Smith U, Gogg S, Johansson A, Olausson T, Rotter V, Svalstedt B
The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Goteborg University, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden.
FASEB J. 2001 Jan;15(1):215-220. doi: 10.1096/fj.00-0020com.
Thiazolidinediones (TZD) improve insulin sensitivity in human as well as in different animal models of insulin resistance and Type 2 diabetes. However, no clear link to the insulin signaling events has been identified. Using differentiated 3T3-L1 adipocytes, we found that TZD rapidly and markedly increased IRS-2 gene expression. This effect was specific for PPARgamma agonists and was not seen with PPARalpha agonists. It was rapidly induced (within 4 h) and maintained throughout the observation period of 48 h. It was also concentration dependent (EC50 approximately 50 nM) and not inhibited by cycloheximide, suggesting a direct effect on the IRS-2 promoter. There was no evidence that TZD altered IRS-2 mRNA stability, supporting that the increased mRNA levels were due to an increased gene transcription. IRS-2 protein expression was increased approximately 30% after 48 h and approximately 50% after 96 h. No effects of TZD were seen on IRS-1, PKB/Akt, or GLUT4 gene expression. TZD also increased IRS-2 mRNA levels in cultured human adipose tissue. These data show the first direct link between TZD and a critical molecule in insulin's signaling cascade in both 3T3-L1 and human adipocytes, and indicate a novel mode of action of these compounds.
噻唑烷二酮类药物（TZD）可改善人体以及不同胰岛素抵抗和2型糖尿病动物模型中的胰岛素敏感性。然而，尚未确定其与胰岛素信号转导事件之间的明确联系。利用分化的3T3-L1脂肪细胞，我们发现TZD能迅速且显著地增加IRS-2基因的表达。这种效应是PPARγ激动剂所特有的，PPARα激动剂则不会产生此效应。它在4小时内迅速诱导产生，并在48小时的观察期内持续存在。它还具有浓度依赖性（半数有效浓度约为50 nM），且不受放线菌酮抑制，这表明其对IRS-2启动子有直接作用。没有证据表明TZD会改变IRS-2 mRNA的稳定性，这支持了mRNA水平的升高是由于基因转录增加所致。48小时后IRS-2蛋白表达增加约30%，96小时后增加约50%。未观察到TZD对IRS-1、蛋白激酶B/蛋白激酶B（PKB/Akt）或葡萄糖转运蛋白4（GLUT4）基因表达有影响。TZD还可增加培养的人体脂肪组织中IRS-2 mRNA的水平。这些数据表明，在3T3-L1和人体脂肪细胞中，TZD与胰岛素信号级联反应中的一个关键分子之间首次建立了直接联系，并揭示了这些化合物的一种新作用模式。
