TY - JOUR
T1 - Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male
AU - Navarro, Guadalupe
AU - Xu, Weiwei
AU - Jacobson, David A.
AU - Wicksteed, Barton
AU - Allard, Camille
AU - Zhang, Guanyi
AU - De Gendt, Karel
AU - Kim, Sung Hoon
AU - Wu, Hongju
AU - Zhang, Haitao
AU - Verhoeven, Guido
AU - Katzenellenbogen, John A.
AU - Mauvais-Jarvis, Franck
N1 - Funding Information:
Acknowledgments Human islets were provided by the Integrated Islet Distribution Program, funded by the National Institute of Diabetes and Digestive and Kidney Diseases and with support from the Juvenile Diabetes Research Foundation International. This work was supported by grants from the NIH (DK074970, HD044405), the American Heart Association (11IRG5570010), and the American Diabetes Association (7-13-BS-101) to F.M.-J. and in part from LA CaTS Center grant 1 U54 GM104940. G.N. was supported in part by NIH training grant T32 DK007169. D.A.J. was supported by NIH grant DK097392. B.W. was supported by NIH grant DK085129. J.A.K. and S.H.K. were supported by NIH grant DK015556.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/10
Y1 - 2016/5/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2016.03.015
DO - 10.1016/j.cmet.2016.03.015
M3 - Article
C2 - 27133133
AN - SCOPUS:84964589443
SN - 1550-4131
VL - 23
SP - 837
EP - 851
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -
