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

Cell Rep. 2023 May 30;42(5):112529. doi: 10.1016/j.celrep.2023.112529. Epub 2023 May 17.


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.

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose / metabolism
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells* / metabolism
  • Islets of Langerhans* / metabolism
  • Male
  • Mammals / metabolism
  • Mice
  • Peptide Fragments / metabolism
  • Receptors, Androgen / metabolism
  • Testosterone


  • Glucagon-Like Peptide 1
  • Adenylyl Cyclases
  • Receptors, Androgen
  • Insulin
  • Glucose
  • Testosterone
  • Peptide Fragments