二甲双胍与艾塞那肽联合治疗与单纯二甲双胍治疗多囊卵巢综合征合并腹型肥胖及基因表达的网络药理学：一项随机临床试验的证据
Combined metformin and exenatide versus only metformin treatments in polycystic ovary syndrome with abdominal obesity and network pharmacology of gene expression: evidence from a randomized clinical trial.
作者信息
Xuesong Ding, Tao Tao, Weilu Wang, Wei Xiong, Wei Xue, Yan Deng, Yanfang Wang, Ruilin Ma, Yingying Guo, Yue Wang, Pérez-López Faustino R, Yang Wang
机构信息
Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
School of Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing, People's Republic of China.
出版信息
Ther Adv Endocrinol Metab. 2025 Aug 19;16:20420188251355411. doi: 10.1177/20420188251355411. eCollection 2025.
OBJECTIVE
To evaluate (1) the metabolic and endocrine effects of metformin combined with exenatide versus only metformin treatments in patients with polycystic ovary syndrome (PCOS) and abdominal obesity (AO) and (2) to determine the molecular mechanisms by which the combined treatment acts on PCOS patients.
DESIGN
Randomized controlled trial of PCOS patients with AO to receive combined treatment with metformin-exenatide or metformin alone, and network pharmacology of gene expression in PCOS patients under the combined exposure.
SETTING
Tertiary teaching hospital.
PATIENTS
Women with PCOS and AO who fulfilled the Rotterdam Criteria under combined treatment with daily cyclical ethinylestradiol (35 μg/day) and cyproterone acetate (2 mg/day).
INTERVENTION
Patients were randomized to either combined oral metformin (1500 mg/day) and exenatide (2 mg weekly subcutaneous injection, = 35 women) treatment or metformin alone ( = 31 women) for 12 weeks. Network pharmacological prediction of gene expression under the combined exposure was studied.
MAIN OUTCOME MEASURES
(1) Basal and after both treatments anthropometric, endocrine, and metabolic changes were compared. (2) Network pharmacological prediction and gene expression were studied in patients under metformin-exenatide treatment. Venn diagram and Markov Cluster Algorithm diagram of core targets for AO were applied to identify key targets.
RESULTS
Both treatments displayed (1) reductions of total testosterone, insulin, and lipoprotein levels and (2) increases of high-density lipoprotein cholesterol and apolipoprotein A1. We identified PCOS, AO, and comorbid genes further intersected with 269 combination therapy genes. Network pharmacology identified 154 key PCOS genes for drug regulation, including 29 closely related to AO and metabolism.
CONCLUSION
Both treatments improved glucose and lipid metabolism, weakening insulin resistance and improving some biochemical indexes. Network pharmacology identified genes related to AO and metabolism in patients with PCOS under the metformin-exenatide treatment.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04029272.
目的
评估（1）二甲双胍联合艾塞那肽与单用二甲双胍治疗多囊卵巢综合征（PCOS）合并腹型肥胖（AO）患者的代谢和内分泌效应，以及（2）确定联合治疗作用于PCOS患者的分子机制。
设计
对PCOS合并AO患者进行随机对照试验，以接受二甲双胍 - 艾塞那肽联合治疗或单用二甲双胍治疗，并对联合暴露下PCOS患者的基因表达进行网络药理学研究。
地点
三级教学医院。
患者
符合鹿特丹标准的PCOS合并AO女性，接受每日周期性乙炔雌二醇（35μg/天）和醋酸环丙孕酮（2mg/天）联合治疗。
干预
患者被随机分为口服二甲双胍（1500mg/天）联合艾塞那肽（每周皮下注射2mg，n = 35名女性）治疗组或单用二甲双胍治疗组（n = 31名女性），为期12周。研究联合暴露下基因表达的网络药理学预测。
主要观察指标
（1）比较两种治疗前后的人体测量学、内分泌和代谢变化。（2）研究二甲双胍 - 艾塞那肽治疗患者的网络药理学预测和基因表达。应用AO核心靶点的维恩图和马尔可夫聚类算法图来识别关键靶点。
结果
两种治疗均显示（1）总睾酮、胰岛素和脂蛋白水平降低，以及（2）高密度脂蛋白胆固醇和载脂蛋白A1增加。我们确定PCOS、AO和共病基因与269个联合治疗基因进一步相交。网络药理学确定了154个关键的PCOS药物调控基因，其中29个与AO和代谢密切相关。
结论
两种治疗均改善了糖脂代谢，减弱了胰岛素抵抗并改善了一些生化指标。网络药理学确定了二甲双胍 - 艾塞那肽治疗下PCOS患者中与AO和代谢相关的基因。
试验注册
ClinicalTrials.gov NCT04029272。
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