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

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


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.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cyclic AMP / metabolism
  • Glucose / pharmacology*
  • Glucose Intolerance / pathology
  • Humans
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice, Knockout
  • Models, Biological
  • Receptors, Androgen / deficiency
  • Receptors, Androgen / metabolism*
  • Signal Transduction / drug effects
  • Testosterone / pharmacology


  • Insulin
  • Receptors, Androgen
  • Testosterone
  • Cyclic AMP
  • Glucose