Mechanisms of Androgen Receptor Stimulation of Insulin Secretion in the Male
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–cell. Our study shows that male pancreatic β–cell specific AR knockout (βARKOMIP) mice develop glucose intolerance because AR potentiates glucose-stimulated insulin secretion (GSIS) through increasing cyclic AMP (cAMP) accumulation and amplifying the insulinotropic effect of glucagon-like peptide-1 (GLP-1). Using transcriptome analysis, we find that AR-deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in β-cell health in the male. Our recent study shows that male βARKOMIP mice exhibit impaired intraperitoneal (IP) glucose tolerance- because of impaired IP-GSIS- without alteration in oral glucose tolerance, suggesting that AR amplifies the islet-derived, but not the gut-derived GLP-1 to potentiate GSIS. Dihydrotestosterone (DHT) increases the insulinotropic effect of GLP-1, not gastric inhibitory polypeptide (GIP) and glucagon, in male insulin-secreting β-cell line 832/3 cells and wild-type male mouse islets. Accordingly, using 832/3 cells transduced with exchange factor directly activated by a cAMP (EPAC)-based fluorescence resonance energy transfer (FRET) sensor, we observe that the AR agonist dihydrotestosterone (DHT) specifically allows GLP-1, not GIP and glucagon, to increase cAMP production above level of the individual hormones. The insulinotropic effect of DHT is abolished using EPAC and PKA inhibitors as well as rapamycin indicating that DHT stimulates GSIS via a cAMP/PKA/EPAC pathway and activation of mTOR. This study identifies AR as a novel receptor that enhances β–cell function, a finding with implications for the prevention of type 2 diabetes (T2D) in aging men.