title: Silibinin improves palmitate-induced insulin resistance in C2C12 myotubes by attenuating IRS-1/PI3K/Akt pathway inhibition.
abstract: The present study investigated the effect of silibinin, the principal potential anti-inflammatory flavonoid contained in silymarin, a mixture of flavonolignans extracted from Silybum marianum seeds, on palmitate-induced insulin resistance in C2C12 myotubes and its potential molecular mechanisms. Silibinin prevented the decrease of insulin-stimulated 2-NBDG (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) uptake and the downregulation of glutamate transporter type 4 (GLUT4) translocation in C2C12 myotubes induced by palmitate. Meanwhile, silibinin suppressed the palmitate-induced decrease of insulin-stimulated Akt Ser473 phosphorylation, which was reversed by wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K). We also found that palmitate downregulated insulin-stimulated Tyr632 phosphorylation of insulin receptor substrate 1 (IRS-1) and up-regulated IRS-1 Ser307 phosphorylation. These effects were rebalanced by silibinin. Considering several serine/threonine kinases reported to phosphorylate IRS-1 at Ser307, treatment with silibinin downregulated the phosphorylation of both c-Jun N-terminal kinase (JNK) and nuclear factor-κB kinase β (IKKβ), which was increased by palmitate in C2C12 myotubes mediating inflammatory status, whereas the phosphorylation of PKC-θ was not significantly modulated by silibinin. Collectively, the results indicated that silibinin prevented inhibition of the IRS-1/PI3K/Akt pathway, thus ameliorating palmitate-induced insulin resistance in C2C12 myotubes.
authors.affiliation: Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
authors.forename: H B
authors.initials: HB
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
authors.forename: Y R Y
authors.initials: YR
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Mo
authors.affiliation: Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
authors.forename: W J
authors.initials: WJ
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects*; D032446:Myoblasts; D032448:Myoblasts, Skeletal / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000187:drug effects / Q000378:metabolism; D019308:Palmitic Acid / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D047428:Protein Kinase Inhibitors; D012838:Silymarin; D019308:Palmitic Acid; D000077385:Silybin; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt