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

Weiwei Xu, M. M.Fahd Qadir, Daniela Nasteska, Paula Mota de Sa, Caroline M. Gorvin, Manuel Blandino-Rosano, Charles R. Evans, Thuong Ho, Evgeniy Potapenko, Rajakrishnan Veluthakal, Fiona B. Ashford, Stavroula Bitsi, Jia Fan, Manika Bhondeley, Kejing Song, Venkata N. Sure, Siva S.V.P. Sakamuri, Lina Schiffer, Wandy Beatty, Rachael WyattDaniel E. Frigo, Xiaowen Liu, Prasad V. Katakam, Wiebke Arlt, Jochen Buck, Lonny R. Levin, Tony Hu, Jay Kolls, Charles F. Burant, Alejandra Tomas, Matthew J. Merrins, Debbie C. Thurmond, Ernesto Bernal-Mizrachi, David J. Hodson, Franck Mauvais-Jarvis

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 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.

Original languageEnglish
Article number112529
JournalCell Reports
Volume42
Issue number5
DOIs
StatePublished - May 30 2023

Keywords

  • CP: Metabolism
  • GLP-1
  • androgen receptor
  • cAMP
  • insulin secretion
  • islet
  • mTORC2
  • mitochondria
  • soluble adenylate cyclase
  • testosterone
  • β cells

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