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

Table 1 Overview of the hormonal milieu, metabolic phenotypes, and key management points across developmental stages in androgen insensitivity syndrome

Stage /subtype	Hormonal exposure and treatment strategy	Dominant metabolic phenotype	Key risk/protective factors	Management priorities
Adolescence - CAIS (testes retained)	High circulating testosterone → aromatized to estradiol; no hormonereplacement therapy (HRT)	Generally, normal body weight and lipid profile; feminine fat distribution; low lean (muscle) mass	Endogenous estradiol confers metabolic protection	Monitor bone mass and body composition; determine optimal timing of gonadectomy
Adolescence - PAIS (reared male + androgen supplementation)	Residual AR activity plus exogenous testosterone	↑ Muscle mass; possible improvement in insulin sensitivity	Partial restoration of androgen action	Tailor testosterone dose individually; guard against excess weight gain
Adulthood - CAIS (early gonadectomy + absent/insufficient HRT)	Prolonged deficiency of both estrogen and androgen	Central obesity, insulin resistance, dyslipidemia	“Silent” hypoestrogenic state	Initiate and maintain adequatedose estradiol as early as feasible
Adulthood - CAIS (postpubertal gonadectomy + standard HRT)	Physiological aromatization peak achieved, followed by lifelong estradiol therapy	Relatively low metabolic risk	Timely and sustained estrogen replacement	Regular monitoring of BMI, lipid profile, and bonemineral density
Adulthood - PAIS (individualized androgen/estrogen regimen)	Lowdose testosterone or estradiol	Body composition and metabolic status depend on residual AR function and treatment adherence	Optimal HRT regimen remains unsettled	Maintain hormones within physiological range; reassess dynamically
Reference: PCOS (hyperandrogenism)	Excess endogenous androgens	Visceral obesity, insulin resistance, metabolic syndrome	AR overactivation	Weight control, insulinsensitizing agents, antiandrogen therapy

HRT: Hormone-replacement therapy; PAIS: Partial androgen insensitivity syndrome; AR: Androgen receptor; CAIS: Complete androgen insensitivity syndrome; PCOS: Polycystic ovary syndrome; BMI: Body mass index.

Table 2 Organ-specific differences in androgen - receptor signaling

Organ/tissue	Principal action of AR	Metabolic consequences when AR signaling is impaired
Skeletal muscle	Drives glucose utilization and myofiber growth	AR loss impairs glycolysis and diminishes insulin sensitivity
Liver	Promotes fattyacid oxidation and enhances insulin responsiveness	AR deficiency predisposes to hepatic steatosis and insulin resistance
Adipose tissue	Restrains visceralfat accumulation and regulates lipid turnover	Lack of adipocyte AR increases visceral obesity and insulin resistance
Pancreatic βcells	Potentiates glucosestimulated insulin secretion	AR activation boosts insulin release, whereas AR knockout blunts excessive secretion
Hypothalamic neurons	Preserves wholebody insulin sensitivity	Neuronal AR deletion elicits hypothalamusdriven insulin resistance

AR: Androgen receptor; β cells: Beta cells (insulin-producing cells in the pancreas).

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.

Table 4 Metabolic surveillance parameters and assessment methods for androgen insensitivity syndrome patients

Monitoring parameter	Assessment method(s)	Purpose/clinical significance
Glucose tolerance	Fasting plasma glucose	Detect impaired glucose tolerance and stratify risk of T2DM
	OGTT
	HbA1c
Insulin resistance	HOMAIR = (fasting insulin × fasting glucose)	Quantifies insulin sensitivity (clamp technique is the gold standard)
	Hyperinsulinemic–euglycemic clamp
Lipid profile	Serum TG, LDL, HDL, etc.	Identifies dyslipidemia and gauges metabolicsyndrome risk
Body composition	BMI	Assesses degree of obesity and fat distribution
	Waisttohip ratio
	DXA for bodyfat percentage
Bone mineral density	DXA of axial skeleton	Monitors bone mass and helps prevent osteoporosis (particularly important after gonadectomy in AIS)
Lifestyle factors	Dietary pattern analysis	Complements metabolic risk assessment and guides targeted interventions
	Physicalactivity questionnaires

OGTT: Oral glucose tolerance test; HbA1c: Glycated hemoglobin; T2DM: Type 2 diabetes mellitus; HOMA-IR: Homeostatic model assessment of insulin resistance; AIS: Androgen insensitivity syndrome; TG: Triglycerides; BMI: Body mass index; DXA: Dual-energy X-ray absorptiometry; HDL: High-density lipoprotein; LDL: Low-density lipoprotein.

Table 5 Framework for individualized management and intervention pathways in androgen insensitivity syndrome

Management/intervention domain	Core measures	Notes/targets
Diagnosis and genetic counseling	AR gene sequencing	Confirm AIS subtype and hereditary risk; inform reproductive and parenting decisions
	Karyotype analysis
	Familybased genetic counseling
Gonadal management (tumor surveillance)	Periodic ultrasound/MRI followup	Lower the risk of gonadal malignancy while allowing testicular hormones to support skeletal maturation
	Elective orchiectomy after puberty
HRT	Initiate estradiol after puberty or postorchidectomy in CAIS	Maintain secondary sexual characteristics and prevent complications such as osteoporosis
	Androgen therapy in PAIS as indicated
Bonemetabolic and cardiometabolic care	Regular monitoring of bonemineral density, blood glucose, and lipid profile	Control body weight, enhance insulin sensitivity, and protect against osteoporosis
	Personalized advice on diet and exercise
Psychological and social support	Multidisciplinary team assessment	Facilitate genderidentity adaptation and mitigate psychological distress
	Professional psychological counseling
Scheduled followup	Tracking of growth parameters, endocrine hormones, and tumor markers	Adjust therapy dynamically to achieve truly individualized care

AIS: Androgen insensitivity syndrome; AR: Androgen receptor; CAIS: Complete androgen insensitivity syndrome; HRT: Hormonereplacement therapy; MRI: Magnetic resonance imaging; PAIS: Partial androgen insensitivity syndrome.