Mangosteen xanthone γ-mangostin exerts lowering blood glucose effect with potentiating insulin sensitivity through the mediation of AMPK/ PPARγ

Diabetes mellitus (DM) is concomitant with significant morbidity and mortality and its prevalence is accumu-lative in worldwide. The conventional antidiabetic agents are known to mitigate the symptoms of diabetes; however, they may also cause side and adverse effects. There is an imperative necessity to conduct preclinical and clinical trials for the discovery of alternative therapeutic agents that can overcome the drawbacks of current synthetic antidiabetic drugs. This study aimed to investigate the efficacy of lowering blood glucose and under -lined mechanism of gamma-mangostin, mangosteen (Garcinia mangostana) xanthones. The results showed gamma-Mangostin had a antihyperglycemic ability in short (2 h)-and long-term (28 days) administrations to diet-induced diabetic mice. The long-term administration of gamma-mangostin attenuated fasting blood glucose of diabetic mice and exhibited no hepatotoxicity and nephrotoxicity. Moreover, AMPK, PPAR gamma, alpha-amylase, and alpha-glucosidase were found to be the potential targets for simulating binds with gamma-mangostin after molecular docking. To validate the docking results, the inhibitory potency of gamma-mangostin against alpha-amylase/alpha-glucosidase was higher than Acarbose via enzymatic assay. Interestingly, an allosteric relationship between gamma-mangostin and insulin was also found in the glucose uptake of VSMC, FL83B, C2C12, and 3T3-L1 cells. Taken together, the results showed that gamma-man-gostin exerts anti-hyperglycemic activity through promoting glucose uptake and reducing saccharide digestion by inhibition of alpha-amylase/alpha-glucosidase with insulin sensitization, suggesting that gamma-mangostin could be a new clue for drug discovery and development to treat diabetes.