Androgen receptor-reduced sensitivity is associated with increased mortality and poorer glycaemia in men with type 2 diabetes mellitus: a prospective cohort study
Adrian Heald, Ghasem Yadegar far, Mark Livingston, Helene Fachim, Mark Lunt, Ram Prakash Narayanan, Kirk Siddals, Gabriela Moreno, Richard L. Jones, Nagaraj Malipatil, Martin K. Rutter, Martin Gibson, Rachelle Donn, Geoff Hackett, Hugh Jones
Abstract
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 (AR) gene is associated with increased AR resistance/insulin resistance. Methods We determined in a long-term 14-year follow-up cohort of 423 T2DM Caucasian men, the association between baseline androgen status/CAG repeat number (by PCR then Sequenom sequencing) and metabolic/cardiovascular outcomes. Results Metabolic outcomes : Lower total testosterone was associated with higher BMI (kg/m 2 ) at 14-year-follow-up: regression coefficient −0.30 (95% confidence interval −0.445 to −0.157), P = 0.0001. The range of CAG repeat number was 9-29 repeats. Higher CAG repeat number in exon-1 of the AR gene was associated with higher follow-up HbA1c2016 – each unit increase in CAG repeat-associated with an increment of 0.1% in HbA1C2016 ( P = 0.04), independent of baseline testosterone. Cardiovascular outcomes and mortality : At an average of 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 number of CAG repeats and mortality. Twenty-one CAG repeats were associated with an up to nearly 50% lower mortality rate than <21 CAG repeats and >21 CAG repeats – independent of baseline testosterone level. Conclusion A higher number of CAG repeats at the AR gene associates with higher future HbA1c. There was a ‘u’ shaped relation between CAG repeat number and mortality rate. Determination of CAG repeat number may become part of assessment of androgen status/its consequences for men with T2DM.