Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon 305-806, Republic of Korea.
Int J Biochem Cell Biol. 2013 Aug;45(8):1538-45. doi: 10.1016/j.biocel.2013.05.004. Epub 2013 May 13.
The small heterodimer partner (SHP; NR0B2) regulates the transcription of a variety of target genes and controls a variety of physiological functions in various tissues. However, the role of SHP in beta cell has not been fully determined yet. We used SHP knockout (SHP KO) mice to investigate the role of SHP in multiple low-dose streptozotocin (MLDS)-induced diabetes. Blood glucose and insulin levels were measured until 20 days, and intraperitoneal glucose tolerance and glucose-stimulated insulin secretion tests were performed. The expression of apoptotic genes and beta cell markers were detected by quantitative realtime-polymerase chain reaction, immunostaining and western blot analysis. SHP KO mice showed significantly lower blood glucose, higher insulin levels, and enhanced glucose tolerance compared with wild type (WT) mice after MLDS treatment. Moreover, beta cell mass and pancreatic insulin content were remarkably increased in SHP KO mice. In the response to glucose stimulation, islets of SHP KO showed increased insulin secretion via up-regulation of beta cell enriched transcription factors compared to WT mice after streptozotocin (STZ) treatment. In quantification for beta cell apoptosis at day 1 post STZ treatment, the SHP KO mice showed significantly increased anti-apoptotic gene expression and decreased release of apoptotic markers cytochrome c, smac/diablo, and only a few apoptotic beta cells were found in SHP KO pancreas through inactivation of caspase-3, compared to those of WT. These data demonstrate that SHP deficiency ameliorates hyperglycemia and preserves islet function by inhibiting apoptosis of pancreatic beta cells and up-regulating of their enriched transcriptional factors.
小异二聚体伴侣（SHP；NR0B2）调节多种靶基因的转录，并控制各种组织中的多种生理功能。然而，SHP 在β细胞中的作用尚未完全确定。我们使用 SHP 敲除（SHP KO）小鼠来研究 SHP 在多种低剂量链脲佐菌素（MLDS）诱导的糖尿病中的作用。测量血糖和胰岛素水平直至 20 天，并进行腹腔内葡萄糖耐量和葡萄糖刺激胰岛素分泌试验。通过定量实时聚合酶链反应、免疫染色和 Western blot 分析检测凋亡基因和β细胞标志物的表达。与野生型（WT）小鼠相比，SHP KO 小鼠在 MLDS 处理后表现出明显更低的血糖、更高的胰岛素水平和增强的葡萄糖耐量。此外，β细胞质量和胰腺胰岛素含量在 SHP KO 小鼠中显著增加。在对葡萄糖刺激的反应中，与 WT 小鼠相比，SHP KO 胰岛通过上调β细胞富集转录因子显示出增加的胰岛素分泌。在 STZ 处理后第 1 天β细胞凋亡的定量分析中，与 WT 相比，SHP KO 小鼠表现出明显增加的抗凋亡基因表达和减少的凋亡标志物细胞色素 c、smac/diablo 的释放，并且仅在 SHP KO 胰腺中发现少数凋亡β细胞，这是通过 caspase-3 的失活实现的。这些数据表明，SHP 缺乏通过抑制胰腺β细胞的凋亡和上调其富集的转录因子来改善高血糖和保护胰岛功能。
