权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Transcriptional network of β-cell compensation in the face of obesity induced insulin resistance

面对肥胖引起的胰岛素抵抗，β细胞补偿的转录网络

基本信息

批准号：
18390095
负责人：
SAKAI Juro
金额：
$ 10.77万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390095/
关键词：
pancreatic β-cell Wnt signal diabetes obesity β-cell adaptation

项目摘要

In obesity-related insulin resistance, pancreatic islets compensate for chronic insulin insensitivity by expanding β-cell mass and increasing insulin secretory capacity. In a previous study, we identified sex-determining region Y-box (SOX) 6 as a down-regulated transcription factor in obesity-related insulin resistant animals. We also showed that SOX6 directly binds with pancreatic-duodenal homeobox factor 1 (PDX1) and negatively regulates glucose-stimulated insulin secretion. Based on the role of PDX1 in the development and proliferation of β-cells, insulin/insulin-like growth factor signaling pathways and the onset of type 2 diabetes, we suggested that the attenuated expression of SOX6 may contribute to β-cell adaptation in obesity-related insulin resistance. To further define the role of SOX6 in obesity-related insulin resistance, we analyzed the effects of SOX6 expression on cell proliferation. SiRNA mediated knockdown of SOX6 significantly stimulated cell proliferation, whereas induced SOX6 expression resulted in the inhibition of cell growth. In the present paper, we demonstrate the mechanism by which SOX6 suppresses cell proliferation. Our current studies reveal that SOX6 binds with β-catenin and recruits histone deacetylase 1 for suppression of cyclin D1 promoter activities induced by β-catenin. Together with the stimulation of glucose-stimulated insulin secretion, the induced cell proliferation by attenuation of SOX6 expression may account for the hyperinsulinemia and hyperplasia characteristic of insulin resistance.

在肥胖相关的胰岛素抵抗中，胰岛通过扩大β细胞群和增加胰岛素分泌能力来补偿慢性胰岛素不敏感性。在以前的研究中，我们确定性别决定区Y盒（SOX）6作为一个下调的肥胖相关的胰岛素抵抗动物的转录因子。我们还发现，SOX 6直接与胰腺十二指肠同源框因子1（PDX 1）结合，并负调节葡萄糖刺激的胰岛素分泌。基于PDX 1在β细胞发育和增殖、胰岛素/胰岛素样生长因子信号通路和2型糖尿病发病中的作用，我们认为SOX 6的表达减弱可能有助于肥胖相关胰岛素抵抗中的β细胞适应。为了进一步明确SOX 6在肥胖相关胰岛素抵抗中的作用，我们分析了SOX 6表达对细胞增殖的影响。siRNA介导的SOX 6敲低显著刺激细胞增殖，而诱导的SOX 6表达导致细胞生长抑制。在本文中，我们展示了SOX 6抑制细胞增殖的机制。我们目前的研究表明，SOX 6与β-catenin结合，并招募组蛋白去乙酰化酶1抑制β-catenin诱导的cyclin D1启动子活性。与葡萄糖刺激的胰岛素分泌的刺激一起，通过减弱S 0X 6表达诱导的细胞增殖可以解释高胰岛素血症和胰岛素抵抗的增生特征。