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.
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Dose-response analysis suggested a 5% reduction of type 2 diabetes risk for each 300 mg/day increment of total flavonoid intake.
“Additionally, the dose-response analysis suggested a 5% reduction of T2D risk for each 300 mg/day increment of total flavonoids intake [59].”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [59]
In vitro, quercetin increases fatty acid β-oxidation in C2C12 myotubes, hepatocytes, and HeLa cells.
“Quercetin has been reported to modulate fatty acid metabolism in vitro with an increase in fatty acid β-oxidation being reported in C2C12 myotubes, hepatocytes and Hela cells (Suchankova et al., 2009; Eid et al., 2010).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Eid et al., 2010
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- Authors
- Eid, H. M., Martineau, L. C., Saleem, A., Muhammad, A., Vallerand, D., Benhaddou-Andaloussi, A., Nistor, L., Afshar, A., Arnason, J. T., & Haddad, P. S.
- Affiliations
- Canadian Institutes of Health Research (CA)
- University of Ottawa (CA)
- Corresponding author
- Haddad, Pierre S.
- Venue
- Molecular Nutrition & Food Research
- Publisher
- Wiley
- Published
- 2010-01-19
- Volume
- 54
- Issue
- 7
- Pages
- 991-1003
- ISSN
- 1613-4125 (ISSN-L)
- 1613-4133
- OpenAlex
- W2157304833
- Cited by
- 218
- References
- 55
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 17 · 2023: 16 · 2022: 22 · 2021: 16 · 2020: 13 · 2019: 11 · 2018: 19 · 2017: 7 · 2016: 13 · 2015: 16 · 2014: 18 · 2013: 8 · 2012: 14
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Nutrition & Food Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytochemistry and Biological Activities
- Keywords
- AMPK, quercetin, quercetin glycosides, quercetin aglycone, lingonberry, glucose uptake, skeletal muscle, insulin-independent glucose uptake, antidiabetic activity, bioassay-guided fractionation, ATP synthase inhibition, mitochondrial oxygen consumption, metabolic stress, insulin resistance
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Line, Diabetes Mellitus, Fruit, Glucose, Glycosides, Hydrogen-Ion Concentration, Hypoglycemic Agents, Kinetics, Male, Mitochondria, Liver, Osmolar Concentration, Plant Extracts, Plants, Medicinal, Quebec, Quercetin, Rats, Wistar, Hepatocytes, Mitochondrial Proton-Translocating ATPases, Vaccinium vitis-idaea, Myoblasts, Skeletal, Mice, Rats, AMP-Activated Protein Kinases
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