College of Life and Environmental Sciences, Geoffrey Pope Building, University of Exeter, Stocker Road, Exeter EX4 4QD, Exeter, United Kingdom.
School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
Sci Rep. 2019 Apr 24;9(1):6477. doi: 10.1038/s41598-019-42574-3.
Type-II Diabetes Mellitus (T2DM) is one of the fastest growing public health issues today, consuming 12% of worldwide health budgets and affecting an estimated 400 million people. One of the key pathological traits of this disease is insulin resistance at 'glucose sink' tissues (mostly skeletal muscle), and this remains one of the features of this disease most intractable to therapeutic intervention. Several lines of evidence have implicated the post-translational modification, SUMOylation, in insulin signalling and insulin resistance in skeletal muscle. In this study, we examined this possibility by manipulation of cellular SUMOylation levels using multiple different tools, and assaying the effect on insulin-stimulated GLUT4 surface expression in differentiated L6 rat myocytes. Although insulin stimulation of L6 myocytes produced a robust decrease in total cellular SUMO1-ylation levels, manipulating cellular SUMOylation had no effect on insulin-responsive GLUT4 surface trafficking using any of the tools we employed. Whilst we cannot totally exclude the possibility that SUMOylation plays a role in the insulin signalling pathway in human health and disease, our data strongly argue that GLUT4 trafficking in response to insulin is not regulated by protein SUMOylation, and that SUMOylation does not therefore represent a viable therapeutic target for the treatment of insulin resistance.
2 型糖尿病（T2DM）是当今增长最快的公共卫生问题之一，消耗了全球卫生预算的 12%，影响了约 4 亿人。这种疾病的一个关键病理特征是“葡萄糖汇”组织（主要是骨骼肌）的胰岛素抵抗，这仍然是这种疾病最难以治疗干预的特征之一。有几条证据表明，翻译后修饰 SUMOylation 参与了胰岛素信号转导和骨骼肌胰岛素抵抗。在这项研究中，我们使用多种不同的工具来操纵细胞 SUMOylation 水平，并检测其对分化的 L6 大鼠肌细胞中胰岛素刺激的 GLUT4 表面表达的影响，从而检验了这种可能性。尽管胰岛素刺激 L6 肌细胞产生了强烈的总细胞 SUMO1 化水平下降，但我们使用的任何工具都没有影响胰岛素反应性 GLUT4 表面转运的细胞 SUMOylation。虽然我们不能完全排除 SUMOylation 在人类健康和疾病中的胰岛素信号通路中发挥作用的可能性，但我们的数据强烈表明，胰岛素刺激后 GLUT4 的转运不受蛋白质 SUMOylation 的调节，因此 SUMOylation 不是治疗胰岛素抵抗的可行治疗靶点。
