Aims 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. Methods 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. Results 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. Conclusions 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.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health (grant numbers DK074970, DK107444), the American Diabetes Association (grant number 7-13-BS-101) and in part from LA CaTS Center (grant number1 U54 GM104940).
- Androgen receptor
- Pancreatic β-cell
- Type 2 diabetes