Department of Endocrinology, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510120, People's Republic of China.
Endocrine. 2010 Feb;37(1):157-66. doi: 10.1007/s12020-009-9283-y. Epub 2009 Nov 24.
Lipid-induced insulin resistance is associated with inflammatory state in epidemiological studies. However, it is still unclear whether the activation of NF-κB, a pivotal transcription factor of inflammation, plays a crucial role in mediating skeletal muscle insulin resistance. This study addressed what was the role of NF-κB in lipid-induced insulin resistance and whether NF-κB activation was sufficient to cause insulin resistance in C2C12 myotubes. A 16 h exposure of myotubes to palmitate reduced net insulin-stimulated glucose uptake by 48%, GLUT4 translocation by 52%, Akt phosphorylation by 54%, induced a 1.8-fold increase in insulin-stimulated insulin receptor substrate (IRS) phosphorylation, and doubled NF-κB activation. Myotubes transfected with NF-κB p65 siRNA for 24 h and followed by a treatment with palmitate for 16 h efficiently blocked NF-κB activation, and prevented the detrimental effects of palmitate on the metabolic actions of insulin. Transfection of myotubes with I-κBα siRNA for 24 h also led to a twofold induction of NF-κB activation, and reduced net insulin-stimulated glucose uptake by 30%, GLUT4 translocation by 35%, Akt phosphorylation by 31%, induced a 0.7-fold increase in insulin-stimulated IRS phosphorylation. These findings suggest that NF-κB overexpression per se is sufficient to impair insulin sensitivity and palmitate-induced insulin resistance is mediated by NF-κB in skeletal muscle cells.
在流行病学研究中，脂诱导的胰岛素抵抗与炎症状态有关。然而，NF-κB（炎症的关键转录因子）的激活是否在介导骨骼肌胰岛素抵抗中起关键作用仍不清楚。本研究旨在探讨 NF-κB 在脂诱导的胰岛素抵抗中的作用，以及 NF-κB 的激活是否足以导致 C2C12 肌管中的胰岛素抵抗。将肌管暴露于棕榈酸 16 小时可使胰岛素刺激的葡萄糖摄取减少 48%，GLUT4 易位减少 52%，Akt 磷酸化减少 54%，诱导胰岛素刺激的胰岛素受体底物（IRS）磷酸化增加 1.8 倍，并使 NF-κB 激活增加两倍。用 NF-κB p65 siRNA 转染肌管 24 小时，然后用棕榈酸处理 16 小时，可有效阻断 NF-κB 的激活，并防止棕榈酸对胰岛素代谢作用的有害影响。用 I-κBα siRNA 转染肌管 24 小时也导致 NF-κB 激活增加两倍，并使胰岛素刺激的葡萄糖摄取减少 30%，GLUT4 易位减少 35%，Akt 磷酸化减少 31%，诱导胰岛素刺激的 IRS 磷酸化增加 0.7 倍。这些发现表明，NF-κB 的过表达本身足以损害胰岛素敏感性，而棕榈酸诱导的胰岛素抵抗是通过骨骼肌细胞中的 NF-κB 介导的。
