1. Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells.
- Author
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Xu W, Qadir MMF, Nasteska D, Mota de Sa P, Gorvin CM, Blandino-Rosano M, Evans CR, Ho T, Potapenko E, Veluthakal R, Ashford FB, Bitsi S, Fan J, Bhondeley M, Song K, Sure VN, Sakamuri SSVP, Schiffer L, Beatty W, Wyatt R, Frigo DE, Liu X, Katakam PV, Arlt W, Buck J, Levin LR, Hu T, Kolls J, Burant CF, Tomas A, Merrins MJ, Thurmond DC, Bernal-Mizrachi E, Hodson DJ, and Mauvais-Jarvis F
- Subjects
- Male, Mice, Humans, Animals, Glucagon-Like Peptide 1 metabolism, Adenylyl Cyclases metabolism, Receptors, Androgen metabolism, Insulin metabolism, Glucose pharmacology, Glucose metabolism, Testosterone, Peptide Fragments metabolism, Mammals metabolism, Insulin-Secreting Cells metabolism, Islets of Langerhans metabolism
- 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 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., Competing Interests: Declaration of interests F.M.-J. received an Investigator-Initiated Study award from Boehringer Ingelheim and Eli Lilly and consulting fees from Mithra Pharmaceutical, Inc. D.E.F. has received research funding from GTx, Inc and has familial relationships with Hummingbird Bioscience, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals, and Barricade Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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