Hepatic gene expression is known to differ between healthy and type 2 diabetes conditions. Identifying these variations will provide better knowledge to the development of gene-targeted therapies. The aim of this study is to assess diet-induced hepatic gene expression of susceptible versus resistant CC lines to T2D development. Next-generation RNA-sequencing was performed for 84 livers of diabetic and non-diabetic mice of 41 different CC lines (both sexes) following 12 weeks on high-fat diet (42% fat). Data analysis revealed significant variations of hepatic gene expression in diabetic versus non-diabetic mice with significant sex effect, where 601 genes were differentially expressed (DE) in overall population (males and females), 718 genes in female mice, and 599 genes in male mice. Top prioritized DE candidate genes were Lepr, Ins2, Mb, Ckm, Mrap2, and Ckmt2 for the overall population; for females-only group were Hdc, Serpina12, Socs1, Socs2, and Mb, while for males-only group were Serpine1, Mb, Ren1, Slc4a1, and Atp2a1. Data analysis for sex differences revealed 193 DE genes in health (Top: Lepr, Cav1, Socs2, Abcg2, and Col5a3), and 389 genes DE between diabetic females versus males (Top: Lepr, Clps, Ins2, Cav1, and Mrap2). Furthermore, integrating gene expression results with previously published QTL, we identified significant variants mapped at chromosomes at positions 36-49 Mb, 62-71 Mb, and 79-99 Mb, on chromosomes 9, 11, and 12, respectively. Our findings emphasize the complexity of T2D development and that significantly controlled by host complex genetic factors. As well, we demonstrate the significant sex differences between males and females during health and increasing to extent levels during disease/diabetes. Altogether, opening the venue for further studies targets the discovery of effective sex-specific and personalized preventions and therapies.

中文翻译：

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肝基因表达变化对高脂饮食诱导的糖耐量降低的反应，使用协作交叉小鼠群体中的RNAseq分析。

已知健康和2型糖尿病患者之间的肝基因表达有所不同。识别这些变异将为基因靶向疗法的发展提供更好的知识。这项研究的目的是评估饮食诱导的肝基因表达的易感性与抗性CC线对T2D的发展。在高脂饮食（42％脂肪）下服用12周后，对41种不同CC系（性别）的糖尿病和非糖尿病小鼠的84只肝脏进行了下一代RNA测序。数据分析显示，在糖尿病小鼠和非糖尿病小鼠中，肝基因表达存在显着差异，并具有明显的性别效应，其中总体种群（雄性和雌性）中的601个基因差异表达（DE），雌性小鼠中的718个基因，雄性中的599个基因老鼠。最优先的DE候选基因是Lepr，Ins2，Mb，Ckm，总人口为Mrap2和Ckmt2；仅女性组为Hdc，Serpina12，Socs1，Socs2和Mb，而仅男性组为Serpine1，Mb，Ren1，Slc4a1和Atp2a1。性别差异的数据分析显示，健康的193个DE基因（上图：Lepr，Cav1，Socs2，Abcg2和Col5a3）以及糖尿病女性与男性之间的389个基因DE（上图：Lepr，Clps，Ins2，Cav1和Mrap2）。此外，将基因表达结果与以前发表的QTL整合在一起，我们确定了分别定位在9、11和12号染色体上36-49 Mb，62-71 Mb和79-99 Mb染色体处的显着变异。我们的发现强调了T2D开发的复杂性，并由宿主复杂的遗传因素显着控制。还有 我们证明了健康期间男性和女性之间存在明显的性别差异，并且在疾病/糖尿病期间增加到一定程度。总而言之，为进一步研究开放场所旨在发现有效的针对性别的个性化预防和治疗方法。