Department of Endocrinology & Metabolism, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
Diabetes Res Clin Pract. 2011 Jan;91(1):94-100. doi: 10.1016/j.diabres.2010.11.006. Epub 2010 Dec 13.
MicroRNAs are small noncoding RNAs that have been highly conserved during evolution and have been implicated to play an important role in many diseases, including diabetes. Several reports indicated the function of miRNAs in insulin production. However, the mechanisms by which miRNAs regulate this process remain poorly understood. Here we found that the expression of miR-15a was up-regulated in the presence of high glucose for 1h, whereas prolonged periods of high glucose exposure resulted in depressed expression of miR-15a, and the change in expression levels of miR-15a coincided with insulin biosynthesis. Moreover, ectopic expression of miR-15a promoted insulin biosynthesis in MIN6 cells, whereas its repression was sufficient to inhibit insulin biosynthesis. Further, we verified that miR-15a directly targeted and inhibited uncoupling protein-2 (UCP-2) gene expression. miR-15a mimics inhibited UCP-2 3'UTR luciferase reporter activity. Western blot analysis showed that miR-15a inhibited endogenous UCP-2 protein levels, and resulted in the increase in oxygen consumption and reduced ATP generation. This study suggests miR-15a is a mediator of β cell function and insulin biosynthesis, thus offering a new target for the development of preventive or therapeutic agents against diabetes.
miRNAs 是在进化过程中高度保守的小非编码 RNA，已被证实在许多疾病中发挥着重要作用，包括糖尿病。有几项报告表明 miRNAs 在胰岛素生成中具有功能。然而，miRNAs 调节这一过程的机制仍知之甚少。在这里，我们发现 miR-15a 的表达在高葡萄糖存在的情况下 1 小时被上调，而长时间暴露于高葡萄糖会导致 miR-15a 的表达下调，其表达水平的变化与胰岛素生物合成相吻合。此外，miR-15a 的异位表达促进了 MIN6 细胞中的胰岛素生物合成，而其抑制足以抑制胰岛素生物合成。此外，我们验证了 miR-15a 可以直接靶向并抑制解偶联蛋白 2（UCP-2）基因的表达。miR-15a 模拟物抑制 UCP-2 3'UTR 荧光素酶报告基因活性。Western blot 分析表明 miR-15a 抑制内源性 UCP-2 蛋白水平，导致耗氧量增加和 ATP 生成减少。本研究表明 miR-15a 是β细胞功能和胰岛素生物合成的介导物，为开发针对糖尿病的预防或治疗药物提供了新的靶点。
