Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells
Weiwei Xu, Mirza Muhammad Fahd Qadir, Daniela Nasteska, Paula Mota de, Caroline M. Gorvin, Manuel Blandino-Rosano, Charles R. Evans, Thuong Ho, Evgeniy Potapenko, Rajakrishnan Veluthakal, Fiona Ashford, Stavroula Bitsi, Jia Fan, Manika Bhondeley, Kejing Song, Venkata N. Sure, Siva S. V. P. Sakamuri, Lina Schiffer, Wandy L. Beatty, Rachael A. Wyatt, Daniel E. Frigo, Xiaowen Liu, Prasad V. G. Katakam, Wiebke Arlt, Jochen Buck, Lonny R. Levin, Ye Hu, Jay K. Kolls, Charles Burant, Alejandra Tomás, Matthew J. Merrins, Debbie C. Thurmond, Ernesto Bernal‐Mizrachi, David J. Hodson, Franck Mauvais‐Jarvis
Abstract
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 CO 2 , activating the HCO 3 − -sensitive soluble adenylate cyclase; and (2) increased Gα s 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.