Walnut green husk polyphenols ameliorate type 2 diabetes in C57BL/6 mice by the gut microbiota and IRS/PI3K/AKT signaling pathway

Walnut green husk, a byproduct of walnut processing, is rich in polyphenols with potential antidiabetic effects. However, the antidiabetic activity of walnut green husk polyphenols (WGHP) in vivo has not been reported and their mechanism of action is still unclear. This study investigated its impact on type 2 diabetes mellitus (T2DM) in mice induced by a high-fat diet and streptozotocin. We found that WGHP improved glycolipid metabolism, reduced inflammation and oxidative stress, and protected the pancreas and liver. WGHP also reshaped the gut microbiota, lowering the Firmicutes/Bacteroidota ratio and boosting beneficial bacteria. Network pharmacology indicated that WGHP’s effects are mediated by the PI3K/AKT signaling pathway, which was confirmed by increased protein expression of phosphorylated insulin receptor substrate 1 (p-IRS-1), phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (p-AKT), and glucose transporter type 4 (GLUT4) in the liver. In conclusion, these results indicate that WGHP ameliorates T2DM by modulating gut microbiota and the IRS/PI3K/AKT pathway, providing a theoretical basis for the in-depth utilization of walnut green husk.