基于Meta和网络药理学分析参苓白术散治疗糖尿病肥胖的作用机制

Mechanism of Shenling Baizhu Powder in Treating Obesity Associated with Diabetes Based on Meta-analysis and Network Pharmacology

目的:采用文献荟萃分析法(Meta)评估参苓白术散对糖尿病型肥胖的治疗作用,再结合网络药理学和动物实验方法分析参苓白术散治疗糖尿病肥胖的作用机制。方法:纳入国内外相关文献,以身体质量指数(BMI)、糖化血红蛋白(HbA1c)、餐后2 h血糖(2 h PG)、空腹血糖(FBG)、胰岛素抵抗指数(Homa-IR)、腰臀比作为结局指标,评估参苓白术散对糖尿病型肥胖的治疗作用。从GEO数据库中下载糖尿病肥胖的相关基因,在中药系统药理学数据库与分析平台(TCMSP)、中医药综合数据库(TCMID)和中药分子机制生物信息学分析工具(BATMAN-TCM)中下载参苓白术散的作用靶点,对两者的交集靶点进行蛋白质-蛋白质相互作用分析,再根据拓扑分析筛选出核心靶点蛋白质;制备糖尿病肥胖小鼠的模型,分组后进行参苓白术散的灌胃治疗,2周后测量各组小鼠体质量、血糖、Lee's指数,采用苏木精-伊红(HE)染色法分析各组小鼠的脂肪细胞体积变化,测量小鼠血清中的胆固醇、三酰甘油及核心靶点蛋白质的浓度。结果:共纳入9篇文献,数据完整,未发现发表偏倚,评估为low risk。患者服用参苓白术散后,BMI、HbA1c、2 h PG、Homa-IR和腰臀比均得到明显改善;参苓白术散-糖尿病肥胖的交集靶点共59个,核心靶点为载脂蛋白E(APO-E)、胰岛素生长因子-1(IGF-1)、纤溶酶原激活物抑制物-1(PAI-1),参苓白术散主要通过影响细胞对油酸的反应(GO:0071400)、转化生长因子β1生产的正调控(GO:0032914)和纤溶酶原激活的负调控(GO:0010757)等生物学功能,影响不饱和脂肪酸的生物合成(hsa01040)、脂肪酸代谢(hsa01212)等信号通路来治疗糖尿病肥胖;动物实验结果表明,经过参苓白术散灌胃治疗后的小鼠血糖变化不显著,体质量和Lee's指数呈现明显下降趋势,脂肪细胞直径明显缩小,胆固醇、三酰甘油浓度及APO-E、IGF-1、PAI-1水平均呈现下调趋势。结论:结合Meta分析和动物实验的结果,参苓白术散对糖尿病肥胖具有明显的治疗作用,其作用机制可能与影响不饱和脂肪酸、脂肪酸的合成,减少糖和脂肪的转化,纠正机体能量代谢失衡,调控自噬促进脂肪组织的分解有关。

Objective:To evaluate the therapeutic effect of Shenling Baizhu Powder on the obesity associated with diabetes by Meta-analysis and decipher the treatment mechanism by combining network pharmacology and animal experiments.Methods:The relevant publications were included in this study.The body mass index(BMI),glycosylated hemoglobin(HbA1c),2 h postprandial blood glucose(2 h PG),fasting blood glucose(FBG),Homeostatic Model Assessment for Insulin Resistance(Home-IR),and waist-to-hip ratio were used as outcome indicators to evaluate the therapeutic effect of Shenling Baizhu Powder on the obesity associated with diabetes.The genes related to this disease were downloaded from the Gene Expression Omnibus(GEO)database,and the targets of Shenling Baizhu Powder were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),Traditional Chinese Medicine Integrated Database(TCMID),and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM).The protein-protein interactions of the common targets shared by the disease and the drug were analyzed,and then the core target proteins were screened out by the topological analysis.A mouse model of obesity associated with diabetes was established.After grouping,the mice were treated with Shenling Baizhu Powder by gavage.After two weeks,the body weight,blood glucose level,and Lee's index were recorded.The volume changes of adipocytes in each group of mice were observed by hematoxylin-eosin staining,and the levels of cholesterol,triglycerides,and core target proteins in the mouse serum were measured.Result:A total of 9 articles were included,with complete data and no publication bias.The evaluation indicated a low risk.After treatment with Shenling Baizhu Powder,the BMI,HbA1c,2 h PG,Home-IR,and waist-to-hip ratio of the patients were recovered to some extent.There were 59 common targets shared by Shenling Baizhu Powder and obesity associated with diabetes,and the core targets were apolipoprotein E(APO-E),insulin growth factor-1(IGF-1),and plasminogen activator inhibitor-1(PAI-1).Shenling Baizhu Powder mainly regulated the biological processes such as cellular response to oleic acid(GO:0071400),positive regulation of transforming growth factor beta 1 production(GO:0032914),and negative regulation of plasminogen activation(GO:0010757).It modulated the signaling pathways such as unsaturated fatty acid biosynthesis(hsa01040)and fatty acid metabolism(hsa01212)to treat obesity associated with diabetes.The results of animal experiments showed that the treatment with Shenling Baizhu Powder by gavage did not cause significant change in blood glucose level,decreased the body weight and Lee's index,reduced the diameter of adipocytes,and lowered the levels of cholesterol,triglycerides,APO-E,IGF-1,and PAI-1.Conclusion:The results of Meta-analysis and animal experiments suggest that Shenling Baizhu Powder has obvious therapeutic effect on the obesity associated with diabetes.Shenling Baizhu Powder may exert the therapeutic effect by regulating the synthesis of unsaturated fatty acids and fatty acids,reducing the transformation of sugar and fat,correcting the imbalance of energy metabolism,and modulating autophagy to promote the decomposition of the adipose tissue.