title: Simvastatin inhibits glucose uptake activity and GLUT4 translocation through suppression of the IR/IRS-1/Akt signaling in C2C12 myotubes.
abstract: Simvastatin,a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, is clinically used in the prevention and treatment of cardiovascular diseases. Numerous studies demonstrate that statins increase the risk of new-onset diabetes in long-term therapy, but mechanisms underpinning this effect are still unclear. Here, we investigated whether simvastatin inhibited the glucose uptake activity and the underlying mechanisms in C2C12 myotubes. Our studies showed that simvastatin significantly inhibited glucose uptake activity and GLUT4 translocation, whereas the effect was reversible with mevalonolactone (ML), which acts as an intermediate of cholesterol synthesis pathway. Mechanistically, the inhibition of glucose uptake and GLUT4 translocation elicited by simvastatin were associated with the suppression of the insulin receptor (IR)/IR substrate (IRS)/Akt signaling cascade. Simvastatin suppressed the phosphorylation of IR, IRS-1 and Akt, and total expression of IR or IRS-1, but did not affect Akt. Furthermore, simvastatin decreased Rac1 GTP binding. In conclusion, our findings indicate that simvastatin suppresses glucose uptake activity and GLUT4 translocation via IR-dependent IRS-1/PI3K/Akt pathway. These results provide an important new insight into the mechanism of statins on insulin sensitivity which may be associated with new-onset diabetes.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China; Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Kaizhen
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Zhan
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Yinzhi
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Huseen
authors.initials: H
authors.lastname: Mansai
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Weitong
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Organ Transplantation Institute, Medical College, Xiamen University, Xiamen City, Fujian Province, China. Electronic address: oti@xmu.edu.cn.
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xiamen University, Xiamen City, Fujian Province, China. Electronic address: huangzhengrong1@gmail.com.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; D019821:Simvastatin; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D005947:Glucose
keywords: Glucose transporter 4; IR-dependent IRS-1/PI3K/Akt pathway; Myotubes; New-onset diabetes; Rac1; Simvastatin