ETHNOPHARMACOLOGICAL RELEVANCE: Gegen Qinlian Decoction (GQD,also known as Gegen Qinlian Tang), a classical Traditional Chinese Medicine formula documented in Zhang Zhongjing's "Treatise on Cold Damage" (circa 200 CE), has been used for nearly two millennia to treat conditions characterized by "damp-heat" patterns, which correspond to modern metabolic disorders including type 2 diabetes mellitus (T2DM). Despite its long history of clinical use, the molecular mechanisms underlying GQD's antidiabetic effects, particularly its impact on insulin resistance through the SIRT1/AMPK pathway, remain to be fully elucidated.
AIM OF THE STUDY: The novelty of this study lies in its pioneering approach of combining a large-scale meta-analysis with molecular docking validation for the first time. This research aims to provide high-quality evidence for GQD's clinical efficacy in improving insulin resistance and to uncover its direct interaction mechanism with the SIRT1/AMPK signaling pathway.
MATERIALS AND METHODS: We conducted a systematic search of six databases (PubMed, EMBASE, Cochrane Library, CNKI, WanFang, VIP) from inception to October 2024. Randomized controlled trials (RCTs) evaluating GQD for T2DM with insulin resistance were included following PICO principles. Study quality was assessed using Cochrane ROB 2.0 tool. Meta-analysis was performed using RevMan 5.4 and Stata 16.0, calculating standardized mean differences (SMD) with 95 % confidence intervals (CI). Molecular docking studies were conducted using AutoDock Vina to evaluate binding affinities between major GQD compounds (puerarin, baicalin, berberine) and SIRT1/AMPK proteins.The crystal structures of SIRT1 (PDB ID: 5BTR) and AMPK γ-subunit (PDB ID: 4CFE) were used. Ligands (puerarin, baicalin, berberine) were prepared in the same conformational state via energy minimization. Docking parameters: exhaustiveness of 8, grid centered on active sites.
RESULTS: A total of 42 randomized controlled trials (RCTs) involving 3247 patients were included. GQD significantly improved insulin resistance (HOMA-IR), fasting blood glucose (FBG), and glycated hemoglobin (HbA1c) compared to controls, with effect sizes of SMD = -1.24, -1.15, and -0.67, respectively (all P < 0.001). Subgroup analysis indicated that treatment duration of 8-12 weeks yielded the optimal therapeutic effect.Molecular docking revealed strong binding affinities between GQD's major bioactive compounds-berberine, baicalin, and puerarin-and key proteins in the SIRT1/AMPK signaling pathway (binding energies ranging from -7.5 to -9.1 kcal/mol), supporting a potential mechanistic basis for its antidiabetic effects.The safety profile of GQD was favorable, with no significant difference in adverse event rates compared to control groups (RR = 1.15, P = 0.34). Most adverse events were mild gastrointestinal symptoms (e.g., nausea, diarrhea), and no serious adverse events were reported. GQD was well-tolerated, even in elderly patients and those with comorbidities.
CONCLUSIONS: By integrating clinical and molecular evidence, this study bridges the gap between traditional empirical knowledge and modern pharmacological understanding. The findings not only provide a higher level of evidence-based support for GQD in treating T2DM but also, through its innovative dual-validation methodology, support a mechanism involving the direct activation of the SIRT1/AMPK signaling pathway. This provides a robust scientific rationale for the contemporary application of this classical formula.Future research should include: biochemical detection in cell models using Western blot or ELISA to quantitatively detect levels of phosphorylated AMPK and deacetylated PGC-1α after GQD treatment; targeted metabolomics to track changes in NAD/NADH ratio and AMP/ATP ratio after treatment; testing GQD in SIRT1 or AMPK gene knockout high-fat diet-induced diabetic mice to confirm pathway dependency; evaluation of potential additive or synergistic effects when GQD is combined with metformin or GLP-1 receptor agonists; and adoption of validated HPLC fingerprint methods to quantify batch-to-batch consistency of bioactive compounds in GQD. +
