Men with Type 2 diabetes have a high prevalence of low testosterone levels. Testosterone replacement therapy (TRT) has been shown to improve insulin sensitivity and glycaemic control in men with Type 2 diabetes. TRT also reduces fat mass and central obesity. The androgen receptor CAG repeat polymorphism length (AR CAG) correlates positively with transcriptional activity of the receptor as well as body fat, and insulin levels in healthy men. Most studies have not found an association of testosterone levels with AR CAG.
We investigated the associations of the AR CAG with testosterone levels and obesity in 233 men with Type 2 diabetes. AR CAG was measured by sequence analysis. Total testosterone (TT) and sex-hormone binding globulin (SHBG) were measured by ELISA. Bioavailable testosterone (BioT) was measured by ammonium sulphate precipitation. Free testosterone (cFT) was also derived using Vermuelens formula. Gonadatrophins, waist circumference and body mass index (BMI) were also assessed.
After adjustment for age, AR CAG correlated positively with TT (r=0.147, P=0.025), BioT (r=0.177, P=0.007), cFT (r=0.138, P=0.035) and luteinising hormone (LH) (r=0.176, P=0.008). There was no association with SHBG. Testosterone measures and SHBG were negatively associated with waist circumference and BMI (r=0.180.26, P<0.01 for all associations). AR CAG was positively associated with BMI (r=0.138, P=0.036). AR CAG was also negatively associated with waist circumference (r=0.164, P=0.013) after adjusting for testosterone and SHBG.
In Type 2 diabetes, testosterone and LH levels are higher in men with longer AR CAG, probably reflecting reduced negative feedback through a less sensitive receptor. Lower testosterone levels and longer AR CAG are both associated with a greater chance of obesity. This is in keeping with previous data linking hypogonadism to obesity and suggests that testosterone acts via the androgen receptor when affecting adiposity.