从Tau蛋白过度磷酸化探讨2型糖尿病所致神经纤维化的机制*

摘要

Objective To observe the effect of high blood sugar on cognitive ability of rats and the degree of phosphorylation of tau protein in the hippocampus, in order to investigate the mechanism of neural fibrosis in type 2 diabetes. Methods Two intervention factors were set in this study. One was type 2 diabetes model-ing method which included 3 levels, i.e. general diet, high-fat high-sugar high-protein diet, and high-fat high-sugar high-protein diet with intraperitoneal injection of small dose of Streptozotocin. The other was drug intervention in 2 levels: no disposal, and 4-week gavage of Rosiglitazone tablets at a dose of 3.0 mg/kg/d. Forty-eight SD rats were divided into 6 groups. Morris water maze was used to test the cognitive ability of the rats. Plasma glucose was determined by glucose oxidase method. The plasma insulin was determined by radioimmunoassay. The degree of insulin resistance was evaluated by HOMA-IR. The concentration of glutamic acid in hippocampus was determined by HPLC. The expressions of p-PHF1Ser396/404, p-AT8Ser199/202, p-12E8Ser262 in the hippocampus were determined by ELISA. Results Insulin resistance and type 2 diabetes could cause cog-nitive impairment. Rosiglitazone alleviated cognitive impairment. Insulin resistance and type 2 diabetes signifi-cantly increased the concentration of glutamic acid in the hippocampus. Rosiglitazone reduced the concentra-tion of glutamic acid. The insulin resistance and type 2 diabetes increased the phosphorylation of tau protein in the hippocampus. Rosiglitazone reduced the expression of phosphorylated tau protein in the hippocampus. Conclusions Insulin resistance and elevated blood sugar may be the causes of phosphorylation of tau protein in the hippocampus of type 2 diabetic rats. Rosiglitazone can mitigate this process.%目的：观察高血糖对大鼠认知能力和Tau蛋白磷酸化程度的影响，从Tau蛋白过度磷酸化探讨2型糖尿病神经纤维化的机制。方法设定两个干预因素，即2型糖尿病造模手段（3水平：普食喂养、高脂高糖高蛋白饮食、高脂高糖高蛋白饮食并腹腔注射小剂量链脲佐菌素）和药物干预（2水平：无处置、罗格列酮片按照3.0 mg/（kg·d）灌胃4周）。48只SD大鼠分为6组。Morris水迷宫检测大鼠认识能力；葡萄糖氧化酶法检测血浆血糖；放射免疫法检测血浆胰岛素；胰岛素抵抗指数HOMA- IR评估胰岛素抵抗程度；高效液相色谱法检测海马谷氨酸浓度；ELISA检测海马p- PHF1Ser396/404、p- AT8Ser199/202、p-12E8Ser262的表达。结果胰岛素抵抗和2型糖尿病造成认知障碍，罗格列酮可缓解认知障碍；胰岛素抵抗和2型糖尿病可明显增加海马中血糖（Glu）浓度，罗格列酮可减少Glu浓度；胰岛素抵抗和2型糖尿病可增加海马中磷酸化Tau蛋白的表达；罗格列酮可减少海马中磷酸化Tau蛋白的表达。结论胰岛素抵抗及血糖升高可能是2型糖尿病时海马Tau蛋白过度磷酸化的原因；罗格列酮可以缓解这一过程。