Development of insulin resistance and reversal by thiazolidinediones in C2C12 skeletal muscle cells |
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Authors: | Kumar Naresh Dey Chinmoy S |
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Institution: | Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India. |
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Abstract: | AIM/HYPOTHESIS: The aim of this study was to develop an insulin-resistant cell culture model in skeletal muscle cell line by chronic presence of insulin in serum-free medium and to determine the effect of thiazolidinediones on insulin signaling. METHODS: We differentiated C2C12 in a combination of serum-free medium in presence or absence of insulin and determined differentiation by creatine kinase activity, myogenin and MyoD expression. The development of insulin resistance was determined by tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 and glucose uptake. We treated the cells with 50 microM of thiazolidinediones to determine the effect on these parameters. RESULTS: C2C12 cells were differentiated normally in the serum-free medium in the absence or presence of insulin. Chronic treatment of insulin resulted in reduced tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1; activation of phosphatidylinositol 3-kinase was impaired and insulin-stimulated glucose uptake was reduced. The treatment of insulin-resistant cells with thiazolidinediones resulted in the enhancement of insulin signaling pathway by increasing tyrosine phosphorylation of insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase activity and glucose uptake. CONCLUSION/INTERPRETATION: These results indicate that insulin resistance can be developed in C2C12 skeletal muscle cell line. These findings implicate a direct mechanism of action of thiazolidinediones on skeletal muscle. |
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Keywords: | KRP Kreb’s Ringer phosphate PBS phosphate buffered saline TZDs thiazolidinediones 2-DOG 2-deoxyglucose IR insulin receptor IRS-1 insulin receptor substrate-1 PI 3-kinase phosphatidylinositol 3-kinase |
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