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.
Weiwei Xu  1 ,  M M Fahd Qadir  2 ,  Daniela Nasteska  3 ,  Paula Mota de Sa  2 ,  Caroline M Gorvin  3 ,  Manuel Blandino-Rosano  4 ,  Charles R Evans  5 ,  Thuong Ho  6 ,  Evgeniy Potapenko  6 ,  Rajakrishnan Veluthakal  7 ,  Fiona B Ashford  3 ,  Stavroula Bitsi  8 ,  Jia Fan  9 ,  Manika Bhondeley  2 ,  Kejing Song  10 ,  Venkata N Sure  11 ,  Siva S V P Sakamuri  11 ,  Lina Schiffer  3 ,  Wandy Beatty  12 ,  Rachael Wyatt  3 ,  Daniel E Frigo  13 ,  Xiaowen Liu  14 ,  Prasad V Katakam  11 ,  Wiebke Arlt  15 ,  Jochen Buck  16 ,  Lonny R Levin  16 ,  Tony Hu  9 ,  Jay Kolls  10 ,  Charles F Burant  5 ,  Alejandra Tomas  8 ,  Matthew J Merrins  17 ,  Debbie C Thurmond  7 ,  Ernesto Bernal-Mizrachi  4 ,  David J Hodson  3 ,  Franck Mauvais-Jarvis  18
Affiliations
  • 1. Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA.
  • 2. Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA.
  • 3. Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK.
  • 4. Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
  • 5. Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6. Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA.
  • 7. Department of Molecular and Cellular Endocrinology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA.
  • 8. Division of Diabetes, Endocrinology & Metabolism, Section of Cell Biology and Functional Genomics, Imperial College London, London SW7 2AZ, UK.
  • 9. Center for Cellular and Molecular Diagnostics, Department of Molecular & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
  • 10. Center for Translational Research in Infection and Inflammation, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
  • 11. Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
  • 12. Molecular Imaging Facility, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 13. Departments of Cancer Systems Imaging and Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 14. Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
  • 15. Institute of Metabolism and Systems Research and Centre for Membrane Proteins and Receptors, University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham B15 2TH, UK.
  • 16. Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA.
  • 17. Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
  • 18. Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA. Electronic address: [email protected].
PMID: 37200193 DOI: 10.1016/j.celrep.2023.112529
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.

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