title: 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.
abstract: 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.
authors.affiliation: Natural Health Products and Metabolic Diseases Laboratory, Department of Pharmacology, Université de Montréal, Montreal, Que. H3C 3J7, Canada.
authors.forename: Hoda M
authors.initials: HM
authors.lastname: Eid
authors.forename: Louis C
authors.initials: LC
authors.lastname: Martineau
authors.forename: Ammar
authors.initials: A
authors.lastname: Saleem
authors.forename: Asim
authors.initials: A
authors.lastname: Muhammad
authors.forename: Diane
authors.initials: D
authors.lastname: Vallerand
authors.forename: Ali
authors.initials: A
authors.lastname: Benhaddou-Andaloussi
authors.forename: Lidia
authors.initials: L
authors.lastname: Nistor
authors.forename: Arvind
authors.initials: A
authors.lastname: Afshar
authors.forename: John T
authors.initials: JT
authors.lastname: Arnason
authors.forename: Pierre S
authors.initials: PS
authors.lastname: Haddad
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003920:Diabetes Mellitus / Q000178:diet therapy / Q000517:prevention & control; D005638:Fruit / Q000737:chemistry; D005947:Glucose / Q000378:metabolism*; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009994:Osmolar Concentration; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D011792:Quebec; D011794:Quercetin / Q000031:analogs & derivatives / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D029801:Vaccinium vitis-idaea / Q000737:chemistry*
chemical_list: D006027:Glycosides; D007004:Hypoglycemic Agents; D010936:Plant Extracts; D000255:Adenosine Triphosphate; D011794:Quercetin; D055372:AMP-Activated Protein Kinases; D025261:Mitochondrial Proton-Translocating ATPases; D005947:Glucose