目的 探讨利拉鲁肽对2型糖尿病小鼠认知功能的影响及作用机制。方法 雄性db/db小鼠16只按照随机数字表法分为模型组、利拉鲁肽组，每组8只，另取8只C57BLKSJ小鼠为对照组。检测血糖和体质量，Morris水迷宫检测小鼠空间记忆能力，行胰岛素耐受试验（ITT）评价小鼠胰岛素抵抗情况，利用全自动生化分析仪检测空腹血糖及三酰甘油（TG），并计算TG-葡萄糖指数（TyG），并，苏木精伊红-染色观察胰腺形态，电镜观察海马神经元形态，酶联免疫吸附试验（ELISA）检测脑组织炎症因子水平，Western blotting检测脑组织磷酸化磷脂酰肌醇3激酶（p-PI3K）/PI3K、磷酸化蛋白激酶B（p-Akt）/ Akt蛋白表达水平。结果 与模型组相比，利拉鲁肽组血糖、体质量、平均逃避潜伏期、ITT的曲线下面积、空腹血糖、TG、TyG、IL-1β、IL-6、TNF-α水平降低，穿越平台区次数、IL-10水平及脑组织p-PI3K/PI3K、p-Akt/Akt蛋白相对表达水平升高（P＜0.05、0.01）。结论 利拉鲁肽改善db/db小鼠认知功能的机制可能与激活脑组织PI3K/Akt信号通路，改善中枢胰岛素抵抗，抑制中枢炎症反应有关，而外周代谢水平的改善协同改善认知功能障碍。

Objective To investigate the effect of liraglutide on cognitive function in type 2 diabetic mice and its underlying mechanism. Methods Sixteen male db/db mice were randomly divided into model group and liraglutide group with 8 mice in each group using a random number table, and another eight C57BLKSJ mice were used as the control group. Blood glucose and body weight were measured. Spatial memory was assessed by the Morris water maze test, and insulin resistance was evaluated by the insulin tolerance test (ITT). Fasting blood glucose and triglyceride (TG) levels were determined using an automatic biochemical analyzer, and the triglyceride-glucose index (TyG) was calculated. Pancreatic morphology was observed by hematoxylin-eosin (HE) staining, and hippocampal neuronal morphology was examined under electron microscopy. The levels of inflammatory factors in brain tissue were detected by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of phosphorylated phosphatidylinositol 3-kinase (p-PI3K)/PI3K and phosphorylated protein kinase B (p-Akt)/Akt in brain tissue were measured by Western blotting. Results Compared with the model group, the levels of blood glucose, body weight, mean escape latency, area under the curve of ITT, fasting blood glucose, TG, TyG, IL-1β, IL-6, and TNF-α in the liraglutide group were significantly decreased (P < 0.05, 0.01), while the number of platform zone crossings, IL-10 level, and relative protein expression levels of p-PI3K/PI3K and p-Akt/Akt in brain tissue were significantly increased (P < 0.05, 0.01). Conclusion Liraglutide may improve cognitive function in db/db mice by activating the brain PI3K/Akt signaling pathway, improving central insulin resistance and inhibiting neuroinflammation. The improvement in peripheral metabolism may synergistically alleviate cognitive dysfunction.

R965

首都医科大学附属北京世纪坛医院中心实验室开放课题（2020-KF26）