Preliminary Study On The Hypoglycemic Mechanism Of Pterostilbene And Its Intestinal Metabolites

Diabetes is the number one health killer in the world today.At present,combination drugs are mostly used in the treatment of diabetes,but single drugs that can adjust multiple targets at the same time have better effects than combination drugs,and may become a new trend in the treatment of diabetes.Chinese diet is characterized by carbohydrate,which leads to postprandial hyperglycemia in Chinese diabetics.Therefore,the key to the treatment of diabetes is to reduce postprandial hyperglycemia and prevent and reduce a variety of fatal and disabling complications caused by long-term hyperglycemia.The key targets for the treatment of diabetes areα-glucosidase and aldose reductase.Pterostilbene is a dietary polyphenolic compound widely found in blueberries,grapes and wine.Pinostilbene is the intestinal metabolite of pterostilbene,which also exists in nature.Both of them are polyphenols.Pterostilbene has been reported to have anti-diabetic and prevent diabetic complications,but its mechanism of action is unclear.In this study,the inhibitory effects and mechanisms of pterostilbene and its metabolite pinostilbene onα-glucosidase and aldose reductase were systematically investigated.The results of in vitro experiments showed that the inhibitory activities of pterostilbene onα-glucosidase and aldose reductase were poor.In contrast,pinostilbene has better inhibitory activity to double enzyme.Inhibition kinetics analysis showed that pinostilbene inhibitedα-glucosidase activity(IC₅₀=11.68±1.54μM,K_i=14.28±2.58μM)and aldose reductase activity（IC50=54.67±7.97μM,K_i=59.89±5.40μM）in a non-competitive form.Further molecular docking results showed that the binding energy of pinostilbene withα-glucosidase and aldose reductase was lower than that of the positive control,and the binding energy of pinostilbene withα-glucosidase and aldose reductase was mainly promoted by hydrogen bond and hydrophobic force.The inhibitory activities of pterostilbene and pinostilbene on recombinant humanα-glucosidase and aldose reductase were also investigated.The results showed that the inhibitory activities of pinostilbene onα-glucosidase and aldose reductase were weaker than those of positive inhibitors,which might be due to the characteristics of phenolic compounds themselves:low solubility,fast metabolism and low bioavailability.However,compared with pterostilbene,pinostilbene still had strong double enzyme inhibition.Therefore,we speculated that the hypoglycemic effect of pterostilbene may be realized through its intestinal metabolite（pinostilbene）.The results of this study not only provide a comprehensive reference for the hypoglycemic mechanism of pterostilbene,but also provide a basis for the development of novel multi-target hypoglycemic drugs.