促葡萄糖摄取细胞模型的构建及应用

The Development and Application of the Glucose Uptake Stimulating Cell Model

植物是发现先导药物的天然宝库,目前抗糖尿病药物的一个重要来源是植物。从植物中发现抗糖尿病药物的关键在于抗糖尿病药物筛选模型的建立。为获得一个更稳定、筛选结果更可靠的抗糖尿病药物筛选模型,本文对基于脂肪细胞摄取葡萄糖的药物筛选模型进行优化。文献报道的该类模型,只将胰岛素作为阳性对照,而本文同时将胰岛素和罗格列酮作为阳性对照,使模型更加稳定、筛选结果更加可靠。此外,本文还以胰岛素信号通路抑制剂Akt1/2抑制剂作为另一阳性对照,使之还可应用于胰岛素信号通路抑制剂的筛选,扩展了该模型的用途。最后,对16个植物来源的天然产物在该模型进行筛选,其结果稳定,并发现3个活性化合物。进一步对活性化合物X15、X16进行浓度梯度实验,结果表明,两者的活性都具有明显的浓度依赖性。X15和X16的细胞增敏活性的研究为后续进一步研究其分子作用机理奠定基础,并为后期可能的药物开发提供分子候选。

The plants are great resources for digging leading compounds, and many current anti-diabetic drugs are derived from plants. The key to discover compounds with anti-diabetic activities from plants relies on the application of anti-diabetic drug screening models. In order to establish a more stable and reliable anti-diabetic drug screening model, we optimized the screening model based on the glucose uptake of adipocytes. In the previous models, insulin was used as the only positive control, while in our model both insulin and rosiglitazone were used as positive con- trols, which made the model more stable and reliable. Furthermore, we expanded the application of the model to screen the insulin signaling pathway inhibitors, and Aktl/2 inhibitor which was an inhibitor of insulin signaling pathway was used as positive control. In the end, we screened 16 compounds isolated from plants using this model and identified three active compounds with glucose uptake stimulating activities. We also performed the dose-re-sponse experiments of compound X15 and X16. Both showed significant dose-responses. These activities were first reported at the cell level, providing fundamental data for their mechanisms study of the activities and for the potential development of the drugs in future.