Zhang Xiongfei, Yong Wei, Lv Jinghuan, Zhu Yunxia, Zhang Jingjing, Chen Fang, Zhang Rihua, Yang Tao, Sun Yujie, Han Xiao
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 210029, People's Republic of China.
Endocrinology. 2009 Sep;150(9):4065-73. doi: 10.1210/en.2009-0343. Epub 2009 May 14.
Forkhead Box O1 (FoxO1) is a key transcription regulator of insulin/IGF-I signaling pathway, and its activity can be increased by dexamethasone (DEX) in several cell types. However, the role of FoxO1 in DEX-induced pancreatic beta-cell dysfunction has not been fully understood. Therefore, in this study, we investigated whether FoxO1 could mediate DEX-induced beta-cell dysfunction and the possible underlying mechanisms in pancreatic beta-cell line RINm5F cells and primary rat islet. We found that DEX markedly increased FoxO1 mRNA and protein expression and decreased FoxO1 phosphorylation through the Akt pathway, which resulted in an increase in active FoxO1 in RINm5F cells and isolated rat islets. Activated FoxO1 subsequently inhibited pancreatic duodenal homeobox-1 expression and induced nuclear exclusion of pancreatic duodenal homeobox-1. Knockdown of FoxO1 by RNA interference restored the expression of pancreatic duodenal homeobox-1 and prevented DEX-induced dysfunction of glucose-stimulated insulin secretion in rat islets. Together, the results of present study demonstrate that FoxO1 is integrally involved in DEX-induced inhibition of pancreatic duodenal homeobox-1 and glucose-stimulated insulin secretion dysfunction in pancreatic islet beta-cells. Inhibition of FoxO1 can effectively protect beta-cells against DEX-induced dysfunction.
叉头框蛋白O1（FoxO1）是胰岛素/胰岛素样生长因子-I信号通路的关键转录调节因子，在多种细胞类型中，其活性可被地塞米松（DEX）增强。然而，FoxO1在DEX诱导的胰腺β细胞功能障碍中的作用尚未完全明确。因此，在本研究中，我们探究了FoxO1是否能介导DEX诱导的β细胞功能障碍以及在胰腺β细胞系RINm5F细胞和原代大鼠胰岛中可能的潜在机制。我们发现，DEX通过Akt途径显著增加FoxO1的mRNA和蛋白表达，并降低FoxO1的磷酸化水平，这导致RINm5F细胞和分离的大鼠胰岛中活性FoxO1增加。激活的FoxO1随后抑制胰腺十二指肠同源盒蛋白-1的表达，并诱导胰腺十二指肠同源盒蛋白-1的核排除。通过RNA干扰敲低FoxO1可恢复胰腺十二指肠同源盒蛋白-1的表达，并预防DEX诱导的大鼠胰岛葡萄糖刺激的胰岛素分泌功能障碍。总之，本研究结果表明，FoxO1整体参与了DEX诱导的胰腺胰岛β细胞中胰腺十二指肠同源盒蛋白-1的抑制和葡萄糖刺激的胰岛素分泌功能障碍。抑制FoxO1可有效保护β细胞免受DEX诱导的功能障碍。
