Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse

Weiwei Xu, Tianhua Niu, Beibei Xu, Guadalupe Navarro, Matthew J. Schipma, Franck Mauvais-Jarvis

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)787-795
Number of pages9
JournalJournal of Diabetes and Its Complications
Volume31
Issue number5
DOIs
StatePublished - May 2017

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Androgen Receptors
Gene Expression Profiling
Islets of Langerhans
Genetic Markers
Insulin
Inflammation
Cyclic AMP-Dependent Protein Kinases
Type 2 Diabetes Mellitus
Genes
Testosterone
RNA Sequence Analysis
Biological Phenomena
Gene Ontology
Cytokine Receptors
Glucagon-Like Peptide 1
Glucose Intolerance
Gene Regulatory Networks
Ion Transport
Exocytosis
Transcriptome

Keywords

  • Androgen receptor
  • Pancreatic β-cell
  • RNA-seq
  • Transcriptome
  • Type 2 diabetes

Cite this

Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse. / Xu, Weiwei; Niu, Tianhua; Xu, Beibei; Navarro, Guadalupe; Schipma, Matthew J.; Mauvais-Jarvis, Franck.

In: Journal of Diabetes and Its Complications, Vol. 31, No. 5, 05.2017, p. 787-795.

Research output: Contribution to journalArticle

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abstract = "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.",
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