Stimulation of AMP-activated protein kinase and enhancement of basal glucose uptake in muscle cells by quercetin and quercetin glycosides, active principles of the antidiabetic medicinal plant Vaccinium vitis-idaea.

Several medicinal plants that stimulate glucose uptake in skeletal muscle cells were identified from among species used by the Cree of Eeyou Istchee of northern Quebec to treat symptoms of diabetes. This study aimed to elucidate the mechanism of action of one of these products, the berries of Vaccinium vitis idaea, as well as to isolate and identify its active constituents using a classical bioassay-guided fractionation approach. Western immunoblot analysis in C2C12 muscle cells revealed that the ethanol extract of the berries stimulated the insulin-independent AMP-activated protein kinase (AMPK) pathway. The extract mildly inhibited ADP-stimulated oxygen consumption in isolated mitochondria, an effect consistent with metabolic stress and the ensuing stimulation of AMPK. This mechanism is highly analogous to that of Metformin. Fractionation guided by glucose uptake activity resulted in the isolation of ten compounds. The two most active, quercetin-3-O-glycosides, enhanced glucose uptake by 38-59% (50 muM; 18 h treatment) in the absence of insulin. Quercetin aglycone, a minor constituent, stimulated uptake by 37%. The quercetin glycosides and the aglycone stimulated the AMPK pathway at concentrations of 25-100 muM, but only the aglycone inhibited ATP synthase in isolated mitochondria (by 34 and 79% at 25 and 100 muM, respectively). This discrepancy suggests that the activity of the glycosides may require hydrolysis to the aglycone form. These findings indicate that quercetin and quercetin 3-O-glycosides are responsible for the antidiabetic activity of V. vitis crude berry extract mediated by AMPK. These common plant products may thus have potential applications for the prevention and treatment of insulin resistance and other metabolic diseases.

Enhancement of muscle cell glucose uptake by medicinal plant species of Canada's native populations is mediated by a common, metformin-like mechanism.

AIM: The purpose of the present study was to elucidate the mechanisms of action mediating enhancement of basal glucose uptake in skeletal muscle cells by seven medicinal plant products recently identified from the pharmacopeia of native Canadian populations (Spoor et al., 2006). METHODS: Activity of the major signaling pathways that regulate glucose uptake was assessed by western immunoblot in C2C12 muscle cells treated with extracts from these plant species. Effects of extracts on mitochondrial function were assessed by respirometry in isolated rat liver mitochondria. Metabolic stress induced by extracts was assessed by measuring ATP concentration and rate of cell medium acidification in C2C12 myotubes and H4IIE hepatocytes. Extracts were applied at a dose of 15-100 microg/ml. RESULTS: The effect of all seven products was achieved through a common mechanism mediated not by the insulin signaling pathway but rather by the AMP-activated protein kinase (AMPK) pathway in response to the disruption of mitochondrial function and ensuing metabolic stress. Disruption of mitochondrial function occurred in the form of uncoupling of oxidative phosphorylation and/or inhibition of ATPsynthase. Activity of the AMPK pathway, in some instances comparable to that stimulated by 4mM of the AMP-mimetic AICAR, was in several cases sustained for at least 18h post-treatment. Duration of metabolic stress, however, was in most cases in the order of 1h. CONCLUSIONS: The mechanism common to the seven products studied here is analogous to that of the antidiabetic drug Metformin. Of interest is the observation that metabolic stress need not be sustained in order to induce important adaptive responses. The results support the use of these products as culturally adapted treatments for insulin resistance and hyperglycemia in susceptible aboriginal populations where adherence to modern diabetes pharmaceuticals is an issue. The mechanism reported here may be widespread and mediate the antidiabetic activity of traditional remedies from various other cultures.