title: Metformin attenuates palmitic acid-induced insulin resistance in L6 cells through the AMP-activated protein kinase/sterol regulatory element-binding protein-1c pathway.
abstract: AMP-activated protein kinase (AMPK) is an important effector of metformin action on glucose uptake in skeletal muscle cells. We recently reported that metformin improved insulin receptor substrate-1 (IRS-1)-associated insulin signaling by downregulating sterol regulatory element-binding protein-1c (SREBP-1c) expression. In this study, we investigated whether AMPK activation and SREBP-1c inhibition contribute to the beneficial effects of metformin on IRS-1-associated insulin signaling in L6 myotubes. L6 muscle cells were incubated with palmitic acid (PA) to induce insulin resistance and then treated with metformin and/or the AMPK inhibitor, compound C. AMPK, SREBP-1c, IRS-1 and Akt protein expression levels were determined by western blot analysis. The effects of metformin on SREBP-1c gene transcription were determined by a luciferase reporter assay. Glucose uptake was evaluated using the 2-NBDG method. In the PA-treated L6 cells, metformin treatment enhanced AMPK phosphorylation, reduced SREBP-1c expression and increased IRS-1 and Akt protein expression, whereas treatment with compound C blocked the effects of metformin on SREBP-1c expression and the IRS-1 and Akt levels. Moreover, metformin suppressed SREBP-1c promoter activity and promoted glucose uptake through AMPK. The results from this study demonstrate that metformin ameliorates PA-induced insulin resistance through the activation of AMPK and the suppression of SREBP-1c in skeletal muscle cells.
authors.affiliation: Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, P.R. China.
authors.forename: Sunyinyan
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Oncology, Nanjing First Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yin
authors.affiliation: Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Shu
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Endocrinology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, P.R. China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Bu
authors.affiliation: Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Dalong
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D019308:Palmitic Acid; D008687:Metformin; D055372:AMP-Activated Protein Kinases