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. 2020 Aug 18;10(1):37-44.
doi: 10.1097/XCE.0000000000000230. eCollection 2021 Mar.

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

Adrian H Heald  1   2 , Ghasem Yadegar Far  1   3 , Mark Livingston  4 , Helene Fachim  1   2 , Mark Lunt  1 , Ram Prakash Narayanan  5 , Kirk Siddals  1 , Gabriela Moreno  6 , Richard Jones  1   7 , Nagaraj Malipatil  1   2 , Martin Rutter  1   8 , Martin Gibson  1   2 , Rachelle Donn  1 , Geoff Hackett  9 , Hugh Jones  10   11
Affiliations

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

Adrian H Heald et al. Cardiovasc Endocrinol Metab. .

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/m2) 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.

Keywords: BMI; androgen receptor; cardiovascular; mortality; testosterone; type 2 diabetes.

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Conflict of interest statement

There are no conflicts of interest.

Figures

Fig. 1
Fig. 1
Frequency distribution of CAG repeat number.
Fig. 2
Fig. 2
Relation between CAG repeat number and BMI 2016. Each unit increase in CAG repeat associated with an increment of 0.43 in BMI 2016 (P = 0.018).
Fig. 3
Fig. 3
Relation between CAG repeat number and HbA1c 2016. Each unit increase in CAG repeat associated with an increment of 0.1% in HbA1C 2016 (P = 0.04).
Fig. 4
Fig. 4
Relation between GAC repeat number and mortality rate. Adjusted logistic regression indicated that the presence of 21 CAG repeats reduced the risk of death by 45% compared with <21 CAG repeats [odds ratio 0.55 (95% CI 0.28–0.92), P = 0.02]; and that >21 repeats increased the risk of death by 48% [odds ratio 1.48 (95% CI 1.08–2.37, P = 0.015]. CI, confidence interval.
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