近日，国际著名学术期刊Diabetologia在线刊登了中科院上海生命科学研究院营养所翟琦巍研究组研究人员的最新研究成果“Downregulation of miR-181aupregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity，”。文章中，研究者研究发现，抑制非编码小RNA miR-181a可以上调去乙酰化酶SIRT1的蛋白水平并改善胰岛素抵抗。
胰岛素抵抗是导致2型糖尿病的关键因素。当胰岛素的靶器官肝脏、骨骼肌、脂肪组织等对于胰岛素的响应变弱时，即发生胰岛素抵抗。缓解胰岛素抵抗是目前防治2型糖尿病的重要途径。翟琦巍研究组的前期研究发现，蛋白质去乙酰化酶SIRT1可以通过在染色质水平抑制PTP1B表达从而改善胰岛素敏感性，并发现葡萄、蓝莓等食物中存在的白藜芦醇可以通过SIRT1改善胰岛素敏感性(Cell Metabolism， 2007； 6(4)：307-19)。目前，SIRT1对胰岛素敏感性的调控作用已被国际同行广泛认可，但SIRT1本身在生理病理条件下是如何被调控，并进一步影响胰岛素敏感性的机理还不太清楚。
翟琦巍研究组博士研究生周犇、李程等研究发现，一种非编码小RNA miR-181a可以靶向Sirt1 mRNA的3’非翻译区，抑制SIRT1翻译，但不影响其转录。在胰岛素抵抗的细胞和动物模型中，miR-181a水平均显著上调，并且糖尿病病人血清中miR-181a水平也显著升高。细胞实验显示，过量表达miR-181a可以降低SIRT1蛋白水平，并诱导胰岛素抵抗；而胰岛素抵抗状态下抑制miR-181a则可以上调SIRT1蛋白水平，并增强胰岛素敏感性(insulin sensitivity)。并且，利用过表达SIRT1的腺病毒、SIRT1基因敲除小鼠等发现，miR-181a对于胰岛素敏感性的调节作用依赖于SIRT1。
进一步研究发现，小鼠体内过表达miR-181a可以导致胰岛素抵抗和糖代谢紊乱，而给高脂饮食诱导的胰岛素抵抗小鼠模型注射锁核酸修饰的miR-181a反义核酸(anti-miR-181a)以抑制miR-181a能够有效地提高SIRT1蛋白水平，并改善机体的葡萄糖耐受性、肝脏和肌肉的胰岛素敏感性，下调血糖水平。
这些研究结果显示，miR-181a有可能成为胰岛素抵抗相关疾病（如2型糖尿病等）的诊断或分型的标志物，以及治疗的药物靶点。
该研究获得了中国科学院、国家自然科学基金委、科技部、上海市科委等机构的资助。（生物谷Bioon.com）
doi:10.1007/s00125-012-2539-8
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Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity
B. Zhou, C. Li, W. Qi, Y. Zhang, F. Zhang, J. X. Wu, Y. N. Hu, D. M. Wu, Y. Liu and T. T. Yan, et al.
Aims/hypothesis Sirtuin-1 (SIRT1) is a potential therapeutic target to combat insulin resistance and type 2 diabetes. This study aims to identify a microRNA (miRNA) targeting SIRT1 to regulate hepatic insulin sensitivity. Methods Luciferase assay combined with mutation and immunoblotting was used to screen and verify the bioinformatically predicted miRNAs. miRNA and mRNA levels were measured by real-time PCR. Insulin signalling was detected by immunoblotting and glycogen synthesis. Involvement of SIRT1 was studied with adenovirus, inhibitor and SIRT1-deficient hepatocytes. The role of miR-181a in vivo was explored with adenovirus and locked nucleic acid antisense oligonucleotides. Results miR-181a targets the 3′ untranslated region (3′UTR) of Sirt1 mRNA through a miR-181a binding site, and downregulates SIRT1 protein abundance at the translational level. miR-181a is increased in insulin-resistant cultured hepatocytes and liver, and in the serum of diabetic patients. Overexpression of miR-181a decreases SIRT1 protein levels and activity, and causes insulin resistance in hepatic cells. Inhibition of miR-181a by antisense oligonucleotides increases SIRT1 protein levels and activity, and improves insulin sensitivity in hepatocytes. Ectopic expression of SIRT1 abrogates the effect of miR-181a on insulin sensitivity, and inhibition of SIRT1 activity or SIRT1 deficiency markedly attenuated the improvement in insulin sensitivity induced by antisense miR-181a. In addition, overexpression of miR-181a by adenovirus impairs hepatic insulin signalling, and intraperitoneal injection of locked nucleic acid antisense oligonucleotides for miR-181a improves glucose homeostasis in diet-induced obesity mice. Conclusions/interpretation miR-181a regulates SIRT1 and improves hepatic insulin sensitivity. Inhibition of miR-181a might be a potential new strategy for treating insulin resistance and type 2 diabetes.
