State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 100050, China.
Eur J Pharmacol. 2012 Nov 5;694(1-3):120-6. doi: 10.1016/j.ejphar.2012.07.052. Epub 2012 Aug 29.
Berberine is one of the main alkaloids of Rhizoma coptidis, proven to have anti-diabetic potentials through activation of AMP activated protein kinase (AMPK) in liver and muscle. However, the role of berberine on the insulin gene is unknown. Therefore, the effect of berberine on insulin gene transcription was investigated in the present study. Reporter gene assays were used in the mouse β-cell line NIT-1 to test the effect of berberine on the promoter of mouse insulin gene Ins2. The mRNA and protein levels of insulin were also detected. Diet induced glucose intolerant mice were used to explore the effect of berberine on blood glucose homeostasis and insulin resistance in vivo. The insulin content in islet was semi-quantified by an image analysis software in the immunohistochemistry sections. The results revealed that berberine caused a reversible concentration-dependent inhibition of insulin gene transcription in NIT-1 cells which showed a significant difference from the long term used AMPK activator metformin. Such inhibition on insulin promoter resulted in the reduction of mRNA and protein of insulin. Furthermore, the inhibition of insulin promoter was totally abolished by AMPK inhibitor Compound C. Berberine significantly improved insulin resistance and glucose intolerance of mice. Likewise, insulin content in islets of berberine treated mice was also decreased. Thus, the insulin gene represents a novel target of AMPK that may contribute to the action of berberine in type 2 diabetes mellitus.
小檗碱是黄连根茎中的主要生物碱之一，已被证明通过激活肝脏和肌肉中的 AMP 激活蛋白激酶（AMPK）具有抗糖尿病潜力。然而，小檗碱对胰岛素基因的作用尚不清楚。因此，本研究探讨了小檗碱对胰岛素基因转录的影响。本研究采用报告基因检测方法，在小鼠β细胞系 NIT-1 中检测小檗碱对小鼠胰岛素基因 Ins2 启动子的影响。还检测了胰岛素的 mRNA 和蛋白水平。利用饮食诱导的葡萄糖耐量异常小鼠模型，探讨了小檗碱在体内对血糖稳态和胰岛素抵抗的影响。通过免疫组织化学切片中的图像分析软件半定量测定胰岛中的胰岛素含量。结果表明，小檗碱可引起 NIT-1 细胞中胰岛素基因转录的可逆浓度依赖性抑制，与长期使用的 AMPK 激活剂二甲双胍相比，差异具有统计学意义。这种对胰岛素启动子的抑制导致胰岛素的 mRNA 和蛋白减少。此外，AMPK 抑制剂 Compound C 可完全消除对胰岛素启动子的抑制。小檗碱可显著改善小鼠的胰岛素抵抗和葡萄糖耐量异常。同样，小檗碱处理小鼠的胰岛中胰岛素含量也减少。因此，胰岛素基因代表了 AMPK 的一个新靶点，可能有助于小檗碱在 2 型糖尿病中的作用。
