Arora Amita, Dey Chinmoy Sankar
Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi 110016, India.
Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi 110016, India.
Biochim Biophys Acta. 2014 Sep;1842(9):1372-8. doi: 10.1016/j.bbadis.2014.04.027. Epub 2014 May 2.
SIRT2 is primarily a cytoplasmic protein deacetylase and is abundantly expressed in metabolically active tissues like adipocytes and brain. However, its role, if any, in regulating insulin signaling in skeletal muscle cells, is not known. We have examined the role of SIRT2 in insulin-mediated glucose disposal in normal and insulin resistant C2C12 skeletal muscle cells in vitro. SIRT2 was over expressed in insulin resistant skeletal muscle cells. Pharmacological inhibition of SIRT2 increased insulin-stimulated glucose uptake and improved phosphorylation of Akt and GSK3β in insulin resistant cells. Knockdown of endogenous SIRT2 and over expression of catalytically-inactive SIRT2 mutant under insulin-resistant condition showed similar amelioration of insulin sensitivity. Our results suggest that down-regulation of SIRT2 improved insulin sensitivity in skeletal muscle cells under insulin-resistant condition. Previously it has been reported that down-regulation of SIRT1 and SIRT3 in C2C12 cells results in impairment of insulin signaling and induces insulin resistance. However, we have observed an altogether different role of SIRT2 in skeletal muscle. This implicates a differential regulation of insulin resistance by sirtuins which otherwise share a conserved catalytic domain. The study significantly directs towards future approaches in targeting inhibition of SIRT2 for therapeutic treatment of insulin resistance which is the major risk factor in Type 2 diabetes.
SIRT2主要是一种细胞质蛋白脱乙酰酶，在脂肪细胞和大脑等代谢活跃的组织中大量表达。然而，其在调节骨骼肌细胞胰岛素信号传导中的作用（如果有）尚不清楚。我们在体外研究了SIRT2在正常和胰岛素抵抗的C2C12骨骼肌细胞中胰岛素介导的葡萄糖处置中的作用。SIRT2在胰岛素抵抗的骨骼肌细胞中过表达。SIRT2的药理学抑制增加了胰岛素刺激的葡萄糖摄取，并改善了胰岛素抵抗细胞中Akt和GSK3β的磷酸化。在胰岛素抵抗条件下，敲低内源性SIRT2并过表达催化失活的SIRT2突变体显示出类似的胰岛素敏感性改善。我们的结果表明，在胰岛素抵抗条件下，SIRT2的下调改善了骨骼肌细胞的胰岛素敏感性。此前有报道称，C2C12细胞中SIRT1和SIRT3的下调会导致胰岛素信号传导受损并诱导胰岛素抵抗。然而，我们观察到SIRT2在骨骼肌中具有完全不同的作用。这意味着沉默调节蛋白对胰岛素抵抗的调节存在差异，而它们原本共享一个保守的催化结构域。该研究为未来通过靶向抑制SIRT2来治疗胰岛素抵抗指明了方向，胰岛素抵抗是2型糖尿病的主要危险因素。
