Abstract: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.
