细胞因子诱导的SH2结构包含蛋白（CISH）调控胰岛素敏感性和糖代谢稳态的作用及机制研究

Diabetes, and particularly type 2 diabetes, is in-creasing at an epidemic scale worldwide. 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 differential expressed genes (DEGs) under leucine deprivation may be involved in regulating insulin sensitivity and glucose metabolism. Then a high-throughput gene microarray, was used to screen the DEGs in the liver of mice under leucine deprivation. The cytokine-inducible SH2-containing gene, CISH, which was downregulated in the liver of leucine-deprived mice, was identified by gene chip analysis. Our preliminary results demonstrated a strong relationship of insulin resistance and CISH levels in vitro. Overexpression of CISH in Hepa1-6 cells and primary cultured mice hepatocytes inhibits insulin signaling. The objectives of this research are to investigate 1) the role of CISH 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 fasting on CISH expression and the cellular and molecular mechanisms. We will explore these in various cell models, wild type and insulin-resistant db/db mice. This work will reveal the novel function of CISH in regulating insulin sensitivity and glucose metabolism, and lead to new strategies for prevention and treatment of type 2 diabetes.

目前2型糖尿病在全球范围内高度流行，其核心病理特征是胰岛素抵抗。实验室前期研究发现，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，亮氨酸缺乏时差异表达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，申请人筛选到细胞因子诱导的SH2结构包含蛋白（cytokine-inducible SH2-containing, CISH）显著下调。前期研究表明，CISH表达水平与胰岛素敏感性密切相关；肝细胞系Hepa1-6和小鼠肝原代细胞中过表达CISH能抑制胰岛素信号。本项目将利用细胞模型、胰岛素抵抗db/db小鼠和尾静脉注射腺病毒，在多个层次深入研究CISH对胰岛素敏感性及糖代谢的调控作用及机制，并探讨各种营养条件对CISH表达的影响。这将增加对CISH功能的认识，为研究2型糖尿病及代谢疾病的发病机制提供重要理论依据。

目前2型糖尿病在全球范围内高度流行，其核心病理特征是胰岛素抵抗。我们从基因芯片结果中筛选到细胞因子诱导的SH2结构包含蛋白（cytokine-inducible SH2-containing, CISH）显著下调。提示Cish对糖脂代谢具有重要作用。本项目利用细胞模型、胰岛素抵抗db/db小鼠和尾静脉注射腺病毒，在多个层次深入探讨了CISH对胰岛素敏感性及糖代谢的调控作用及机制。结果发现，细胞以及动物水平明确Cish具有抑制肝脏糖异生的作用，但对肝脏胰岛素敏感性影响不明显。进一步发现，Cish主要通过抑制Creb磷酸化，从而抑制糖异生关键因子Pepck和G6pase的表达；并在动物水平验证了Cish影响糖异生依赖于对Creb的调控；最后利用糖尿病模型小鼠db/db小鼠验证了对Cish对糖代谢的调控。该研究将丰富增人们对CISH功能的认识，为解析2型糖尿病及代谢疾病的发病机制提供重要理论依据。