respectively. Embryos cultured in high glucose showed increases in HK2 concentration (42%), glucose consumption (75%), and MG formation (27%), normalized to embryo volume. These elevated HK2 levels were normalized by treatment with 10 μM tRES + HESP. Thus, high-glucose-induced metabolic dysfunction and embryopathy may both be initiated by HK2 accumulation and may be preventable with tRES + HESP treatment.
早期胚胎发育过程中的高血糖与糖尿病胚胎病有关。高葡萄糖浓度诱导的己糖激酶-2（HK2）积累可能引发代谢功能障碍，进而导致糖尿病胚胎病，包括甲基乙二醛（MG）生成增加。在本研究中，我们在糖尿病胚胎病实验模型中评估了HK2蛋白水平的变化和胚胎畸形发生情况。将大鼠胚胎置于高葡萄糖浓度下培养，并评估乙二醛酶1（Glo1）诱导剂白藜芦醇和橙皮素（tRES + HESP）的影响。妊娠第9天的大鼠胚胎在添加或不添加tRES + HESP的低葡萄糖和高葡萄糖浓度下培养48小时。评估胚胎的顶臀长度、体节数、畸形评分、HK2和Glo1蛋白浓度、葡萄糖消耗率以及MG生成情况。在低葡萄糖条件下，胚胎表现出正常的形态发生。相反，高葡萄糖条件导致顶臀长度和体节数减少，畸形评分增加。添加10μM tRES + HESP分别使这些高葡萄糖诱导的变化逆转了60%、49%和47%。在高葡萄糖中培养的胚胎，以胚胎体积归一化后，HK2浓度增加了42%，葡萄糖消耗增加了75%，MG生成增加了27%。用10μM tRES + HESP处理可使这些升高的HK2水平恢复正常。因此，高葡萄糖诱导的代谢功能障碍和胚胎病可能均由HK2积累引发，且tRES + HESP治疗可能具有预防作用。
