摘要
目的:2型糖尿病(type 2 diabetes,T2D)时大脑出现胰岛素水平下降及胰岛素信号通路下调,使大脑海马tau蛋白出现过度磷酸化的阿尔茨海默病(Alzheimer disease,AD)样改变。本研究选取2型糖尿病大鼠,皮下注射及鼻腔滴入胰岛素,观察大脑AD样病变的改变,并探讨其机制。方法:高糖、高脂、高蛋白喂饲3个月后链脲佐菌素腹腔注射制备T2D大鼠模型。运用2种方法干预:鼻腔滴入胰岛素(T2D+I-I)及皮下注射胰岛素(T2D+S-I)。检测血浆葡萄糖、血浆胰岛素和脑脊液胰岛素水平,免疫印记方法检测大脑海马总tau蛋白和tau蛋白部分位点磷酸化状态、胰岛素信号转导途径中关键酶磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3K)/Akt及糖原合成激酶3β(glycogen synthase kinase 3β,GSK-3β)活性。结果:T2D组大鼠血浆葡萄糖及胰岛素水平显著升高,脑脊液胰岛素水平显著降低,大脑海马组织中tau蛋白呈过度磷酸化状态,PI3K/Akt活性下降,GSK-3β磷酸化水平升高;T2D+I-I组大鼠血浆胰岛素及葡萄糖水平无显著改变,但大脑海马tau蛋白过度磷酸化状态显著好转,PI3K/Akt活性显著升高,GSK-3β活性显著下降;T2D+S-I组大鼠血糖显著下降,但血浆及脑脊液胰岛素水平无显著改变,大脑海马tau蛋白磷酸化水平有轻度改善,但变化不显著。结论:运用鼻腔滴入胰岛素可减轻T2D时大脑海马组织的AD样病变;外周皮下胰岛素注射对T2D时AD样病变无明显作用。
AilM: To investigate Alzheimer disease (AD) -like changes and 2 key components of the insulin signaling pathway in the brain of a rat model of type 2 diabetes (T2D) after insulin treatment. METHODS: The rat model of T2D was established by feeding a high-protein, high-glucose and high-fat diet followed by intrasubcutaneous injection of streptozocin. Intranasal insulin treatment (T2D + I-I) and subcutaneous insulin injection (T2D + S-I) were applied to ele- vate the insulin level in the brain. The insulin levels in plasma and cerebrospinal fluid as well as the concentration of plas- ma glucose were measured. Total tan level, the phosphorylation level of tau at some phosphorylation sites, and the activa- tion of GSK-3β and Akt in subcutaneous of the rats were also analyzed by Western blotting. RESULTS: AD-like changes, decreased Akt activation and over-activation of GSK-3β in the hippocampus of the T2D rats were observed. Intranasal insu- lin treatment for 4 weeks normalized the levels of Akt and GSK-3β, as well as reduced the AD-like changes in the bippo- campus of the T2D rats, whereas the treatment with insulin by subcutaneous injection for 4 weeks had minimal effects on the levels of GSK-3β and tau phosphorylation in the hippocampus. CONCLUSION: Intranasal insulin treatment, but not subcutaneous insulin treatment, might decrease the risk of AD in T2D rats by reducing AD-like changes and up-regulating the impaired insulin signaling pathway in the hippocampus, indicating the potential use of intranasal insulin delivery for treatment of AD.
出处
《中国病理生理杂志》
CAS
CSCD
北大核心
2013年第1期56-61,共6页
Chinese Journal of Pathophysiology
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)