大脑胰岛素信号途径受损导致2型糖尿病时阿尔茨海默病发病风险增高  

Impaired Brain Insulin Signal Transduction Caused High Risk of Alzheimer's Disease in Type 2 Diabetes

作　　者：杨雁[1] 王玉萍[1] 谢君辉[1] 姜腾[1] 胡蜀红[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院,内分泌科,武汉430030

出　　处：《中国生物化学与分子生物学报》2012年第5期449-454,共6页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金青年基金资助项目(No.81100582);教育部博士点新教师基金资助项目(No.200804871047);湖北省卫生厅一般项目(No.JX5B04)~~

摘　　要：大脑胰岛素不仅可调节血糖,而且可改善记忆和认知,而大脑胰岛素缺乏常导致Alzheimer病(Alzheimer’s disease,AD)的发生.本研究检测了正常及2型糖尿病(type 2 diabetes,T2D)大鼠外周及大脑胰岛素信号传导途径,以探讨T2D时由于大脑胰岛素异常导致AD发病的可能性.以同龄正常SD大鼠为对照(CTL组),高糖、高脂、高蛋白饮食加链脲佐菌素(streptozotocin,STZ)腹腔注射建造T2D大鼠模型(T2D组).葡萄糖氧化酶法检测血浆血糖,放免法检测脑脊液及血浆胰岛素,免疫印迹技术检测大脑海马tau蛋白上部分位点磷酸化水平,大脑及肝脏、肌肉组织胰岛素信号传导途径中磷脂酰肌醇3激酶(phosphatidylinositol 3 kinase,PI3K)/蛋白激酶B(protein kinaseB,Akt)、糖原合成激酶3β(glycogen synthase kinase-3β,GSK-3β)活性.结果显示:和对照组相比,T2D大鼠血浆葡萄糖水平及胰岛素水平显著升高,脑脊液胰岛素水平显著降低,大脑海马组织tau蛋白上所检测位点均呈过度磷酸化改变,海马及外周组织(肝脏、肌肉)胰岛素信号传导途径PI3K/Akt活性均显著下降,GSK-3β活性升高.研究结果表明:2型糖尿病大鼠大脑胰岛素缺乏及其信号传导途径下调可能是导致阿尔茨海默病发病的重要原因.Brain insulin could regulate brain glucose metabolism,and accelerate the memory and cognition,while the lack of brain insulin is one of the mechanisms of Alzheimer＇s disease（AD）,the most common form of dementia.Type 2 diabetes（T2D） has the potential to increase the risk of AD,but the underlying mechanism is obscured.This study was to determine the possibility that the impaired brain insulin signal transduction was the key factor which induced AD in T2D.We studied the insulin levels and insulin signal transduction in both normal（CTL group） and diabetic（high protein,high glucose,high fat diet and streptozocin induced,T2D group） rats.Plasma insulin level was measured by RIA method,and the plasma glucose by glucose-oxidase method.The activities of PI3K/Akt and glycogen synthase kinase-3β（GSK-3β） in insulin signal transduction in brain,liver and skeletal muscle were analyzed by Western blotting.Our data showed that diabetic rats had significant higher insulin in plasma but its level is significant lower insulin in brain than that in the normal rats.The levels of phosphorylated tau protein at site Ser199,Ser202 and Ser396 in hippocampus of T2D rats were found to be raised notably compared with CTL group.The phosphorylation of Akt and GSK-3β in brain,liver and skeletal muscle were all significantly down-regulated versus CTL group.Our present data indicated that the brain insulin defiency and down-regulation of insulin signal transduction might be a key factor which triggers AD.

关 键 词：2型糖尿病 阿尔茨海默病 胰岛素信号传导途径 TAU蛋白 

分 类 号：R587.1[医药卫生—内分泌]