Xu Weiwei, Niu Tianhua, Xu Beibei, Navarro Guadalupe, Schipma Matthew J, Mauvais-Jarvis Franck
Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, New Orleans.
Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
J Diabetes Complications. 2017 May;31(5):787-795. doi: 10.1016/j.jdiacomp.2017.03.002. Epub 2017 Mar 9.
Testosterone action is mediated via the androgen receptor (AR). We have reported that male mice lacking AR selectively in β-cells (βARKO) 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 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.
睾酮作用通过雄激素受体（AR）介导。我们已报道，在β细胞中选择性缺失AR的雄性小鼠（βARKO）葡萄糖刺激的胰岛素分泌（GSIS）减少，导致葡萄糖不耐受。我们发现，睾酮作用于β细胞中的AR可通过环磷酸腺苷依赖性蛋白激酶 - A途径增强胰高血糖素样肽 - 1对其受体的促胰岛素作用。
为了研究β细胞中AR依赖性基因网络，我们对雄性βARKO小鼠和对照小鼠的胰岛进行了高通量全转录组测序（RNA测序）。
我们鉴定出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且变化倍数（FC）>2。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312个FDR<0.05的DEG，通路分析显示23条显著富集的通路，包括细胞因子 - 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（T2D）和胰腺分泌。基因本体分析证实了单个DEG和通路分析的结果，表明富集的生物学过程包括炎症、离子转运、胞吐作用和胰岛素分泌。
AR缺陷的胰岛表现出参与炎症和胰岛素分泌的基因表达改变，这表明雄激素作用对男性β细胞健康很重要，对男性T2D的发展具有影响。
