壳寡糖胍的固相合成及其与葡萄糖转运蛋白的作用关系研究

葡萄糖转运蛋白（GLUTS）对于介导葡萄糖的细胞内外转运至关重要，GLUTS表达受损就可能造成胰岛β细胞营养供给缺失，引起胰岛β细胞功能下降，进而引发糖尿病。本项目参照经典口服降糖药二甲双胍的分子结构，采用高反应活性的胍基化试剂，通过微波固相合成，制备高产率、高纯度壳寡糖胍（COSG）。期望产物不仅因胍基拥有明显的降糖效果，而且因壳寡糖具有对GLUTS的分子识别作用，和缓解双胍药物胃肠刺激的作用。在此基础上，通过COSG对糖尿病大鼠的治疗实验，明晰其对胰岛β细胞功能的修复作用，深入研究COSG与GLUTS的作用关系，分析其对不同组织、器官细胞中GLUTS活性和基因表达的影响，比较COSG对糖吸收关键蛋白（GLUT2、GLUT5）和胰岛素关键蛋白（GLUT4）的作用效果。探索其以GLUTS为靶向治疗糖尿病的机理，设计更高效和安全的壳寡糖胍及其制备方法。

Glucose transporters (GLUTS) are crucial to the mediation of glucose transport process. Abnormal expression of GLUTS might contribute to limitations of nutrition supplying, causing a decline in the function of islet beta cells, and thus give rise to diabetes. By reference to the molecular structure of metformin (an oral hypoglycemic drug), this project is based on designing and preparing chitooligosaccharide guanidines (COSG), which can exhibit both hypoglycemic effects as metformin and molecular recognition abilities to GLUTS as chitooligosaccharides (COS). Moreover, the gastrointestinal irritation caused by biguanides could also be reduced by COS. Firstly, COSG of high yield and high purity are prepared by microwave assisted solid-state synthesis and membrane filtration, where high reactive guanidinylation reagents are used. Secondly, through the experimental treatment on rats of type 2 diabetes mellitus (T2DM), the recovery effect of COS and COSG on islet beta cells is investigated. Further research on the interactions between COSG and GLUTS is made to analyze the influence of COSG on the activities, gene expression and glucose transport capacity of GLUTS in cells of different tissues or organs. Besides, the effects of COSG on the key proteins responsible for sugar absorption (GLUT2, GLUT5) and insulin (GLUT4) are also compared and discussed. Finally, a safer and more targeted and efficient COSG will be designed with the deepening research into the therapeutic mechanism by affecting GLUTS.