研究表明，葡萄糖毒性作用致tau蛋白过度磷酸化参与2型糖尿病(T2DM)认知障碍的发生、进展。我们前期进一步发现高血糖致O-GlcNAc糖基化途径异常，进而使部分tau蛋白位点磷酸化水平显著增高，机制尚不明确。本研究首先以自发T2DM模型KK-Ay小鼠为研究对象，观察其出现认知障碍时脑内tau蛋白O-GlcNAc糖基化及关键酶、磷酸化水平；细胞层面，则通过构建质粒等方式改变O-GlcNAc糖基化修饰水平，观察其后对tau蛋白磷酸化的影响；在体层面，分层收集、比较临床病例静息态功能磁共振(fMRI)数据，并与血糖、O-GlcNAc糖基化水平作相关分析，以明确高血糖致O-GlcNAc糖基化修饰异常的神经网络特征。本研究在前期工作取得进展的基础上，旨在明确葡萄糖毒性致tau蛋白过度磷酸化的分子机制，并结合在体影像学特征以期早期预警糖尿病认知障碍，为其有效防治提供可靠的理论依据。

Several studies have demonstrated that tau protein hyperphosphorylation induced by glucose toxicity was involved in cognitive impairment in type 2 diabetes mellitus (T2DM). Our previous studies further showed that hyperglycemia could lead to the abnormal pathway of O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, and lead to significant increase of some tau protein loci phosphorylation, while the exact mechanism is uncertain. This study first detected brain O-GlcNAc glycosylation, key enzymes of O-GlcNAc glycosylation and tau protein phosphorylation levels in appearance of cognitive impairment using the spontaneous T2DM model of KK-Ay mice. In vitro, the effect of O-GlcNAc glycosylation on tau protein phosphorylation levels were examined by altering O-GlcNAc glycosylation levels with plasmids transfection. In vivo, resting-state functional magnetic resonance imaging (fMRI) data of the enrolled subjects were collected and compared, and then the correlations of neural network features with blood glucose and O-GlcNAc glycosylation levels were analyzed to clarify the neural network characteristics of abnormal O-GlcNAc glycosylation pathways induced by glucose toxicity. Based on the progresses of our previous works, the current study was aimed to determine the molecular mechanisms of tau protein hyperphosphorylation induced by glucose toxicity, to warn diabetes-related cognitive deficits early in combination with imaging characteristics, and to provide reliable theoretical evidences for early prevention and treatment.