Metabolomics-driven elucidation of the synergistic therapeutic mechanism of a novel SGLT-2/PPAR-γ dual receptor supramolecular system for treatment diabetes and obesity

A supramolecular system of active pharmaceutical ingredients (APIs) can modify the physicochemical properties and enhance the synergistic efficacy of their components; however, the relevant underlying mechanisms <i>in vivo</i> remain unclear. This study employed a metabolomics-driven approach, combined with biological validation, to investigate the synergistic mechanisms of API-based supramolecular systems. Metabolic dysfunction exacerbates insulin resistance and obesity, contributing to hepatic steatosis and cardiac hypertrophy. A novel sodium-dependent glucose transporter 2 (SGLT-2)/peroxisome proliferator-activated receptor-γ (PPAR-γ) dual receptor (dapagliflozin-pioglitazone (DAP-PIO)) supramolecular system was selected as the model to explore the synergistic mechanism involved in the treatment of metabolic dysfunctions, diabetes and obesity. First, metabolomics analyses were performed to compare the effects of a simple physical mixture (PM) of DAP and PIO with the DAP-PIO supramolecular system after absorption into the bloodstream. The results demonstrated significant differences, with the supramolecular system activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways. Ceramide (Cer), a key metabolite in sphingolipid metabolism, emerged as a critical mediator. Subsequently, the mechanisms underlying the DAP-PIO supramolecular system's hypoglycemic effects and its ability to ameliorate hepatic steatosis and myocardial hypertrophy by reducing insulin resistance were evaluated and confirmed. These findings provide an innovative strategy for developing SGLT-2/PPAR-γ dual-receptor supramolecular systems to enhance the therapeutic outcomes for diabetes and obesity.