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; Ghasem Yadegar Far; Mark Livingston; Helene Fachim; Mark Lunt; Ram Prakash Narayanan; Kirk Siddals; Gabriela Moreno; Richard Jones; Nagaraj Malipatil; Martin Rutter; Martin Gibson; Rachelle Donn; Geoff Hackett; Hugh Jones

doi:10.1097/XCE.0000000000000230

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

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

Authors

Adrian H Heald^{1

2}, Ghasem Yadegar Far^{1

3}, Mark Livingston⁴, Helene Fachim^{1

2}, Mark Lunt¹, Ram Prakash Narayanan⁵, Kirk Siddals¹, Gabriela Moreno⁶, Richard Jones^{1

7}, Nagaraj Malipatil^{1

2}, Martin Rutter^{1

8}, Martin Gibson^{1

2}, Rachelle Donn¹, Geoff Hackett⁹, Hugh Jones^{10

11}

Affiliations

¹ Manchester Academic Health Sciences Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester.
² Department of Diabetes and Endocrinology, Salford Royal Hospital, Salford, UK.
³ Heart Failure Research Centre & Epidemiology, Biostatics Department School of Public Heath, Isfahan University of Medical Sciences, Isfahan, Iran.
⁴ Department of Clinical Biochemistry, Black Country Pathology Services, Walsall Manor Hospital, Walsall.
⁵ Institute for Ageing and Chronic Diseases, University of Liverpool, Liverpool, UK.
⁶ General Directorate for Quality and Health Education, Mexico City, Mexico.
⁷ Besins Healthcare, London.
⁸ Diabetes Centre Manchester University NHS Foundation Trust, Manchester.
⁹ Department of Sexual Urology, Heartlands Hospital, Birmingham.
¹⁰ Centre for Diabetes and Endocrinology, Barnsley Hospital, Barnsley.
¹¹ Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

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.