Department of Biochemistry, National University of Singapore, Singapore.
Cell Signal. 2012 Aug;24(8):1700-5. doi: 10.1016/j.cellsig.2012.04.017. Epub 2012 Apr 27.
Metformin (dimethylbiguanide) is widely used among diabetic patients to lower the blood sugar level. Although several mechanisms have been proposed, its mode of action in enhancing peripheral glucose uptake and inhibiting hepatic glucose production is not fully understood. Thioredoxin-interacting protein (Txnip) is known to play important roles in glucose metabolism by inhibiting cellular glucose uptake and metabolism and promoting hepatic gluconeogenesis. The expression of the gene encoding Txnip is regulated in a glucose dependent manner via the Mondo:MLX transcription factor complex. In the present study, we report that Txnip mRNA as well as protein expression in cultured cells is markedly reduced upon metformin administration. The binding of Mondo:MLX to the Txnip gene promoter is reduced, suggesting that the transcription of the Txnip gene is repressed by metformin. Moreover, we show that the effect of metformin on Txnip gene transcription is due to the inhibition of mitochondrial complex I and increased glycolysis, and is partially mediated by the AMP activated kinase (AMPK). These observations prompt us to propose that the novel action of metformin on the Txnip gene expression may contribute to its therapeutic effects in the treatment of type II diabetes.
二甲双胍（二甲双胍）广泛用于糖尿病患者降低血糖水平。尽管已经提出了几种机制，但它增强外周葡萄糖摄取和抑制肝葡萄糖生成的作用方式仍不完全清楚。硫氧还蛋白相互作用蛋白（Txnip）通过抑制细胞葡萄糖摄取和代谢并促进肝糖异生，在葡萄糖代谢中发挥重要作用。Txnip 基因的表达通过 Mondo：MLX 转录因子复合物以葡萄糖依赖性方式调节。在本研究中，我们报告在培养细胞中，二甲双胍给药后 Txnip mRNA 以及蛋白表达明显降低。Mondo：MLX 与 Txnip 基因启动子的结合减少，表明二甲双胍抑制 Txnip 基因的转录。此外，我们表明，二甲双胍对 Txnip 基因转录的作用是由于线粒体复合物 I 的抑制和糖酵解的增加，并且部分由 AMP 激活的激酶（AMPK）介导。这些观察结果促使我们提出，二甲双胍对 Txnip 基因表达的新作用可能有助于其在治疗 2 型糖尿病中的治疗效果。
