Adrian H Heald1,2, Ghasem Yadegar Far1,3, Mark Livingston4, Helene Fachim1,2, Mark Lunt1, Ram Prakash Narayanan5, Kirk Siddals1, Gabriela Moreno6, Richard Jones1,7, Nagaraj Malipatil1,2, Martin Rutter1,8, Martin Gibson1,2, Rachelle Donn1, Geoff Hackett9, Hugh Jones10,11. 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.
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.
Authors: Linda M Thienpont; Katleen Van Uytfanghe; Stuart Blincko; Carol S Ramsay; Hui Xie; Robert C Doss; Brian G Keevil; Laura J Owen; Alan L Rockwood; Mark M Kushnir; Kelly Y Chun; Donald W Chandler; Helen P Field; Patrick M Sluss Journal: Clin Chem Date: 2008-06-12 Impact factor: 8.327