情志所致糖尿病认知功能障碍的机理及滋补脾阴法防治基础研究

Extreme emotion is a key risk factor for diabetes-associated cognitive decline (DACD), the pathogenesis and prevention strategy of which still remain to be explored. As reported in our previous articles (Diabetologia, 2011; 54(7):1888-1899), nourishing spleen yin can effectively prevent and treat DACD by regulating endoplasmic reticulum (ER) stress, energy metabolism dysfunction and insulin resistance in brain. On the basis of previous works, we will further study the role of ZiBu PiYin recipe in the improvements of insulin resistance and amyloid beta peptide accumulation in brain through regulating ER-mitochondrion contact and insulin signaling transduction networks, which were induced by activated HPA axis and following metabolism dysfunction. The rats injected of low-dose STZ intraperitoneally combined with chronic psychological stress (Si, consideration) were used as reaserch objects in this study. The purpose of this study is to reveal the biological basis of "consideration impairs spleen and spleen doesn't house idea" and enrich Visceral Picture theory of spleen in Chinese traditional medicine, also invest the mechanisms of DACD induced by emotion and prevention mechanism of ZiBu PiYin recipe to develop a new treatment of DACD.

情志过度是糖尿病认知功能障碍发病的重要因素，其发病机制及防治策略尚有待深入探讨。申请者前期研究发现滋补脾阴法能有效防治糖尿病认知功能障碍,且与调节脑组织内质网应激、能量代谢障碍及胰岛素抵抗密切相关（Diabetologia, 2011; 54（7）:1888-1899）。本研究在此基础上，以小剂量STZ联合慢性心理应激建立情志（思）过度所致糖尿病认知功能障碍大鼠为研究对象，以下丘脑-垂体-肾上腺轴激活致能量代谢紊乱诱发脑胰岛素抵抗为切入，探讨滋补脾阴法通过调节线粒体、内质网及其交互作用及与胰岛素信号形成的信号网络，改善脑胰岛素抵抗、减少淀粉样蛋白在脑中沉积，防治糖尿病认知功能障碍的作用及其机制。揭示中医学"思伤脾、脾失藏意"现代生物学基础，为丰富完善中医"脾"藏象系统奠定基础；阐明糖尿病认知功能障碍尤其是因情志因素所致的机理及滋补脾阴法的防治机制，为糖尿病认知功能障碍的防治提供有效策略。

随着糖尿病发病率在全国乃至全球范围内的逐年升高，心理应激与糖尿病发病的相关性越来越引起人们的关注，其发病机制及其防治策略成为亟待解决的重大课题。目前糖尿病认知功能障碍的治疗以控制原发病和改善认知功能障碍为主，但尚无满意疗效。中医药治疗多靶点的优势已引起世界范围的关注。本课题在对情志所致糖尿病认知功能障碍大鼠模型研究中取得的主要进展包括：（1）滋补脾阴方药能够明显改善情志所致糖尿病认知功能障碍大鼠的学习记忆成绩。（2）通过体内和体外实验，证实HPA轴激活诱发脑内质网应激，导致脑胰岛素信号转导障碍，滋补脾阴方药具有调控作用。（3）证实HPA轴激活诱发线粒体功能障碍，导致脑胰岛素信号转导障碍，滋补脾阴方药具有调控作用。（4）应用iTRAQ蛋白质组学技术，成功筛选出脑线粒体相关膜中与情志所致糖尿病认知功能障碍发病以及滋补脾阴方药作用可能相关的差异表达蛋白质，并揭示了差异表达蛋白质的GO分类、KEGG通路和蛋白质相互作用网络。（5）慢性心理应激加重模型大鼠脑胰岛素信号转导障碍，促进Aβ沉积，滋补脾阴方药具有调控作用。阐明糖尿病认知功能障碍尤其是因情志因素所致的机理及滋补脾阴法的防治机制，为糖尿病认知功能障碍的防治提供有效策略。