Dyslipidaemia is associated with testosterone, oestradiol and androgen receptor CAG repeat polymorphism in men with type 2 diabetes.

OBJECTIVE: There is a high prevalence of low testosterone and dyslipidaemia in men with type 2 diabetes. The androgen receptor CAG repeat polymorphism (AR CAG) affects receptor transcriptional activity (the shorter repeats the more sensitive AR) and is associated with androgenic parameters and obesity. This study describes the relationships between testosterone, AR CAG and serum lipids in men with type 2 diabetes. DESIGN AND PATIENTS: Cross-sectional study of men with type 2 diabetes in a District General Hospital Diabetes Centre. MEASUREMENTS: Correlation between testosterone, AR CAG and serum lipids. RESULTS: HDL cholesterol (HDL-C) correlated with total testosterone (TT) (r = 0·251, P < 0·001), bioavailable testosterone (BT) (r = 0·19, P = 0·001), free testosterone (FT) (r = 0·165, P = 0·005) and sex hormone-binding globulin (SHBG) (r = 0·147, P = 0·014). HDL-C did not correlate with oestradiol, but men with the lowest quartile of oestradiol had lower HDL-C compared to highest quartile (P = 0·046). Triglycerides correlated negatively with TT (r = -0·195, P = 0·001), BT (r = -0·148, P = 0·013) and SHBG (-0·14, P = 0·019) but not with FT or oestradiol. Total and LDL cholesterol (LDL-C) correlated negatively with oestradiol (r = -0·121, P = 0·05) but not with testosterone or SHBG. One-way anova testing across four quartiles of AR CAG showed a trend to alteration in HDL-C across groups of AR CAG (P = 0·08). HDL-C was significantly higher in men with the longest AR CAG compared with the shortest (1·19 vs 1·08 mmol/l, P = 0·02). CONCLUSIONS: Lower testosterone and oestradiol levels in men with diabetes are associated with an adverse lipid profile. Shorter AR CAG is associated with low HDL-C and testosterone. The paradox that HDL-C is associated with low testosterone levels and a more active AR may suggest divergent effect of testosterone on HDL-C via genomic vs nongenomic mechanisms.

The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study.

CONTEXT: The TIMES2 (testosterone replacement in hypogonadal men with either metabolic syndrome or type 2 diabetes) study reported beneficial effects of testosterone replacement therapy (TRT) on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated AR activity and has been linked to various clinically relevant variables. OBJECTIVE: To assess the role of AR CAG in the alteration of clinical response to TRT in the TIMES2 study. DESIGN: Subgroup analysis from a multicentre, randomised, double-blind, placebo-controlled and parallel group study. SETTING: Outpatient study recruiting from secondary and primary care. PATIENTS: A total of 139 men with hypogonadism and type 2 diabetes or metabolic syndrome, of which 73 received testosterone during the TIMES2 study. INTERVENTION: Testosterone 2% transdermal gel vs placebo. MAIN OUTCOME MEASURE: Regression coefficient of AR CAG from linear regression models for each variable. RESULTS: AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during TRT with a trend to association with HOMA-IR - the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity. CONCLUSION: AR CAG affected the response of some variables to TRT in the TIMES2 study, although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect the significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted.

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

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.