Role of the Androgen Receptor in Insulin Secretion in the Male

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The goal of this renewal application is to further elucidate the mechanisms by which testosterone action on the androgen receptor (AR) in male insulin-producing pancreatic β-cells enhances insulin secretion by amplifying glucagon-like peptide-1 (GLP-1) actions. The role of testosterone deficiency as a cause of pancreatic β–cell dysfunction predisposing to type 2 diabetes (T2D) in men is poorly studied. While it is established that testosterone action is mediated via the AR, a ligand-activated transcription factor, the role of the AR in β-cell function is still poorly understood. Funded by this Merit Award I01BX003725, the new and recently published far-reaching preliminary data from our laboratory investigating the role of the AR in β-cell function provides the following information: 1) male mice with conditional deletion of the AR in β-cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS) and develop β-cell failure to produce enough insulin, leading to T2D; 2) the insulinotropic function of AR is recapitulated in islets from male human donors that have the enzymatic machinery to convert circulating testosterone to the potent AR agonist dihydrotestosterone (DHT); 3) DHT activates an extranuclear AR in mouse and human β-cells that enhances GSIS by amplifying the actions of glucagon-like peptide-1 (GLP-1) on the GLP-1 receptor, increasing cAMP production at the plasma membrane and endosomes; 4) DHT selectively enhances GLP-1-mediated cAMP production and GSIS but not that of glucose-insulinotropic polypeptide (GIP) or glucagon (GCN); 5) DHT amplification of GSIS from islets requires the tyrosine kinase SRC, the mammalian target of rapamycin complex 2 (mTORC2), and the activities of transmembrane (tmAC) and soluble (sAC) adenylate cyclases. Based on this extensive preliminary data and the scientific rigor of previous research presented in the application, our overarching hypothesis is that in male β-cells, DHT action on AR in the vicinity of the plasma membrane binds SRC and phosphoinositide 3-kinase (PI3K), thus recruiting mTORC2 and increasing the activities of tmAC and sAC at the plasma membrane and endosomes. This enhances GLP-1 receptor (GLP-1R) production of cAMP and GSIS. DHT-activated AR is selectively biased toward the GLP-1R, because AR and GLP-1R uniquely converge on mTORC2 signaling to activate tmAC and sAC to produce cAMP in similar microdomains. The proposed work uses genetic, physiological and pharmacological tools in genetically modified mice, as well as in human islets and β-cells. This work is particularly relevant against to the aging and androgen-deficient male Veterans and the T2D epidemic, because the AR is a well-characterized drug target. The goal of the work proposed in this application is to elucidate the molecular bases by which DHT-activated AR stimulates cAMP production and enhances GLP-1 signaling at the plasma membrane and endosomes to increase insulin secretion in males. Accordingly, the specific aims of this application are to 1) Test the hypothesis that AR activation in human β cells enhances GLP-1 insulinotropic action following docking to SRC, recruitment of mTORC2, and activation of tmAC and sAC, which increases cAMP production at the plasma membrane and endosomes; 2) Unmask novel androgen actions on insulin secretion by mapping the AR interactome and functional signaling network in human β cells; 3) Translate the findings of androgen stimulation of insulin secretion in vivo in mice using an androgen dendrimer conjugate that selectively activates AR membrane/extranuclear actions. The proposed work will fill key gaps in our understanding of the fundamental mechanisms of b-cell function and will have a lasting scientific impact and open clinically relevant avenues for androgen-deficient male Veterans with diabetes.