The role of testosterone deficiency as a cause of pancreatic beta–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 beta-cell function is still poorly understood. Our published far-reaching preliminary data demonstrated that testosterone action on the androgen receptor (AR) in male insulin-producing pancreatic beta-cells enhances insulin secretion by amplifying glucagon-like peptide-1 (GLP-1) actions. The goal of this project is to further 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. This study will fill key gaps in our understanding of the fundamental mechanisms of beta-cell function and will have a lasting scientific impact and open clinically relevant avenues for androgen-deficient male with diabetes.
