目的: 探讨2型糖尿病家族史与胰岛素抵抗间的关系,采用信息学方法对从基因表达库（Gene Expression Omnibus, GEO）获取的具有2型糖尿病家族史但自身血糖正常的研究对象进行相关基因表达谱分析,识别2型糖尿病疾病风险通路,并对关键基因产物进行功能分析。方法: 对美国国立生物技术信息中心（National Center for Biotechnology Information,NCBI）的综合性基因表达与杂交阵列数据库中26名有2型糖尿病家族史但自身血糖正常的研究对象和15名无糖尿病家族史的血糖正常的人群进行数据分析（GSE25462）,运用Bergman微小模型技术结合静脉糖耐量试验评估胰岛素敏感指数,并对骨骼肌细胞基因表达谱芯片采用生物信息学方法（基因功能富集分析方法、风险通路识别方法等）进行数据分析,进而在分子层面进行2型糖尿病致病机制研究。结果: 有2型糖尿病家族史但自身血糖正常的研究对象其胰岛素敏感性下降41%（P<0.05）。通过差异表达分析,共发现202个基因表达在家族史阳性组与家族史阴性组间的差异有统计学意义,同时鉴定了富集差异显著的5条通路,分别是多能干细胞的造血功能、万能干细胞的造血功能、JAK1/3在c-细胞活素信号通路的作用、TOB在T细胞信号通路中的抗增殖作用、B细胞的发育。结论: 有2型糖尿病家族史但自身血糖正常的研究对象存在胰岛素抵抗,2型糖尿病的致病机制与造血干细胞功能及免疫状态有重要联系。
Objective: To investigate the relationship between family history of type 2 diabetes (T2D) and insulin resistance. Bioinformatic approach was used to identify the risk pathways in subjects with a family history (FH) of T2D, and then functions of key driver genes were analyzed using gene expression profiles from Gene Expression Omnibus (GEO). Methods: Gene expression data set was retrieved using GSE 25462 at NCBI GEO. The data set contained 26 normoglycemic individuals with 1 or both parents having T2D (FH+) and 15 normoglycemic individuals with no one having diabetes in first-degree relatives(FH-). Insulin sensitivity was assessed by the Bergman minimal model from intravenous glucose tolerance test. Gene expression in quadriceps muscle biopsies was analyzed to identify the differentially expressed genes associated with insulin resistance. Gene set enrichment analysis and identification of risk pathways were used to explore the pathogenesis of T2D at molecular level. Results: Compared with FH- subjects, FH+ subjects were insulin resistant as demonstrated by a 41% reduction in insulin sensitivity(P<0.05). A total of 202 genes showed differential expression in our analysis. Five biological pathways of gene set enrichment in FH+ were identified, including hematopoiesis from multipotent stem cells, hematopoiesis from pluripotent stem cells, role of JAK1 and JAK3 in c-cytokine signaling, antiproliferative role of TOB in T cell signaling, and B cell development. Conclusions: Family history of T2D in normal subjects is associated with insulin resistance. Significantly enriched pathways identified by gene set enrichment analysis reveale that pathogenesis of T2D is associated with function of multipotent stem cells and immune status.
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