Androgen receptor-reduced sensitivity is associated with increased mortality and poorer glycaemia in men with type 2 diabetes mellitus: a prospective cohort study

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 - 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. Copyright (c) 2020 Wolters Kluwer Health, Inc. All rights reserved.