title: Metformin ameliorates high uric acid-induced insulin resistance in skeletal muscle cells.
abstract: Hyperuricemia occurs together with abnormal glucose metabolism and insulin resistance. Skeletal muscle is an important organ of glucose uptake, disposal, and storage. Metformin activates adenosine monophosphate-activated protein kinase (AMPK) to regulate insulin signaling and promote the translocation of glucose transporter type 4 (GLUT4), thereby stimulating glucose uptake to maintain energy balance. Our previous study showed that high uric acid (HUA) induced insulin resistance in skeletal muscle tissue. However, the mechanism of metformin ameliorating UA-induced insulin resistance in muscle cells is unknown and we aimed to determine it. In this study, differentiated C2C12 cells were exposed to UA (15 mg/dl), then reactive oxygen species (ROS) was detected with DCFH-DA and glucose uptake with 2-NBDG. The levels of phospho-insulin receptor substrate 1 (IRS1; Ser307), phospho-AKT (Ser473) and membrane GLUT4 were examined by western blot analysis. The impact of metformin on UA-induced insulin resistance was monitored by adding Compound C, an AMPK inhibitor, and LY294002, a PI3K/AKT inhibitor. Our data indicate that UA can increase ROS production, inhibit IRS1-AKT signaling and insulin-stimulated glucose uptake, and induce insulin resistance in C2C12 cells. Metformin can reverse this process by increasing intracellular glucose uptake and ameliorating UA-induced insulin resistance.
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Huier
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Yaqiu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Yongneng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Chaohuan
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Wen
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Wanling
authors.initials: W
authors.lastname: Zhuang
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Liangli
authors.initials: L
authors.lastname: Hong
authors.affiliation: The Laboratory of Molecular Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.affiliation: Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China. Electronic address: jidongcheng36@hotmail.com.
authors.forename: Jidong
authors.initials: J
authors.lastname: Cheng
mesh_terms: D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives / Q000378:metabolism; D000111:Acetylcysteine / Q000494:pharmacology; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D003847:Deoxyglucose / Q000031:analogs & derivatives / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014527:Uric Acid / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D014527:Uric Acid; D008687:Metformin; D003847:Deoxyglucose; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase; D009327:4-Chloro-7-nitrobenzofurazan; C098340:2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose; D000111:Acetylcysteine
keywords: High uric acid; Insulin resistance; Metformin; Signal pathway; Skeletal muscle cells