Androgen receptor CAG repeat polymorphism is associated with serum testosterone levels, obesity and serum leptin in men with type 2 diabetes

Abstract

Objective: To determine the relationships between androgen receptor CAG repeat polymorphism length (AR CAG), sex hormones and clinical variables in men with type 2 diabetes (DM2). Men with DM2 are known to have a high prevalence of low testosterone levels. Studies suggest that testosterone replacement therapy may improve insulin sensitivity and glycaemic control in men with DM2 and reduces central obesity and serum leptin. AR CAG is known to correlate negatively with AR sensitivity and positively with body fat, insulin levels, and leptin in healthy men. Design: Cross-sectional study set in a district general hospital diabetes centre. Methods: Sex hormones, AR CAG and symptoms of hypogonadism were assessed in 233 men with DM2. Associations were sought between these variables and others such as obesity, leptin, glycaemic control, and blood pressure. Results: Testosterone was negatively associated and AR CAG positively associated with obesity and leptin. The associations of AR CAG with leptin and obesity were independent of testosterone, estradiol, gonadotropins, and age. AR CAG was also independently associated with total, bioavailable and free testosterone, LH, waist circumference, body mass index, leptin, and systolic blood pressure. There was no association of AR CAG with sex hormone binding globulin, estradiol, HbA 1C or the symptoms of hypogonadism. Conclusions: The association of longer AR CAG with obesity and leptin suggests that shorter AR CAG may have an influence in maintaining healthy anthropomorphics and metabolism in men with DM2. Testosterone and LH levels are higher in men with longer AR CAG, probably reflecting reduced negative feedback through a less sensitive receptor. European Journal of Endocrinology 159 739-746

Androgen receptor CAG repeat length polymorphism modifies the impact of testosterone on insulin sensitivity in men

“…In contrast to several previous reports (20,35,38,39), there was no correlation between the CAG length polymorphism and total or free testosterone, which, however, is in line with another recent publication (40). In our cohort, insulin sensitivity ranged from very sensitive to highly resistant.…”

The modulating effect of the androgen receptor on craving in alcohol withdrawal of men is partially mediated by leptin

“…35,36 Supplementation of androgenic sex hormones decreases serum leptin levels, whereas suppression increases serum leptin concentration, independently of changes in body fat mass in healthy men. This observation is likely to be up to a suppressive effect of testosterone on serum leptin concentration in males, [36][37][38] an effect multiply reproduced by independent researchers. 39,40 Unfortunately, we were not able to determine testosterone serum levels in our study.…”

Testosterone: a metabolic hormone in health and disease

“…Patients with Kennedy disease (a neuromuscular disorder) possess a genetic polymorphism with excess CAG repeats in exon 1 of the AR, leading to a condition associated with a relatively insensitive AR. In support of AR-dependent mechanisms, men with Kennedy disease have an increased risk of developing diabetes, thus providing further evidence of a link between impaired androgen status and diabetes (Stanworth et al 2008, Zitzmann 2009b. Glut4 expression in the AR-deficient testicular feminised (Tfm) mouse, however, was shown to be up-regulated following testosterone replacement, suggesting some AR-independent actions (McLaren et al 2012).…”