Hu S-H, Jiang T, Yang S-S, Yang Y
Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
Exp Clin Endocrinol Diabetes. 2013 Apr;121(4):220-4. doi: 10.1055/s-0032-1333277. Epub 2013 Mar 19.
To investigate intracerebral insulin resistance and its relationship with tau-protein hyperphosphorylation.
A rat model of type 2 diabetes (T2D) was established with streptozotocin (STZ). Diabetic rats received intragastric administration of pioglitazone (PIO group) or normal saline (T2D group) for 4 weeks. As a control, non-diabetic rats received intragastric normal saline (CTL group). The insulin concentrations in cerebrospinal fluid (CSF) and blood were determined with radioimmunoassay, and blood glucose concentration was determined using a glucose oxidation technique. Total and phosphorylated levels of protein kinase B (AKT), glycogen synthase kinase-3β (GSK-3β) and tau-protein in the hippocampus were analyzed using western blotting.
The plasma insulin level in the T2D group was higher, and the CSF insulin level in the T2D group lower than in the CTL group. Hippocampal phosphorylated AKT and phosphorylated GSK-3β levels were significantly lower in the T2D group than in the CTL group. Hippocampal tau-protein in the T2D group was hyperphosphorylated at Ser199 and Ser396. Plasma insulin levels in the PIO group were lower than in the T2D group, with no differences in CSF insulin levels. Phosphorylated AKT and phosphorylated GSK-3β levels in the PIO group were significantly higher than in the T2D group Hippocampal phosphorylated tau-protein (Ser199/Ser396) was lower in the PIO group than in the T2D group.
Hyperphosphorylation of tau-protein in pioglitazone-treated rats with T2D was improved. Rats with T2D have both cerebral insulin resistance and cerebral hypoinsulinism. Pioglitazone can ameliorate intracerebral insulin resistance and decrease tau-protein hyperphosphorylation, but cannot increase intracerebral insulin levels.
研究脑内胰岛素抵抗及其与tau蛋白过度磷酸化的关系。
用链脲佐菌素（STZ）建立2型糖尿病（T2D）大鼠模型。糖尿病大鼠接受吡格列酮灌胃（PIO组）或生理盐水灌胃（T2D组）4周。作为对照，非糖尿病大鼠接受生理盐水灌胃（CTL组）。采用放射免疫分析法测定脑脊液（CSF）和血液中的胰岛素浓度，用葡萄糖氧化技术测定血糖浓度。用蛋白质免疫印迹法分析海马中蛋白激酶B（AKT）、糖原合成酶激酶-3β（GSK-3β）和tau蛋白的总水平及磷酸化水平。
T2D组血浆胰岛素水平较高，而CSF胰岛素水平低于CTL组。T2D组海马中磷酸化AKT和磷酸化GSK-3β水平显著低于CTL组。T2D组海马tau蛋白在Ser199和Ser396位点过度磷酸化。PIO组血浆胰岛素水平低于T2D组，CSF胰岛素水平无差异。PIO组磷酸化AKT和磷酸化GSK-3β水平显著高于T2D组。PIO组海马磷酸化tau蛋白（Ser199/Ser396）低于T2D组。
吡格列酮治疗的T2D大鼠中tau蛋白的过度磷酸化得到改善。T2D大鼠存在脑内胰岛素抵抗和脑内胰岛素不足。吡格列酮可改善脑内胰岛素抵抗并降低tau蛋白过度磷酸化，但不能提高脑内胰岛素水平。
