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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 publication

DOI

10.1016/j.celrep.2023.112529

Type

Journal article

Journal

Cell Rep

Publication Date

30/05/2023

Volume

42

Keywords

CP: Metabolism, GLP-1, androgen receptor, cAMP, insulin secretion, islet, mTORC2, mitochondria, soluble adenylate cyclase, testosterone, β cells, Male, Mice, Humans, Animals, Glucagon-Like Peptide 1, Insulin-Secreting Cells, Adenylyl Cyclases, Receptors, Androgen, Insulin, Glucose, Testosterone, Islets of Langerhans, Peptide Fragments, Mammals