BTG1调控胰岛素敏感性和糖代谢稳态的作用及机制研究

In recent years, there has been an increase in the reported global prevalence of diabetes, 90% of which is type 2 diabetes (T2D).Insulin resistance and glucose intolerance are two symptoms characteristic of diabetes. Our previous study demonstrated that leucine deprivation improves insulin sensitivity and glucose tolerance （Cell Metabolism.2007,5:103-114; Diabetes. 2011, 60: 746-756）.We propose that the genes changed under leucine deprivation may be involved in regulating insulin sensitivity and glucose metabolism. Then a high-throughput screening technique, gene chip, was used to screen the differentially expressed genes in the liver of mice under leucine deprivation. The B-Cell Translocation Gene 1, BTG1, which was upregulated in the liver of leucin-deprived mice, was identified by gene chip analysis. Our preliminary results demonstrated a strong relationship of insulin resistance and BTG1 levels in vitro and in vivo. Overexpression of BTG1 in HepG2 cells and primary cultured mice hepatocytes improves insulin signaling. Besides, insulin sensitivity and glucose tolerance is improved in mice injected with adenovirus that overexpress BTG1 expression. The objectives of this research are to investigate 1) the role of BTG1 in regulating insulin sensitivity and glucose metabolism and the underlying mechanisms. 2) the effects of nutrition condition such as amino acids, high fat, high fructose or high cholesterol on BTG1 expression and the cellular and molecular mechanisms. We will explore these in various cell models, insulin-resistant db/db mice and BTG1 transgenic mice. This work will reveal the novel function of BTG1 in regulating insulin sensitivity and glucose metabolism, and lead to new strategies for prevention and treatment of diabetes.

胰岛素抵抗及糖代谢稳态失衡是Ⅱ型糖尿病及相关代谢疾病的重要发病机制之一。申请人前期研究发现（Diabetes. 2011, 60: 746-756），短期亮氨酸缺乏能提高小鼠整体和各脏器的胰岛素敏感性，改善糖代谢；由此推测，亮氨酸缺乏时发生变化的基因可能具有调控胰岛素敏感性和糖代谢稳态的功能。利用基因芯片对亮氨酸缺乏时肝脏基因表达谱进行分析研究，申请人筛选到B细胞易位基因（B-Cell Translocation Gene 1,BTG1）。前期研究表明，BTG1表达水平与胰岛素抵抗密切相关；利用腺病毒在小鼠肝脏中过表达BTG1能增强胰岛素敏感性。本项目将利用细胞模型、胰岛素抵抗db/db小鼠和BTG1转基因小鼠，在多个层次深入研究BTG1对胰岛素敏感性及糖代谢稳态的调控作用及机制，并探讨各种营养条件对BTG1表达的影响。这将增加对BTG1功能的认识，为营养学干预治疗代谢疾病增加新的内容。

胰岛素抵抗及糖代谢稳态失衡是Ⅱ型糖尿病及相关代谢疾病的重要发病机制之一。申请人前期研究发现（Diabetes. 2011, 60: 746-756），短期亮氨酸缺乏能提高小鼠整体和各脏器的胰岛素敏感性，改善糖代谢；由此推测，亮氨酸缺乏时发生变化的基因可能具有调控胰岛素敏感性和糖代谢稳态的功能。利用基因芯片对亮氨酸缺乏时肝脏基因表达谱进行分析研究，申请人筛选到B细胞易位基因（B-Cell Translocation Gene 1,BTG1）。本项目利用细胞模型、胰岛素抵抗db/db小鼠和BTG1转基因小鼠，在多个层次深入研究了BTG1对胰岛素敏感性及糖代谢稳态的调控作用及机制，并探讨了各种营养条件对BTG1表达的影响。研究发现，BTG1表达水平与胰岛素抵抗密切相关；细胞水平过表达BTG1能激活胰岛素信号通路，敲除BTG1将抑制胰岛素信号通路；利用腺病毒在野生型或db/db小鼠肝脏中过表达BTG1能增强胰岛素敏感性；利用腺病毒减少野生型小鼠肝脏中BTG1表达会降低全身胰岛素敏感性。BTG1转基因小鼠能够抵抗高糖饮食诱导的胰岛素抵抗。进一步研究发现BTG1通过调节c-Jun的表达来影响机体的胰岛素敏感性。亮氨酸缺乏和高糖饮食通过Mammalian Target of Rapamycin（mTOR）/ Ribosomal S6 Kinase 1（S6K1）信号通路影响BTG1的表达。此外，我们还发现BTG1通过抑制activating transcription factor 4（ATF4）和stearoyl-CoA desaturase 1 （SCD1）调节肝脏脂质代谢。这些工作将增加对BTG1功能的认识，为营养学干预治疗代谢疾病增加新的内容。