Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic 0 cells

Male mice lacking the androgen receptor (AR) in pancreatic 0 cells exhibit blunted glucose-stimulated in-sulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in 0 cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male 0 cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial pro-duction of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gas recruit-ment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testos-terone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these ef-fects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male 0 cells.

Automated summary

Male mice without androgen receptor (AR) in pancreatic 0 cells have reduced insulin secretion and develop hyperglycemia. Testosterone activates an extranuclear AR, which enhances glucagon-like peptide-1 (GLP-1) insulin action. This study investigates the mechanisms through which testosterone enhances GLP-1-stimulated insulin secretion in male 0 cells, including the activation of cAMP production and the recruitment of Gas to GLP-1 receptor and AR complexes. Additionally, testosterone promotes insulin secretion in human islets through an actin remodeling cascade. The study provides insights into the genomic and non-genomic actions of AR in regulating insulin exocytosis.