Ginseng-derived GABAFG ameliorates type 2 diabetes mellitus by modulating autophagy-lysosome pathway and gut microbiota

• The first demonstration that γ-aminobutyric acid-fructosyl-glucose (GABAFG) is present in red ginseng and is a non-saponin active ingredient. • GABAFG ameliorates high-fat diet- and streptozotocin-induced type 2 diabetes mellitus in mice. • GABAFG restores glucose homeostasis, lowers blood lipids, and improves pancreatic β-cells dysfunction in mice with type 2 diabetic mellitus. • GABAFG relieves insulin resistance by correcting autophagic lysosomal dysfunction and inhibiting caspase 3-mediated apoptosis. • GABAFGA ameliorates type 2 diabetes mellitus by modulating gut flora and serum metabolism. Hyperglycemia and hyperlipidemia are the hallmarks of type 2 diabetes mellitus (T2DM). T2DM is a systemic metabolic disease caused by insulin resistance and malfunctioning pancreatic β-cells. Although ginseng (the roots of Panax ginseng C.A. Meyer) can be used to treat T2DM, the underlying mechanism is unclear. To assess the role and mechanism of, γ-aminobutyric acid-fructosyl-glucose (GABAFG), a maillard reaction product of ginseng, in T2DM treatment. The metabolism of GABAFG in serum and tissues was analyzed via ultra-high performance liquid chromatography-Q exactive-mass spectrometry (UHPLC-QE-MS). The molecular mechanisms of GABAFG in pancreatic β-cells (in vivo and in vitro) were investigated via Western blotting, qPCR and immunofluorescence. In addition, the results were validated via high-throughput sequencing and serum metabolomics. GABAFG alleviated the elevation of blood glucose and blood lipids in HFD/STZ-induced T2DM mice. Also, GABAFG reduced the insulin resistance-associated IRS-1 signaling axis in pancreatic β-cells in vitro . Mechanistically, GABAFG targeted the nuclear translocation of TFEB inhibited apoptosis of pancreatic β-cells by enhancing autophagolysosome function. In addition, GABAFG remodeled the gut microbiota. Specifically, GABAFG increased Akkermansia, decreased Romboutsia abundance, and decreased serum glycerophospholipid metabolism, thus alleviating T2DM-induced dyslipidemia. This is the first study to assess the pharmacological effects of ginseng-derived GABAFG in T2DM. Therefore, this study provides a new theoretical basis for understanding ginseng effect in metabolic diseases.