Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.
Cell Metabolism. 2016-05-01; 23(5): 837-851
DOI: 10.1016/j.cmet.2016.03.015
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Navarro G(1), Xu W(2), Jacobson DA(3), Wicksteed B(4), Allard C(2), Zhang G(5),
De Gendt K(6), Kim SH(7), Wu H(2), Zhang H(5), Verhoeven G(6), Katzenellenbogen
JA(7), Mauvais-Jarvis F(8).
Author information:
(1)Department of Medicine, Division of Endocrinology, Metabolism and Molecular
Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL
60611, USA.
(2)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.
(3)Department of Molecular Physiology and Biophysics, Vanderbilt University,
Nashville, TN 37212, USA.
(4)Kovler Diabetes Center, Section of Endocrinology, Diabetes and Metabolism, and
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
(5)Department of Pathology and Laboratory Medicine, Tulane Cancer Center, School
of Medicine, New Orleans, LA 70112, USA.
(6)Laboratory of Clinical and Experimental Endocrinology, Department of Clinical
and Experimental Medicine, Gasthuisberg, Catholic University of Leuven, Leuven
3000, Belgium.
(7)Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
(8)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:
.
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cmet.2016.03.015
PMCID: PMC4864089
PMID: 27133133 [Indexed for MEDLINE]