Integration of In Vitro Glucose Utilization, Metabolomics and Network Pharmacology Strategy to Explore Antidiabetic Mechanisms of Gunnera perpensa and Erythrina zeyheri Extracts

Background: Type 2 diabetes mellitus (T2DM) is a complex metabolic disease requiring multi-targeted therapeutic strategies. Gunnera perpensa and Erythrina zeyheri are traditionally used in diabetes management, but their mechanisms remain poorly understood. Methods: This study used in vitro, metabolomics, and network pharmacology approaches to elucidate their antidiabetic potential. Leaf extracts were screened for glucose utilization in C2C12 cells, and cytotoxicity in Vero cells. Metabolites profiled via GC×GC-TOF-MS and those retrieved from Phytochemical Interaction Database were evaluated for drug-likeness and target prediction using SwissADME and SwissTargetPrediction. Diabetes-related targets were obtained from databases, and overlapping targets were used to construct interaction networks using Cytoscape and STRING. Functional enrichment analyses were conducted via DAVID for GO and KEGG pathways. Results: G. perpensa acetone and methanol extracts enhanced superior glucose utilization (IC50 = 78.5 and 94.8 µg/mL, respectively), with low cytotoxicity (LC50 > 600 µg/mL). Key compounds including arabinose, identified from both plants, showed multi-target binding potential against STAT3, PIK3RI and JAK2. Enrichment analyses revealed pathways related to insulin signaling, inflammation, and glucose metabolism. Conclusions: This study supports the therapeutic relevance of phytochemical synergy in the traditional use of both plants and demonstrated systems-level approaches for elucidating complex drug–target interactions in T2DM.