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

Journal article

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β 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 β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3−-sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment 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 testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male β cells.

Authors: Xu, W; Qadir, MMF; Nasteska, D; Hodson, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Cell Reports
• Volume: 42
• Article number: 112529
• Publication date: 2023-05-17
• Acceptance date: 2023-05-03
• DOI: 10.1016/j.celrep.2023.112529
• ISSN: 2211-1247
• Language: English
• Keywords: FFR; soluble adenylate cyclase; mitochondria; testosterone; islet; androgen receptor; mTORC2; insulin secretion; GLP-1; cAMP; β cells