2. Academic Validation
  3. Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells

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

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: fmauvais@tulane.edu.
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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