Pharmacological Advances in Multi-Targeted Strategies for Type 2 Diabetes Mellitus: A Systematic Perspective Based on Traditional Chinese Medicine

Yanli Zhao¹Jiabao Liao¹Panpan Pang²JingYuan Li¹Suocai Su¹Mengqiu Shao¹Weibo Wen¹Furong Xu^3*

• ¹Yunnan University of Chinese Medicine, Kunming, China
• ²Kunming Medical University, Kunming, China
• ³Yunnan University of Traditional Chinese Medicine, Kunming, China

Type 2 Diabetes Mellitus (T2DM) is a complex systemic metabolic disease driven by insulin resistance, β-cell dysfunction, chronic low-grade inflammation, oxidative stress, and neuro-immune dysregulation. It frequently progresses to multi-organ complications affecting the kidneys, retina, heart, and central nervous system. This review synthesizes mechanistic and translational evidence on Traditional Chinese Medicine (TCM)-related botanical drugs and botanical preparations (formula-based interventions), along with representative plant metabolites that are frequently investigated in the TCM research context (e.g., berberine, baicalin, and tanshinone IIA, which are not unique to TCM). For formula-based preparations, we extracted and reported the intervention identity (dosage form, complete composition, and processing/standardization as described in the primary studies); any missing identity items were recorded as not reported (NR) and not inferred. We organized findings across shared T2DM-relevant pathogenic modules, including PI3K/Akt and AMPK signaling, inflammatory outputs (NF-κB/NLRP3), redox regulation (NRF2/ROS), angiogenic signaling (VEGF), and gut– liver–brain–immune network interactions, emphasizing studies in which pathway modulation is accompanied by metabolic or complication-relevant endpoints. To strengthen interpretability and reproducibility, we performed a structured literature search (2000–2025) and applied evidence grading (human/RCT vs. animal vs. in vitro/in silico), with the study selection summarized in a PRISMA-style flow diagram (Figure S1). Reporting quality and extract characterization were critically appraised using the GA-online Best Practice in Research – ConPhyMP tool (Tables 1 and 2A), provided as Supplementary File S3, and key pharmacological/clinical details were captured in Supplementary Tables S1–S2. All source organisms were taxonomically validated using authoritative resources (e.g., Kew MPNS and/or Plants of the World Online), and full scientific names,, including author citation and family, are provided in the tables and supplementary materials. We further caution that compound–target links, especially from in silico predictions or single-assay readouts, may be vulnerable to assay interference liabilities (including PAINS) and therefore should be supported by orthogonal validation and outcome-linked readouts before strong mechanistic claims are made. Finally, we outline translational priorities, including rigorous standardization and quality control (distinguishing analytical marker metabolites from bioactive metabolites), improved study design and controls, and well-designed randomized, pragmatic, and real-world evaluations with clinically meaningful endpoints (e.g., HbA1c, complication progression, and safety).