The Positive Effect of 6-Gingerol on High-Fat Diet and Streptozotocin-Induced Prediabetic Mice: Potential Pathways and Underlying Mechanisms

The purposes of the present work are to assess how 6-gingerol (6G) positively influences serum glucose regulation in mice with prediabetes triggered by streptozotocin (STZ) plus a high-fat diet (HFD) and to clarify its underlying mechanisms. An analysis of prediabetic symptoms and biochemical characteristics found that 6G intervention was significantly associated with reduced fasting glucose levels, alleviated insulin resistance, better glucose tolerance, hepatic and pancreatic impairment, and dyslipidemia. For the recognition of the target gut microbiota and the pathways linked to 6G’s hypoglycemic function, a combination of hepatic RNA and 16S rRNA sequencing was employed. Specifically, 6G significantly improved the dysbiosis of the gut microbiota and elevated the relative abundances of Alistipes, Alloprevotella, and Ruminococcus_1. Furthermore, 6G supplementation inhibited gluconeogenesis and stimulated glycolysis by activating the PI3K/AKT axis, which also repressed the oxidative stress through Nrf2/Keap1-axis initiation. In addition, Spearman’s correlation analyses reveal a complex interdependency set among the gut microbiota, metabolic variables, and signaling axes. Taken together, the hypoglycemic effect of 6G is partially mediated by altered gut microbiota, as well as by activated Nrf2/Keap1 and PI3K/AKT axes. Thus, 6G may be used as a candidate dietary supplement for relieving prediabetes.