A Combination of Psidium guajava and Seriphium plumosum Modulates Glucose Metabolism and Reduces Hepatic GLUT2 Expression Through Additive-to-Synergistic Interactions

Background: Type 2 diabetes mellitus (T2DM) remains a major global health challenge, prompting interest in plant-based interventions with multi-target metabolic effects. This study evaluated the individual and combined effects of Psidium guajava (PG) and Seriphium plumosum (SP) on hepatic and skeletal muscle glucose metabolism. Methods: HepG2 hepatocytes and differentiated C2C12 myotubes were treated with PG, SP, and a 1:1 PG+SP combination. Cell viability, glucose uptake, GLUT2 expression, glycogen content, and AMP levels were assessed. Interactions were evaluated using Bliss Independence, Combination Index (CI), Loewe Additivity, and Zero Interaction Potency (ZIP) models. Results: SP exhibited minimal cytotoxicity, whereas PG induced concentration-dependent reductions in HepG2 viability. The PG+SP combination maintained higher viability than PG alone and demonstrated additive-to-synergistic interactions (CI = 0.51–0.89). In HepG2 cells, all treatments significantly enhanced glucose uptake relative to controls (p < 0.05), with the combination achieving approximately 94% of the metformin response. The combination also significantly reduced GLUT2 expression, with the greatest effect observed at 125 + 125 µg/mL (0.77 ± 0.14-fold, p < 0.0001). In C2C12 myotubes, PG, SP, and PG+SP significantly increased glucose uptake and glycogen accumulation (p < 0.05). SP increased AMP levels at lower concentrations, whereas the PG+SP combination reduced AMP levels below control values. Synergy analyses consistently indicated concentration- and endpoint-dependent interactions ranging from additivity to synergy. Conclusions: The PG+SP combination co-ordinately modulated glucose uptake, glycogen storage, GLUT2 expression, and AMP-related energy status across hepatic and skeletal muscle models. These findings provide mechanistic support for further investigation of this botanical combination as a potential multi-target strategy for T2DM and metabolic dysfunction.