Phlorizin mitigates high glucose-induced metabolic disorders through the IIS pathway in <i>Caenorhabditis elegans</i>

Phlorizin is a dihydrochalcone with various biological activities. To elucidate the mechanism of mitigating high glucose-induced metabolic disorders by phlorizin, the integrated approach combining metabolomics and gene expression profiling was used. The results demonstrated that phlorizin effectively mitigated the impact of high glucose on various growth indicators of <i>C. elegans</i>, as well as decreased lipofuscin, ROS, glucose and triglyceride levels. Metabolomics analysis revealed that phlorizin significantly affected the metabolic pathways of carbohydrates, lipids, and amino acids in <i>C. elegans</i>, indicating its potential role in maintaining energy homeostasis. Gene expression analysis indicated that phlorizin reversed the downregulation of IIS, mTOR and lipid metabolism pathways and promoted the nuclear translocation of DAF-16. In the <i>C. elegans</i> mutant BQ1, the effect of phlorizin on lowering glucose and triglyceride levels was eliminated, meaning that AKT-1 was found to be a key target protein for phlorizin's hypoglycemic and lipid-lowering effects. Molecular docking results also indicated a strong interaction between phlorizin and AKT-1 protein. In summary, phlorizin alleviated metabolic disorders and gene expression imbalances induced by high glucose, and AKT-1 was first found as the key target protein for phlorizin achieving hypoglycemic and hypolipidemic effects.