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Cell Metab. 2016 May 10;23(5):837-51. doi: 10.1016/j.cmet.2016.03.015. Epub 2016 Apr 28.

Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.

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: fmauvais@tulane.edu.

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.

PMID:
27133133
PMCID:
PMC4864089
DOI:
10.1016/j.cmet.2016.03.015
[Indexed for MEDLINE]
Free PMC Article

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