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广 东 医 科 大 学 学 报JOURNAL OF GUANGDONG MEDICAL UNIVERSITY第 44 卷第 4 期2026 年 8 月Vol. 44 No. 4Aug. 2026中药活性小分子的结构优化及其在2型糖尿病治疗中的研究进展刘宇兰，袁扬航，吴都督广东医科大学药学院，广东东莞 523808摘 要： 2型糖尿。═2DM）以胰岛素抵抗和胰岛β细胞功能进行性衰退为核心病理特征。临床常用降糖药能有效控制血糖，但长期使用后，面临副作用累积与疗效衰减。中药来源的活性小分子则不同：结构多样、靶点广、毒副作用低，并能通过多条通路协同调控，在T2DM防治中具有独特价值。黄酮类、生物碱类、皂苷类、酚酸类、萜类等天然成分，通过调节胰岛素信号传导、缓解氧化应激与炎症、调控肠道菌群，从不同路径协同改善胰岛素敏感性。然而，多数天然小分子口服吸收率低、靶向递送能力弱。对此，官能团修饰、糖苷化/去糖苷化及分子骨架改造3种结构优化手段已被采用。经过这些改造，化合物的溶解性、膜穿透力、代谢稳定性均得到提升，抗糖尿病效果也随之增强。本文梳理中药活性小分子在T2DM防治中的作用机制、构效关系及结构优化的最新进展，为基于天然产物的抗糖尿病新药研发与临床转化提供参考。关键词： 2型糖尿。 中药活性小分子； 黄酮类化合物； 胰岛素抵抗； 糖苷化； 分子骨架改造DOI：10.20227/j.cnki.2096-3610.2026.04.006 Research progress on bioactive small molecules from traditional Chinese medicine and their structural optimization in the improvement of type 2 diabetes mellitusLIU Yulan,YUAN Yanghang, WU DuduSchool of Pharmacy, Guangdong Medical University, Dongguan, 523808, ChinaAbstract: Type 2 diabetes mellitus (T2DM) is defined by insulin resistance and progressive loss of pancreatic β?cell function. Commonly used glucose?lowering drugs can control blood sugar, but long?term use often leads to cumulative side effects and diminishing efficacy. In contrast, bioactive small molecules from traditional Chinese medicine differ in several ways: they are structurally diverse, act on multiple targets, exhibit relatively low toxicity, and can work through different pathways at the same time. These properties endow them with unique value in T2DM prevention and treatment. Natural compounds such as flavonoids, alkaloids, saponins, phenolic acids and terpenoids improve insulin sensitivity through multiple routes, including modulating insulin signaling, reducing oxidative stress and inflammation, and regulating gut microbiota. However, most of these natural small molecules suffer from low oral absorption and poor targeting. To address this, three structural optimization strategies have been applied: functional group modification, (de)glycosylation, and molecular skeleton remodeling. After such modifications, these compounds exhibit better solubility, membrane permeability, and metabolic stability, and their antidiabetic effects are strengthened. This article summarizes the mechanisms, structure?activity relationships, and recent advances in structural optimization of these TCM-derived bioactive small molecules in T2DM management, providing a reference for developing and translating next-generation antidiabetic drugs based on natural products.Keywords:type 2 diabetes mellitus; bioactive small molecules from traditional Chinese medicine; flavanoid ;insulin resistance; Glycosylation; Molecular Framework Modification2型糖尿。═2DM）以胰岛 β细胞功能障碍和胰岛素抵抗为核心，发病涉及胰岛素信号异常、氧化应激、慢性炎症及肠道菌群失衡等机制 [1-3] 。2021年全球患病人数达5.37亿，预计2045年将增至7.83收稿日期： 2026-02-12基金项目： 广东省自然科学基金（2021B1515140020）作者简介： 刘宇兰，在读研究生，E-mail： yulanliu_hi@163.com通信作者： 吴都督，博士，教授，E-mail： wududuwdd@126.com465