title: Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.
abstract: Although men with testosterone deficiency are at increased risk for type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β cells. We show that male mice lacking AR in β cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS), leading to glucose intolerance. The AR agonist dihydrotestosterone (DHT) enhances GSIS in cultured male islets, an effect that is abolished in βARKO(-/y) islets and human islets treated with an AR antagonist. In β cells, DHT-activated AR is predominantly extranuclear and enhances GSIS by increasing islet cAMP and activating the protein kinase A. In mouse and human islets, the insulinotropic effect of DHT depends on activation of the glucagon-like peptide-1 (GLP-1) receptor, and accordingly, DHT amplifies the incretin effect of GLP-1. This study identifies AR as a novel receptor that enhances β cell function, a finding with implications for the prevention of T2D in aging men.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37212, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
authors.affiliation: Kovler Diabetes Center, Section of Endocrinology, Diabetes and Metabolism, and Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Barton
authors.initials: B
authors.lastname: Wicksteed
authors.affiliation: Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Allard
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane Cancer Center, School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Guanyi
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, Gasthuisberg, Catholic University of Leuven, Leuven 3000, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: De Gendt
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Hongju
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane Cancer Center, School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, Gasthuisberg, Catholic University of Leuven, Leuven 3000, Belgium.
authors.forename: Guido
authors.initials: G
authors.lastname: Verhoeven
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: fmauvais@tulane.edu.
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008954:Models, Biological; D011944:Receptors, Androgen / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology
chemical_list: D007328:Insulin; D011944:Receptors, Androgen; D013739:Testosterone; D000242:Cyclic AMP; D005947:Glucose