Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse.
OBJECTIVE
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-/yand 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.
Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, New Orleans.
Weiwei
W
Xu
Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Tianhua
T
Niu
Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, New Orleans.
Beibei
B
Xu
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Guadalupe
G
Navarro
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Matthew J
MJ
Schipma
Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, New Orleans. Electronic address: fmauvais@tulane.edu.
Franck
F
Mauvais-Jarvis
D000818:Animals; D045744:Cell Line, Tumor; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D005819:Genetic Markers; D059014:High-Throughput Nucleotide Sequencing; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009928:Organ Specificity; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D059467:Transcriptome
C000607144:AR protein, mouse; D005819:Genetic Markers; D007328:Insulin; D011944:Receptors, Androgen
Androgen receptor; Pancreatic β-cell; RNA-seq; Transcriptome; Type 2 diabetes