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

Figure 1 Genomic location of the androgen receptor gene on the X chromosome and schematic structure of the encoded protein. The upper panel shows the short (p) and long (q) arms of the X chromosome, with the androgen receptor (AR) gene located at Xq11-12. The middle panel illustrates the 5'→3'orientation of the AR gene, which contains eight exons (colored boxes). Exon 1 encodes the N-terminal transactivation domain (NTD), whereas exons 2-3 and 4-8 encode the DNA-binding domain (including zinc finger motifs) and ligand-binding domain (LBD), respectively. The lower panel displays the major structural domains of the AR protein: The NTD, which contains two polymorphic polyglutamine glutamine tracts; the DNA-binding domain, comprising two zinc fingers and a hinge region; and the LBD located at the C-terminus. Black arrows indicate the distribution of mutation sites identified in this study, which are predominantly clustered in the NTD and LBD. AR: Androgen receptor; NTD: N-terminal transactivation domain; DBD: DNA-binding domain; LBD: Ligand-binding domain; Gln: Glutamine; ZFM: Zinc finger motif; Gln(n): Glutamine (n repeats).

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.