Solomon S S, Usdan L S, Palazzolo M R
Research Service, Veterans Affairs Medical Center, Memphis, Tennessee 38104, USA.
Am J Med Sci. 2001 Aug;322(2):75-8. doi: 10.1097/00000441-200108000-00005.
Insulin resistance (IR) remains one of the major pathogenic mechanisms for non-insulin-dependent type 2 diabetes mellitus. We have previously modelled IR in H-411E liver cells in culture. In past experiments, we used both labeled glucose uptake, lipogenesis, and stimulation of calmodulin gene expression to quantify the ability of the antidiabetic drugs (pioglitazone and metformin) to reverse tumor necrosis factor-alpha (TNF-alpha)-induced IR in these insulin-treated cells. In these current experiments, H-411E liver cells were rendered IR by a combination of TNF-alpha and insulin. In other experiments, the ability of C2 ceramide (Cer) to inhibit insulin action and induce IR was assessed as well as the phospholipase C inhibitor D609 to reverse IR induced by these TNF-alpha-like agents. C2 Cer, like TNF-alpha, inhibited insulin action. D609 reversed TNF-alpha induced--and to a lesser extent, C2 Cer-induced--IR. At selected times, the cells were also treated with troglitazone (TRG) in 2 groups: (1) 1-time exposure and (2) chronic exposure followed by acute exposure. TRG concentrations ranged from 0.015 to 15.0 micromol/L. Our data demonstrate a powerful effect of TRG in reducing IR and restoring insulin sensitivity in TNF-alpha-treated H-411E cells. Furthermore, pretreatment with TRG, reflecting chronic exposure, as in human clinical use, was more potent than 1-time acute exposure. These data support the efficacy of using thiazolidinediones (TRG) in human type 2 diabetes, and support the use of this cell culture model to further study the effects of thiazolidinediones on TNF-alpha-induced insulin resistance.
胰岛素抵抗（IR）仍然是非胰岛素依赖型2型糖尿病的主要致病机制之一。我们之前在培养的H - 411E肝细胞中建立了IR模型。在过去的实验中，我们使用标记的葡萄糖摄取、脂肪生成以及钙调蛋白基因表达的刺激来量化抗糖尿病药物（吡格列酮和二甲双胍）逆转肿瘤坏死因子 - α（TNF - α）诱导的这些胰岛素处理细胞中IR的能力。在当前这些实验中，通过TNF - α和胰岛素的联合作用使H - 411E肝细胞产生IR。在其他实验中，评估了C2神经酰胺（Cer）抑制胰岛素作用和诱导IR的能力，以及磷脂酶C抑制剂D609逆转这些TNF - α样试剂诱导的IR的能力。C2 Cer与TNF - α一样，抑制胰岛素作用。D609逆转了TNF - α诱导的以及在较小程度上C2 Cer诱导的IR。在选定的时间，细胞还在两组中用曲格列酮（TRG）处理：（1）单次暴露和（2）慢性暴露后急性暴露。TRG浓度范围为0.015至15.0微摩尔/升。我们的数据表明TRG在降低TNF - α处理的H - 411E细胞中的IR和恢复胰岛素敏感性方面具有强大作用。此外，如在人类临床应用中那样，反映慢性暴露的TRG预处理比单次急性暴露更有效。这些数据支持噻唑烷二酮类药物（TRG）在人类2型糖尿病中的疗效，并支持使用这种细胞培养模型进一步研究噻唑烷二酮类药物对TNF - α诱导的胰岛素抵抗的影响。
