Introduction: Hypogonadism is associated with poorer glycaemic outcomes/increased all cause and cardiovascular morbidity/mortality in type 2 diabetes mellitus (T2DM). Increasing CAG repeat number within exon 1 of the androgen receptor gene is associated with increased androgen receptor resistance/insulin resistance. We here investigated the link between CAG repeat number and outcomes in T2DM men.
Methods: We determined in a long-term 14-year follow-up cohort of 274 T2DM Caucasian men in Salford UK, the association between baseline androgen status/CAG repeat number and metabolic trajectory/mortality. Baseline serum total testosterone was determined by tandem mass spectrometry and CAG repeats by PCR followed by Sequenom sequencing.
Results: Lower baseline total testosterone was associated with higher Body Mass Index (BMI)(kg/m2) at 14-year follow-up: regression coefficient −0.30 (95% CI −0.445 to −0.157), P=0.0001 (total testosterone data). A higher baseline CAG repeat number associated with higher follow-up BMI in 2016 each unit increase in CAG repeat associated with an increment of 0.43 in BMI 2016; and also higher HbA1c 2016. At an average 14 year follow-up 55.8% of hypogonadal men had died vs. 36.1% of eugonadal men (P=0.001). There was a u shaped relation between the number of CAG repeats and mortality such that 21-23 CAG repeats was associated with an up to 58% lower mortality rate than <21 CAG repeats and >23 CAG repeats. Thus there was an optimal number of CAG repeats in relation to mortality rate. This relation was independent of baseline testosterone.
Conclusion: A higher number of CAG repeats at the testosterone receptor gene is associated with a higher future BMI/increased HbA1c. There was a u shaped relation between CAG repeat number and mortality rate. A greater understanding of the interaction between CAG repeat number and circulating testosterone level may aid understanding of longer term health outcomes in men with T2DM.