Bouzakri Karim, Zachrisson Anna, Al-Khalili Lubna, Zhang Bei B, Koistinen Heikki A, Krook Anna, Zierath Juleen R
Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Cell Metab. 2006 Jul;4(1):89-96. doi: 10.1016/j.cmet.2006.04.008.
Type 2 diabetes is associated with defects in insulin signaling and the resulting abnormal glucose and lipid metabolism. The complexity of insulin signaling cascades is highlighted by the existence of multiple isoforms of target proteins implicated in metabolic and gene-regulatory events. We utilized siRNA to decipher the specific role of predominant insulin receptor substrates and Akt isoforms expressed in human skeletal muscle. Gene silencing revealed specialized roles of insulin signaling cascades to metabolic endpoints. IRS-1 and Akt2 were required for myoblast differentiation and glucose metabolism, whereas IRS-2 and Akt1 were dispensable. A key role of IRS-2 and Akt1 in lipid metabolism was revealed, highlighting reciprocal relationships between metabolic pathways. Unraveling the isoform-specific regulation of glucose and lipid metabolism by key elements along insulin signaling cascades through siRNA-mediated gene silencing in human tissues will facilitate the discovery of novel targets for the treatment of diabetes and related metabolic disorders.
2型糖尿病与胰岛素信号传导缺陷以及由此导致的异常葡萄糖和脂质代谢有关。胰岛素信号级联反应的复杂性体现在参与代谢和基因调控事件的靶蛋白存在多种异构体。我们利用小干扰RNA（siRNA）来解读在人类骨骼肌中表达的主要胰岛素受体底物和Akt异构体的特定作用。基因沉默揭示了胰岛素信号级联反应对代谢终点的特殊作用。成肌细胞分化和葡萄糖代谢需要胰岛素受体底物1（IRS-1）和蛋白激酶B2（Akt2），而胰岛素受体底物2（IRS-2）和蛋白激酶B1（Akt1）则并非必需。研究揭示了IRS-2和Akt1在脂质代谢中的关键作用，突出了代谢途径之间的相互关系。通过在人体组织中利用siRNA介导的基因沉默来阐明胰岛素信号级联反应关键元件对葡萄糖和脂质代谢的异构体特异性调节，将有助于发现治疗糖尿病及相关代谢紊乱的新靶点。
