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

在肥胖相关的胰岛素抵抗中，胰岛通过扩大β细胞团和增加胰岛素分泌量来补偿慢性胰岛素不敏感。在之前的一项研究中，我们发现性别决定区域Y-box(SOX)6是肥胖相关胰岛素抵抗动物中下调的转录因子。我们还发现SOX6直接与胰腺-十二指肠同源盒因子1(PDX1)结合，负向调节葡萄糖刺激的胰岛素分泌。根据PDX1在β细胞的发育和增殖中的作用、胰岛素/胰岛素样生长因子信号通路以及2型糖尿病的发生，我们认为SOX6的表达减弱可能有助于β细胞在肥胖相关的胰岛素抵抗中的适应。为了进一步明确SOX6在肥胖相关胰岛素抵抗中的作用，我们分析了SOX6表达对细胞增殖的影响。SiRNA介导的SOX6基因敲除显著促进了细胞的增殖，而诱导的SOX6表达则抑制了细胞生长。在本文中，我们论证了SOX6抑制细胞增殖的机制。我们目前的研究表明，SOX6与β-连环蛋白结合，并招募组蛋白脱乙酰基酶1来抑制β-连环蛋白诱导的细胞周期蛋白D1启动子活性。SOX6表达减弱导致的细胞增殖与葡萄糖刺激的胰岛素分泌共同作用，可能是胰岛素抵抗的高胰岛素血症和细胞增殖特征的原因。

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.