核糖代谢异常在糖尿病脑病中的作用及机制研究

Diabetic encephalopathy is one of the complications caused by diabetes and characterized by cognitive impairment. Previously, we have found that not only glucose, but also the level of ribose in the blood and urine of type 2 diabetic patients increased; uric ribose level increased in animal model of diabetic encephalopathy, and ribose is much more active in glycation of protein than glucose, resulting in cytotoxic AGEs, suggesting that ribose may play an important role in the pathogenesis and development of diabetes. Ribose can also induce cognitive impairment in mice along with insulin elevation in mouse brain. Based on these results, this project will go further to explore the relationship of ribose metabolic disorder and diabetic encephalopathy. By molecular, cell and animal experiments, we will investigate the pathogenesis of ribose increasing in diabetes, including changes in related enzymes and the mechanism of ribose induced cognitive impairment. The application of this project will give light on the relationship between the cognitive impairment and diabetes, and provide a new clue for the mechanism and cure of diabetes and its complications.

糖尿病脑病是由糖尿病引起的脑部并发症之一。申请者的前期工作表明，2型糖尿病患者不仅血、尿葡萄糖浓度异常升高，而且核糖浓度也异常升高；在糖尿病脑病大鼠模型中尿核糖也明显升高，而且核糖糖基化蛋白质的效率远高于葡萄糖，并快速形成具有细胞毒性的糖基化终末产物，提示核糖可能在糖尿病的发生发展中起重要作用。核糖浓度升高引起小鼠认知障碍，同时伴随脑内胰岛素升高等现象。因此，本项目拟探索核糖代谢失调与糖尿病脑病之间的关系。通过分子、细胞、动物实验，研究糖尿病发生核糖代谢异常的原因，包括相关代谢酶的变化，阐明核糖代谢异常造成鼠认知损伤的机制。本项目的实施，将从一个崭新角度认识糖尿病引发的认知损伤，同时可能为糖尿病的发病机制及其并发症提供新的防治策略。

糖代谢异常是糖尿病及糖尿病并发症如脑病发生发展的重要原因。糖尿病患者体内不仅存在葡萄糖代谢异常，也出现核糖代谢异常的现象。由于核糖的强还原性，它能够与蛋白质快速发生非酶促糖基化修饰，形成具有明显细胞毒性的聚集物；核糖能够诱导神经细胞凋亡和动物的认知功能损伤。这就提示核糖可能在糖尿病及糖尿病脑病中起一定的作用。针对核糖代谢，本项目通过分子、细胞、动物实验，研究了核糖代谢失调与糖尿病脑病之间的关系，深入探索糖尿病发生核糖代谢异常的原因，包括相关代谢酶的变化，阐明核糖代谢异常造成鼠认知损伤的机制。结果表明，在糖尿病及糖尿病脑病的动物体内，核糖水平显著升高，出现代谢失调；深入研究发现转酮酶（TKT）主要调节糖尿病大鼠体内的核糖代谢，TKT的激动剂苯磷硫胺能够缓解糖尿病脑病的核糖代谢异常，并挽回动物的认知损伤；在临床调研和数据分析中，核糖在2型糖尿病患者体内糖化血清蛋白的形成中起重要作用。本项目的实施，对于糖尿病脑病的理解具有重要的理论意义，同时对于糖尿病及糖尿病脑病的诊治都具有潜在应用价值。