GLP-1通过上调大脑AMPK/PGC1α通路降低2型糖尿病并发帕金森病风险的机制研究

项目名称： GLP-1通过上调大脑AMPK/PGC1α通路降低2型糖尿病并发帕金森病风险的机制研究

项目编号： No.81500636

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 马德琳

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 2型糖尿病（T2D）可显著增加帕金森病（PD）的发病风险。GLP-1类药物作为T2D的治疗药物，在PD中亦有减轻多巴胺神经元损伤的作用，但机制未明。研究发现，多巴胺神经元损伤多由线粒体功能异常引起，且后者是T2D和PD发病的共同改变。AMPK/PGC1α是调控线粒体功能的重要通路，而GLP-1可直接激活AMPK。申请者亦发现，糖耐量受损大鼠纹状体内多巴胺含量下降，AMPK活性下调。据此推测：T2D时GLP-1类药物可通过上调脑内AMPK/PGC1α通路，改善线粒体功能，减轻多巴胺神经元损伤，降低PD风险。本项目拟考察T2D小鼠模型中，GLP-1受体激动剂EX-4对AMPK/PGC1α信号通路、PD早期病理生理改变的影响；并研究在高糖、胰岛素抵抗、以及毒物环境下，EX-4对原代多巴胺神经元的保护作用及机制。本课题旨在阐明GLP-1类药物保护多巴胺神经元的机制，为其应用于T2D合并PD的防治提供理论基础。

中文关键词： 2型糖尿病；帕金森病；胰高血糖素样肽-1；线粒体功能异常

英文摘要： Type 2 diabetes (T2D) increases risk of Parkinson's disease (PD). Meanwhile, glucagon-like peptide-1 (GLP-1) mimetics, a type of anti-diabetic drugs, has been proved to be effective in reducing dopaminergic neuron loss, but the mechanism is unclear. Previous studies implicated that T2D and PD might be linked by mitochondrial dysfunction. AMPK/PGC1α pathway is an important pathway in regulating mitochondrial function, while GLP-1 can activate AMPK directly. And our previous work found that in striatum of glucose intolerant rats, the DA level decreased, and AMPK activation was down regulated. Thus, we hypothesize that in T2D, GLP-1 mimetics can improve mitochondrial function via up-regulating AMPK/PGC1α pathway, and then alleviate dopaminergic neuron damage, and decrease risk of PD. This project will determine the effect of EX-4, a GLP-1 receptor agonist, on AMPK/PGC1α pathways, and on the early pathophysiologic changes of PD in T2D mice. Meanwhile, we will also study the effect of EX-4 on primary dopaminergic neurons under high glucose, insulin resistant, or toxin environment, and the related mechanism. The aim of this project is to explore the mechanism underlying the protective effect of GLP-1 mimetics on dopaminergic neurons, and to provide a solid theoretical foundation for the application of GLP-1 mimetics in preventing T2D patients progressing into PD, or in treating patients with both T2D and PD.

英文关键词： type 2 diabetes;Parkinson's disease;Glucagon-like peptide-1;mitochondrial dysfunction