Type 2 diabetes mellitus (T2D), as a chronic metabolic disease affecting millions of people worldwide, has become a major public health threat. Anthocyanins are phenolic compounds ubiquitously distributed in berry fruits including blueberry, raspberry, bayberry, mulberry and blackberry. Recently, increasing evidence indicates a positive relationship between increased consumption of anthocyanin-rich food and lowered diabetes complications. However, the anti-diabetic effect of purified anthocyanins as well as its molecular mechanisms remain largely unknown. In the present study, six major types of anthocyanidins from berry fruits were obtained including delphinidin, petunidin, malvidin, cyanidin, peonidin and pelargonidin as well as their derivatives. Our study screened natural anthocyanins targeted for α-glucosidase inhibition and identified a potent α-glucosidase inhibitor pelargonidin-3-O-rutinoside (Pg3R) that can improve postprandial hyperglycemia both in vivo and in vitro. The structural determinants for α-glucosidase inhibition by Pg3R and the structure activity relationship (SAR) of natural anthocyanins were further revealed by enzymatic kinetics and molecular docking analysis. On the other hand, we examined the effect of pelargonidin-3-O-glucoside (Pg3G) on high-glucose/high-fat (HG+HF)-induced hepatocytes and db/db mice. Our results showed that Pg3G treatment contributed to a significant increase in glucose uptake in HG+HF-induced hepatocytes. In addition, Pg3G suppressed HG+HF-induced oxidative stress by inhibiting excessive ROS, reversing mitochondrial membrane potential disruption and preventing glutathione depletion. Moreover, Pg3G induced autophagy in HG+HF-induced hepatocytes, whereas autophagy inhibitor abrogated the anti-hyperglycemic effect of Pg3G. In consistent with the in vitro study, administration of Pg3G contributed to the improvement of glucose tolerance, insulin sensitivity and induction of autophagy. Furthermore, Pg3G not only modified the gut microbiota composition, but also strengthened the intestinal barrier integrity. Collectively, our results unveil novel mechanisms for Pg3R by targeted inhibition of α-glucosidase activity, and for Pg3G by coordinately regulating autophagy pathway and modulating gut microbiota composition, suggesting the potential application of anthocyanins for T2D therapeutics.

Natural anthocyanin ameliorates type 2 diabetes through targeted inhibition of α-glucosidase activity and coordinately regulating autophagy pathway and gut microbiota composition

2019 Fall National Meeting

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