Cell Reports (May 2023)
Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells
- Weiwei Xu,
- M.M. Fahd Qadir,
- Daniela Nasteska,
- Paula Mota de Sa,
- Caroline M. Gorvin,
- Manuel Blandino-Rosano,
- Charles R. Evans,
- Thuong Ho,
- Evgeniy Potapenko,
- Rajakrishnan Veluthakal,
- Fiona B. Ashford,
- Stavroula Bitsi,
- Jia Fan,
- Manika Bhondeley,
- Kejing Song,
- Venkata N. Sure,
- Siva S.V.P. Sakamuri,
- Lina Schiffer,
- Wandy Beatty,
- Rachael Wyatt,
- Daniel E. Frigo,
- Xiaowen Liu,
- Prasad V. Katakam,
- Wiebke Arlt,
- Jochen Buck,
- Lonny R. Levin,
- Tony Hu,
- Jay Kolls,
- Charles F. Burant,
- Alejandra Tomas,
- Matthew J. Merrins,
- Debbie C. Thurmond,
- Ernesto Bernal-Mizrachi,
- David J. Hodson,
- Franck Mauvais-Jarvis
Affiliations
- Weiwei Xu
- 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
- M.M. Fahd Qadir
- 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
- Daniela Nasteska
- 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
- Paula Mota de Sa
- 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
- Caroline M. Gorvin
- 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
- Manuel Blandino-Rosano
- Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Charles R. Evans
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Thuong Ho
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA
- Evgeniy Potapenko
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA
- Rajakrishnan Veluthakal
- Department of Molecular and Cellular Endocrinology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
- Fiona B. Ashford
- 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
- Stavroula Bitsi
- Division of Diabetes, Endocrinology & Metabolism, Section of Cell Biology and Functional Genomics, Imperial College London, London SW7 2AZ, UK
- Jia Fan
- Center for Cellular and Molecular Diagnostics, Department of Molecular & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Manika Bhondeley
- 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
- Kejing Song
- Center for Translational Research in Infection and Inflammation, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Venkata N. Sure
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Siva S.V.P. Sakamuri
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Lina Schiffer
- 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
- Wandy Beatty
- Molecular Imaging Facility, Washington University School of Medicine, St. Louis, MO 63110, USA
- Rachael Wyatt
- 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
- Daniel E. Frigo
- Departments of Cancer Systems Imaging and Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Xiaowen Liu
- Division of Biomedical Informatics and Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Prasad V. Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Wiebke Arlt
- 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
- Jochen Buck
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
- Lonny R. Levin
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
- Tony Hu
- Center for Cellular and Molecular Diagnostics, Department of Molecular & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Jay Kolls
- Center for Translational Research in Infection and Inflammation, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Charles F. Burant
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Alejandra Tomas
- Division of Diabetes, Endocrinology & Metabolism, Section of Cell Biology and Functional Genomics, Imperial College London, London SW7 2AZ, UK
- Matthew J. Merrins
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
- Debbie C. Thurmond
- Department of Molecular and Cellular Endocrinology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
- Ernesto Bernal-Mizrachi
- Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- David J. Hodson
- 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
- Franck Mauvais-Jarvis
- 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; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 5
p. 112529
Abstract
Summary: 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.
