Kaempferol and quercetin, as dietary flavonoids, are beneficial to diabetes risk reduction. Clarifying the mechanism of dietary flavonoids in improving glucose metabolism may meet the functional and nutritional requirements. In this paper, PCA revealed two glucuronides, kaempferol-3-glucuronide (K-3-G) and quercetin-3-glucuronide (Q-3-G), which were the primary metabolites. Target prediction, enzymatic activity, and AKT plasma translocation assays indicated that K-3-G and Q-3-G could target the AKT PH domain. Fluorescence spectrometry was used to measure the dissociation constants of K-3-G (K_D = 27.6 μM) and Q-3-G (K_D = 10.8 μM). Molecular docking provided interaction insights for K-3-G and Q-3-G with the AKT PH domain. K-3-G and Q-3-G activated the AKT/GSK3β phosphorylation, thereby improving glucose consumption. Our study demonstrates that the glucuronide metabolites of flavonoids directly target the AKT PH domain and activate AKT/GSK3β signal pathway, thereby improving glucose metabolism.

山茱fer醇和槲皮素，作为膳食类黄酮，对降低糖尿病风险有益。阐明饮食中类黄酮改善葡萄糖代谢的机制可能满足功能和营养要求。在PCA中，PCA揭示了两种葡糖醛酸，主要的代谢产物是山奈酚3-葡糖醛酸（K-3-G）和槲皮素-3-葡糖醛酸（Q-3-G）。靶标预测，酶活性和AKT血浆易位测定表明K-3-G和Q-3-G可以靶向AKT PH域。荧光光谱法用于测量K-3-G（K _D  = 27.6μM）和Q-3-G（K _D = 10.8μM）。分子对接为K-3-G和Q-3-G与AKT PH域的相互作用提供了见解。K-3-G和Q-3-G激活了AKT /GSK3β磷酸化，从而改善了葡萄糖消耗。我们的研究表明，类黄酮的葡萄糖醛酸苷代谢产物直接靶向AKT PH域并激活AKT /GSK3β信号通路，从而改善了葡萄糖的代谢。