Androgen receptor mutations in familial androgen insensitivity syndrome: A metabolic reprogramming pathway to type 2 diabetes susceptibility

Figure 2 Androgen receptor enhances insulin secretion in pancreatic β-cells via nongenomic coactivation of the glucagon-1 receptor-cyclic adenosine monophosphate/protein kinase A signaling axis. Upon binding to the glucagon (GLP)-1 receptor on the plasma membrane, GLP-1 stimulates adenylate cyclase through a stimulatory G alpha subunit-dependent mechanism, leading to the generation of cyclic adenosine monophosphate (cAMP), activation of protein kinase A (PKA), and an increase in cytosolic Ca²⁺, which together trigger insulin secretion. The dihydrotestosterone-activated androgen receptor, which is predominantly localized outside the nucleus, further enhances this pathway by recruiting additional stimulatory G alpha subunit proteins to amplify adenylate cyclase activity, thereby potentiating GLP-1-cAMP-PKA signaling and promoting insulin release. In β-cell-specific androgen receptor knockout mice, this amplification loop is disrupted, resulting in impaired GLP-1 signaling, a reduced cAMP/PKA response, abnormal Ca²⁺ dynamics, attenuated glucose-stimulated insulin secretion, and ultimately glucose intolerance. AR: Androgen receptor; DHT: Dihydrotestosterone; GLP-1: Glucagon-like peptide-1; GLP-1R: Glucagon-1 receptor; AC: Adenylyl cyclase; cAMP: Cyclic adenosine monophosphate; PKA: Protein kinase A; GSIS: Glucose-stimulated insulin secretion; βARKO: Β-cell-specific androgen receptor knockout; Gαs: Stimulatory G alpha subunit; AIS: Androgen insensitivity syndrome; iPSC: Induced pluripotent stem cell.