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GLP-1降低2型糖尿病大鼠海马AD样改变

发表时间:2012-06-15  浏览量:1152  下载量:572
全部作者: 杨雁,姜腾,胡蜀红,袁刚
作者单位: 华中科技大学同济医学院附属同济医院内分泌科
摘 要: 目的:运用胰高血糖样肽1(glucagon- like peptide- 1,GLP- 1)对2型糖尿病(type 2 diabetes,T2D)大鼠进行干预,检测大脑阿尔茨海默病(Alzheimer's disease, AD)样改变及胰岛素信号途径在用药前后的变化,探讨GLP- 1降低T2D大鼠AD发生风险的可能机制。方法:造T2D大鼠模型后,GLP- 1皮下注射4周(T2D+GLP- 1)。检测血浆葡萄糖、胰岛素水平,大鼠海马tau蛋白、tau蛋白上部分磷酸化位点水平、胰岛素信号途径中磷脂酰肌醇3- 激酶/蛋白激酶B(phosphatidylinositol 3 kinase/protein kinase B,PI3K/AKT)及下游糖原合成激酶3β(glycogen synthase kinase- 3β,GSK- 3β)水平。结果:T2D组血糖及胰岛素水平显著高于对照组(CTL), 运用GLP- 1后,血糖、胰岛素水平及胰岛素抵抗程度逐渐下降,到运用GLP- 1干预第4周,血糖、胰岛素水平及胰岛素抵抗程度与T2D比较已显著下降。T2D大鼠海马tau蛋白上位点Ser199/202,Thr217磷酸化程度显著高于CTL组,但经GLP- 1干预后,上述位点磷酸化程度显著下降, PI3K/AKT活性受抑状态显著改善,GSK- 3β活性显著受抑。结论:T2D大鼠大脑tau蛋白呈AD样改变,运用GLP- 1干预后AD样改变可显著减轻。GLP- 1可能通过2个途径改善T2D大鼠大脑AD样改变:1) 使大脑胰岛素信号传导途径中PI3K/AKT/GSK- 3β活性得到恢复来减轻tau蛋白过度磷酸化状态;2) 通过减轻外周胰岛素抵抗来改善大脑AD样改变。
关 键 词: 内科学;胰高血糖素样肽1;2型糖尿病;阿尔茨海默病;胰岛素信号途径;糖原合成激酶- 3β
Title: Glucagon-like peptide-1 prevents Alzheimer's disease-like changes in hippocampus of a rat model with type 2 diabetes
Author: YANG Yan, JIANG Teng, HU Shuhong, YUAN Gang
Organization: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Abstract: Objective: This study intervened glucagon- like peptide- 1(GLP- 1) on type 2 diabetes (T2D) rats, detected the insulin signaling pathway in the brain before and after treatment, and tested whether GLP- 1 could relate to decrease the risk of Alzheimer's disease (AD) in T2D. Methods: The models of T2D rats were fed with high glucose, high fat and high protein for 8 weeks, and then injected by STZ (T2D). Liraglutide- GLP- 1 analogues were subcutaneous injection for 4 weeks in T2D rats (T2D+GLP- 1). The level of plasma insulin, plasma glucose, total tau protein, the phosphorylation of tau at individual phosphorylation sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase- 3β (GSK- 3β) were detected. Results: Plasma glucose, insulin and insulin resistance levels in T2D group were obviously higher than those in CTL group. Moreover, those indexes were gradually decreased after GLP- 1 subcutaneous injection, and the decrease became significant in week 4 between T2D and T2D+GLP- 1. The level of phosphorylated tau protein at site Ser199/202 and Thr217 in hippocampus of T2D rats were found to be raised notably compared with CTL group, and evidently decreased after GLP- 1 intervention. There were decreased activities of PI3K/AKT and increased activities of GSK- 3β in hippocampus of T2D rats which indicated an impaired insulin signaling pathway, while there were a rise of PI3K/AKT activity and a decline of GSK- 3β activity after 4 weeks intervention of GLP- 1. Conclusion: Tau protein was hyperphosphorylated in hippocampus of T2D rats, and these AD- like changes could be reversed after GLP- 1 intervention for 4 weeks. GLP- 1 might reduce AD- like changes in brain of T2D rats by two ways: 1) GLP- 1 could activate brain insulin signaling pathway in T2D, therefore, it might improve the AD- like changes by down- regulating the activities of GSK- 3β, which acts as a phosphorylated kinase of tau protein. 2) GLP- 1 could improve AD- like changes in T2D brain by reducing peripheral insulin resistance.
Key words: internal medicine; glucagon- like peptide- 1; type 2 diabetes; Alzheimer's disease; insulin signaling pathway; glycogen synthase kinase- 3β
发表期数: 2012年6月第11期
引用格式: 杨雁,姜腾,胡蜀红,等. GLP-1降低2型糖尿病大鼠海马AD样改变[J]. 中国科技论文在线精品论文,2012,5(11):1058-1064.
 
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