Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse.
Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse.
复制标题
DOI：
10.1016/j.jdiacomp.2017.03.002
复制
发表时间：
2017-05
影响因子：
3
通讯作者：
Mauvais-Jarvis F
中科院分区：
文献类型：
--
作者：
Xu W;Niu T;Xu B;Navarro G;Schipma MJ;Mauvais-Jarvis F
睾酮作用是通过雄激素受体（AR）介导的。我们已经报道了在β细胞中缺乏AR选择性（βARKO−/y）的雄性小鼠出现葡萄糖刺激的胰岛素分泌（GSIS）减少，产生葡萄糖耐受不良。我们发现，睾酮对β细胞中AR的作用通过cAMP依赖性蛋白激酶-A途径放大了GLP-1对其受体的促胰岛素作用。为了研究β细胞中AR依赖的基因网络，我们在雄性βARKO−/y和对照小鼠的胰岛中进行了高通量全转录组测序（RNA-Seq）。我们鉴定了214个差异表达基因（DEG）（158个上调和56个下调），错误发现率（FDR）< 0.05，倍数变化（FC）> 2。我们对单个转录本的分析揭示了参与细胞炎症/应激和胰岛素分泌的β细胞基因的改变。基于FDR < 0.05的312个DEG，通路分析揭示了23个显著富集的通路，包括精氨酸-细胞因子受体相互作用、Jak-STAT信号传导、胰岛素信号传导、MAPK信号传导、2型糖尿病（T2 D）和胰腺分泌。基因本体分析证实了个体DEG和途径分析的结果，显示了丰富的生物过程，包括炎症、离子转运、胞吐和胰岛素分泌。AR缺陷型胰岛表现出参与炎症和胰岛素分泌的基因表达改变，证明雄激素作用在男性β细胞健康中的重要性，并对男性T2 D发展产生影响。
Testosterone action is mediated via the androgen receptor (AR). We have reported that male mice lacking AR selectively in β-cells (βARKO−/y) develop decreased glucose-stimulated insulin secretion (GSIS), producing glucose intolerance. We showed that testosterone action on AR in β-cells amplifies the insulinotropic action of GLP-1 on its receptor via a cAMP- dependent protein kinase-A pathway. To investigate AR-dependent gene networks in β-cells, we performed a high throughput whole transcriptome sequencing (RNA-Seq) in islets from male βARKO−/y and control mice. We identified 214 differentially expressed genes (DEGs) (158 up- and 56 down-regulated) with a false discovery rate (FDR) < 0.05 and a fold change (FC) > 2. Our analysis of individual transcripts revealed alterations in β-cell genes involved in cellular inflammation/stress and insulin secretion. Based on 312 DEGs with an FDR < 0.05, the pathway analysis revealed 23 significantly enriched pathways, including cytokine-cytokine receptor interaction, Jak-STAT signaling, insulin signaling, MAPK signaling, type 2 diabetes (T2D) and pancreatic secretion. The gene ontology analysis confirmed the results of the individual DEGs and the pathway analysis in showing enriched biological processes encompassing inflammation, ion transport, exocytosis and insulin secretion. AR-deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in β-cell health in the male with implications for T2D development in men.