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

Table 3 Tissue-specific metabolic alterations associated with androgen receptor dysfunction in androgen insensitivity syndrome and their relevance to type 2 diabetes mellitus susceptibility

Target tissue/system	AR-mediated function (normal)	Effect of AR dysfunction in AIS	Associated metabolic consequences	Ref.
Pancreatic β-cells	Promotes β-cell mass, insulin transcription, and GLP-1 sensitivity	Reduced insulin synthesis and secretion	Impaired glucose-stimulated insulin release	[51]
Skeletal muscle	Enhances insulin sensitivity, glucose uptake via GLUT4	Decreased insulin-stimulated glucose uptake	Peripheral insulin resistance	[7]
Liver	Suppresses lipogenesis, supports insulin signaling	Upregulated SREBP-1c, increased hepatic glucose output	Hyperglycemia, fatty liver	[31]
White adipose tissue	Regulates adipocyte differentiation, inhibits visceral fat accumulation	Adipocyte hypertrophy, increased inflammatory cytokines	Visceral obesity, systemic inflammation	[57]
Central nervous system	Modulates energy homeostasis via hypothalamic AR	Altered appetite regulation and energy expenditure	Obesity, leptin resistance	[71]
Lipid profile	Maintains lipid oxidation and HDL levels	Increased TGs, LDL; decreased HDL	Dyslipidemia, pro-atherogenic state	[46]

AIS: Androgen insensitivity syndrome; AR: Androgen receptor; GLP-1: Glucagon-like peptide-1; GLUT4: Glucose transporter type 4; SREBP-1c: Sterol regulatory element-binding protein 1c; TG: Triglyceride; LDL: Low-density lipoprotein; HDL: High-density lipoprotein.