Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle.
Biochem Pharmacol
; 164: 23-33, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30796916
ABSTRACT
Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. They are generally well tolerated, but can cause insulin resistance in patients. Therefore, we investigated the mechanisms underlying the statin-induced insulin resistance. We used mice and C2C12 myotubes (murine cell line) mice (nâ¯=â¯10) were treated with oral simvastatin (5â¯mg/kg/day) or water (control) for 21â¯days and C2C12 cells were exposed to 10⯵M simvastatin for 24â¯h. After intraperitoneal glucose application (2â¯g/kg), simvastatin-treated mice had higher glucose but equal insulin plasma concentrations than controls and lower glucose transport into skeletal muscle. Similarly, glucose uptake by C2C12 myotubes exposed to 10⯵M simvastatin for 24â¯h was impaired compared to control cells. In simvastatin-treated C2C12 myotubes, mRNA and protein expression of the insulin receptor (IR) ß-chain was increased, but the phosphorylation (Tyr1361) was impaired. Simvastatin decreased numerically Akt/PKB Thr308 phosphorylation (via insulin signaling pathway) and significantly Akt/PKB Ser473 phosphorylation (via mTORC2), which was explained by impaired phosphorylation of mTOR Ser2448. Reduced phosphorylation of Akt/PKB impaired downstream phosphorylation of GSK3ß, leading to impaired translocation of GLUT4 into plasma membranes of C2C12 myotubes. In contrast, reduced phosphorylation of AS160 could be excluded as a reason for impaired GLUT4 translocation. In conclusion, simvastatin caused insulin resistance in mice and impaired glucose uptake in C2C12 myotubes. The findings in myotubes can be explained by diminished activation of Akt/PKB by mTORC2 and downstream effects on GSK3ß, impairing the translocation of GLUT4 and the uptake of glucose.
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MEDLINE
Assunto principal:
Resistência à Insulina
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Músculo Esquelético
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Fibras Musculares Esqueléticas
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Inibidores de Hidroximetilglutaril-CoA Redutases
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Sinvastatina
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article