Stimulation of AMPK and enhancement of glucose uptake in muscle cells by quercetin and quercetin glycosides, the actives principles of Vaccinium vitis-idaea

Abstract

As a part of an ongoing project aiming to develop culturally-adapted diabetes treatment for Canadian native populations, our team has identified several medicinal plants that stimulate glucose uptake in C2C12 muscle cells from among species used by the Cree of Eeyou Istchee (James Bay area of northern Quebec) to treat symptoms related to diabetes. The goal of this study was to elucidate the mechanism of action of one of these plants, the berries of Vaccinium vitis idaea, as well as to isolate and identify its active constituents. Western immunoblot analysis in C2C12 cells revealed that the ethanol extract of the berries did not stimulate insulin signaling pathways, but instead activated the AMP-activated protein kinase (AMPK) pathway. The extract was observed to mildly inhibit ADP-stimulated oxygen consumption in isolated mitochondria, an effect likely responsible for metabolic stress and ensuing activation of AMPK. Fractionation guided by glucose uptake activity resulted in the isolation of 9 compounds. The 3 most active, quercetin, quercetin-3-O-galactoside and quercetin-3-O-glucoside, enhanced glucose uptake by 37±9%, 38±3% and 59±2%, respectively, after an 18 hour treatment. These flavonoid glycosides, as well as the aglycone, were observed to stimulate the AMPK pathway. Quercetin was a powerful inhibitor of ATP synthase in isolated mitochondria. These finding indicate that quercetin and its glycosides are likely responsible for the antidiabetic activity of V.vitis crude berry extract mediated by AMPK. Quercetin and quercetin-3-glycosides thus potentially have applications for the prevention and treatment of metabolic diseases.