目的 研究左归降糖解郁方对糖尿病并发抑郁症大鼠海马胰岛素抵抗的调节作用。方法 建立糖尿病并发抑郁症大鼠模型，并随机分为4组，模型组，阳性药组（二甲双胍0.18 g/kg+氟西汀1.8 mg/kg），左归降糖解郁方高、低剂量组（20.52、10.26 g/kg），另设健康大鼠为对照组。各组大鼠ig给药28 d后，采用血糖仪及ELISA法检测空腹血糖及外周胰岛素抵抗程度。采用旷野实验和强迫游泳实验检测大鼠抑郁样行为。采用免疫荧光法和Western blotting法检测大鼠海马胰岛素受体磷酸化蛋白（p-IR）、磷酸化的胰岛素受体底物-1（p-IRS-1）的表达，采用Western blotting法检测海马磷酸化的磷脂酰肌醇3-激酶（p-PI3K）、磷酸化蛋白激酶B（p-Akt）蛋白的表达。结果 与对照组比较，模型组大鼠血糖显著升高并伴随明显的外周胰岛素抵抗，其在旷野实验中的活动次数显著降低、在强迫游泳实验中的不动时间显著延长；蛋白检测结果表明大鼠脑内p-IR、p-IRS-1、p-PI3K、p-Akt表达水平均显著降低。与模型组比较，左归降糖解郁方高剂量组大鼠血糖水平显著降低，外周胰岛素抵抗水平减轻，其在旷野实验中的活动次数显著增加、在强迫游泳实验中的不动时间显著缩短，而海马内p-IR、p-IRS-1、p-PI3K、p-Akt表达显著升高。结论 左归降糖解郁方可有效调节糖尿病并发抑郁症大鼠海马胰岛素信号通路，从而改善动物脑内的胰岛素抵抗状态。

Objective To investigate the function of Zuogui Jiangtang Jieyu Formulation on hippocampal insulin resistance in rats with diabetes-related depression. Methods The rat model of diabetes-related depression was established and randomly divided into four groups, including model group, positive drug group (metformin 0.18 g/kg + fluoxetine 1.8 mg/kg), high (20.53 g/kg) and low (10.26 g/kg) doses of Zuogui Jiangtang Jieyu Formulation groups. After 28 d of gavage, fasting blood glucose and peripheral insulin resistance were measured by blood glucose meter and ELISA. The depression-like behaviors of rats were tested by open field experiment and forced swimming test. The expression of p-IR and p-IRS-1 in hippocampus of rats were detected by immunofluorescence and Western blotting, while the levels of p-PI3K and p-Akt were detected by Western blotting. Results Compared with the normal group, the blood glucose of rats in model group were significantly increased, which accompanied by obvious peripheral insulin resistance. The number of activities in open field experiment was significantly reduced in model group, and the immobility time in forced swimming experiment was significantly prolonged. In addition, it was showed that the levels of p-IR, p-IRS-1, p-PI3K and p-Akt in the brain of model rats were all significantly decreased. Compared with the model group, the blood glucose and insulin levels were significantly decreased in high-dose of Zuogui Jiangtang Jieyu Formulation group. Furthermore, the depression-like behaviors manifested in open field experiment and forced swimming experiment were improves by high dose of Zuogui Jiangtang Jieyu Formulation. More importantly, the expression of p-IR, p-IRS-1, p-PI3K and p-Akt in hippocampus was significantly increased in high dose of Zuogui Jiangtang Jieyu Formulation group compared with model group. Conclusion Zuogui Jiangtang Jieyu Formulation can effectively regulate the insulin signaling pathway in hippocampus of rats with diabetes-related depression, and then improve the insulin resistance in the brain of model rats.

R285.5

国家自然科学基金资助项目（81603604）；湖南省自然科学基金项目（2019JJ50464）；湖南中医药大学中医学国内一流建设学科开放基金（2018ZYX46）；湖南中医药大学中医学国内一流建设学科项目（2018）