The glucuronide metabolites of kaempferol and quercetin, targeting to the AKT PH domain, activate AKT/GSK3β signaling pathway and improve glucose metabolism

Abstract 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 (KD = 27.6 μM) and Q-3-G (KD = 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.