Grape-Derived Exosome-like Nanoparticles Ameliorate Prediabetes in Mice via Amino Acid Metabolic Reprogramming

This study investigates the effects of grape-derived exosomes on prediabetic mice and elucidates their underlying mechanisms through an integrated metabolomics approach. A prediabetic mouse model was established, with 18 mice randomly assigned to three groups: model control group, grape exosome treatment group, and antioxidant nutrient supplementation group. Therapeutic efficacy was assessed using fasting plasma glucose (FPG) and homeostasis model assessment of β-cell function (HOMA-β). Intestinal content metabolites were profiled via both untargeted ultra-high performance liquid chromatography coupled with orbitrap electrospray mass spectrometry (UHPLC-OE-MS) and targeted metabolomics analyses. Grape exosomes effectively mitigated prediabetes progression. Untargeted metabolomics revealed 1222 downregulated and 425 upregulated metabolites in the grape exosome group relative to the model control group, among which riboflavin (upregulated) was potentially associated with amino acid metabolism. Targeted metabolomics identified 23 upregulated and 41 downregulated metabolites, with glycine showing a significant elevation. Notably, both the grape exosome group and antioxidant nutrient supplementation group exhibited increased glycine levels and shared enriched metabolic pathways, including D-glutamine and D-glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, as well as valine, leucine, and isoleucine biosynthesis. Integrated untargeted and targeted metabolomics analysis demonstrates that grape exosomes ameliorate diabetes-related metabolic disorders and slow the progression of prediabetes, indicating that grape-derived exosomes have great potential as a functional intervention agent for early glucose metabolism dysfunction.