title: Quercetin oppositely regulates insulin-mediated glucose disposal in skeletal muscle under normal and inflammatory conditions: The dual roles of AMPK activation.
abstract: METHODS
  Quercetin is a dietary flavonoid whose role in the regulation of the activity of insulin remains controversial. Our study aimed to investigate how quercetin and its major metabolite quercetin-3-glucuronide (Q-3-G) regulate insulin-mediated glucose disposal in skeletal muscle under normal and inflammatory conditions.
  
  
  RESULTS
  Under normal conditions, quercetin impaired glucose and insulin tolerance and attenuated insulin-mediated phosphorylation of Akt substrate of 160 kDa (AS160) and TBC1D1 without affecting Akt activity in male Institute of Cancer Research (ICR) mice. However, under inflammatory conditions, quercetin exhibited an opposite effect in these animals. In C2C12 cells, quercetin also decreased insulin-stimulated AS160 and TBC1D1 phosphorylation and glucose uptake in the absence of an inflammatory insult, whereas it improved the action of insulin under inflammatory conditions. Knockdown of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) blocked the differential effects of quercetin under both conditions. Unlike quercetin, Q-3-G had no influence on insulin-induced phosphorylation of AS160 and TBC1D1 and glucose uptake in C2C12 myotubes under normal conditions. Q-3-G displayed a similar regulation with quercetin in glucose disposal under inflammatory conditions.
  
  
  CONCLUSIONS
  Quercetin suppressed insulin-mediated glucose disposal in skeletal muscle tissue/cells under normal conditions while it ameliorated impaired glucose uptake under inflammatory conditions with activation of AMPK. In contrast, Q-3-G ameliorated insulin resistance in skeletal cells under inflammatory conditions without affecting glucose disposal under normal conditions.
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Mei
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Yapu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Lele
authors.initials: L
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Yilei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Kou
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors.forename: Baolin
authors.initials: B
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
authors.forename: Lian-Wen
authors.initials: LW
authors.lastname: Qi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008813:Mice, Inbred ICR; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009220:Myositis / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D020690:GTPase-Activating Proteins; D007328:Insulin; C095906:Tbc1d1 protein, mouse; C505647:Tbc1d4 protein, mouse; C443401:quercetin 3-O-glucuronide; D011794:Quercetin; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: Adenosine 5′-monophosphate-activated protein kinase; Akt substrate of 160 kDa; Quercetin; Skeletal muscle insulin resistance; TBC1D1