Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus

Aye N. Tint, Rudolf Hoermann, Henry Wong, Elif I. Ekinci, Richard J MacIsaac, George Jerums, Jeffrey D. Zajac, Mathis Grossmann

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective: Low circulating testosterone levels have beenassociated with increased mortality in men. We hypothesized that the prognosticrole of testosterone in men with type 2 diabetes mellitus (T2DM) is influencedby its carrier protein sex hormone-binding globulin (SHBG).

Design: We conducted a prospective cohort study at atertiary referral centre. Methods: In total, 531 men with T2DM presenting to adiabetes clinic in 2004-2005 were followed prospectively until death, or July31, 2014, and a survival analysis was performed. The main outcome measure wasall cause mortality.

Results: Over a mean (S.D.) follow up of 7.6 years (2.6) 175men (33%) died. In Cox proportional hazard models both higher SHBG (HazardRatio (HR) 1.012 (95% CI 1.002-1.022), PZ0.02) and lower calculated freetestosterone (cFT) (HR 0.995 (95% CI 0.993-0.998), PZ0.001) were risk factorsfor all cause mortality independently of age, BMI, presence of macro- andmicrovascular disease, duration of T2DM, hemoglobin, renal function, insulinuse, C-reactive protein and homeostatic model of insulin resistance. Bycontrast, the inverse association of total testosterone (TT) with mortalityweakened after these adjustments (PZ0.11). SHBG remained associated withmortality (P7lt;0.001) both if substituted for or added to TT in themultivariable model. In the fully adjusted model, an increase of SHBG by 17.3nmol/l (1 S.D.) increased mortality by 22% and a decrease in cFT by 81 pmol/l(1 S.D.) increased mortality by 45%.

Conclusions: The association of SHBG with mortality in menwith T2DM is novel. Whether SHBG acts via regulation of testosterone, hasintrinsic biological roles, or is a marker of poor health requires furtherstudy.

Original languageEnglish
Pages (from-to)59-68
Number of pages10
JournalEuropean Journal of Endocrinology
Volume174
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016
Externally publishedYes

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Sex Hormone-Binding Globulin
Type 2 Diabetes Mellitus
Testosterone
Mortality
Survival Analysis
Proportional Hazards Models
C-Reactive Protein
Insulin Resistance
Carrier Proteins
Hemoglobins
Cohort Studies
Referral and Consultation
Outcome Assessment (Health Care)
Prospective Studies
Kidney
Health

Cite this

Tint, A. N., Hoermann, R., Wong, H., Ekinci, E. I., MacIsaac, R. J., Jerums, G., ... Grossmann, M. (2016). Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus. European Journal of Endocrinology, 174(1), 59-68. https://doi.org/10.1530/EJE-15-0672
Tint, Aye N. ; Hoermann, Rudolf ; Wong, Henry ; Ekinci, Elif I. ; MacIsaac, Richard J ; Jerums, George ; Zajac, Jeffrey D. ; Grossmann, Mathis. / Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus. In: European Journal of Endocrinology. 2016 ; Vol. 174, No. 1. pp. 59-68.
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title = "Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus",
abstract = "Objective: Low circulating testosterone levels have beenassociated with increased mortality in men. We hypothesized that the prognosticrole of testosterone in men with type 2 diabetes mellitus (T2DM) is influencedby its carrier protein sex hormone-binding globulin (SHBG). Design: We conducted a prospective cohort study at atertiary referral centre. Methods: In total, 531 men with T2DM presenting to adiabetes clinic in 2004-2005 were followed prospectively until death, or July31, 2014, and a survival analysis was performed. The main outcome measure wasall cause mortality. Results: Over a mean (S.D.) follow up of 7.6 years (2.6) 175men (33{\%}) died. In Cox proportional hazard models both higher SHBG (HazardRatio (HR) 1.012 (95{\%} CI 1.002-1.022), PZ0.02) and lower calculated freetestosterone (cFT) (HR 0.995 (95{\%} CI 0.993-0.998), PZ0.001) were risk factorsfor all cause mortality independently of age, BMI, presence of macro- andmicrovascular disease, duration of T2DM, hemoglobin, renal function, insulinuse, C-reactive protein and homeostatic model of insulin resistance. Bycontrast, the inverse association of total testosterone (TT) with mortalityweakened after these adjustments (PZ0.11). SHBG remained associated withmortality (P7lt;0.001) both if substituted for or added to TT in themultivariable model. In the fully adjusted model, an increase of SHBG by 17.3nmol/l (1 S.D.) increased mortality by 22{\%} and a decrease in cFT by 81 pmol/l(1 S.D.) increased mortality by 45{\%}. Conclusions: The association of SHBG with mortality in menwith T2DM is novel. Whether SHBG acts via regulation of testosterone, hasintrinsic biological roles, or is a marker of poor health requires furtherstudy.",
author = "Tint, {Aye N.} and Rudolf Hoermann and Henry Wong and Ekinci, {Elif I.} and MacIsaac, {Richard J} and George Jerums and Zajac, {Jeffrey D.} and Mathis Grossmann",
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Tint, AN, Hoermann, R, Wong, H, Ekinci, EI, MacIsaac, RJ, Jerums, G, Zajac, JD & Grossmann, M 2016, 'Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus', European Journal of Endocrinology, vol. 174, no. 1, pp. 59-68. https://doi.org/10.1530/EJE-15-0672

Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus. / Tint, Aye N.; Hoermann, Rudolf; Wong, Henry; Ekinci, Elif I.; MacIsaac, Richard J; Jerums, George; Zajac, Jeffrey D.; Grossmann, Mathis.

In: European Journal of Endocrinology, Vol. 174, No. 1, 01.01.2016, p. 59-68.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus

AU - Tint, Aye N.

AU - Hoermann, Rudolf

AU - Wong, Henry

AU - Ekinci, Elif I.

AU - MacIsaac, Richard J

AU - Jerums, George

AU - Zajac, Jeffrey D.

AU - Grossmann, Mathis

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Objective: Low circulating testosterone levels have beenassociated with increased mortality in men. We hypothesized that the prognosticrole of testosterone in men with type 2 diabetes mellitus (T2DM) is influencedby its carrier protein sex hormone-binding globulin (SHBG). Design: We conducted a prospective cohort study at atertiary referral centre. Methods: In total, 531 men with T2DM presenting to adiabetes clinic in 2004-2005 were followed prospectively until death, or July31, 2014, and a survival analysis was performed. The main outcome measure wasall cause mortality. Results: Over a mean (S.D.) follow up of 7.6 years (2.6) 175men (33%) died. In Cox proportional hazard models both higher SHBG (HazardRatio (HR) 1.012 (95% CI 1.002-1.022), PZ0.02) and lower calculated freetestosterone (cFT) (HR 0.995 (95% CI 0.993-0.998), PZ0.001) were risk factorsfor all cause mortality independently of age, BMI, presence of macro- andmicrovascular disease, duration of T2DM, hemoglobin, renal function, insulinuse, C-reactive protein and homeostatic model of insulin resistance. Bycontrast, the inverse association of total testosterone (TT) with mortalityweakened after these adjustments (PZ0.11). SHBG remained associated withmortality (P7lt;0.001) both if substituted for or added to TT in themultivariable model. In the fully adjusted model, an increase of SHBG by 17.3nmol/l (1 S.D.) increased mortality by 22% and a decrease in cFT by 81 pmol/l(1 S.D.) increased mortality by 45%. Conclusions: The association of SHBG with mortality in menwith T2DM is novel. Whether SHBG acts via regulation of testosterone, hasintrinsic biological roles, or is a marker of poor health requires furtherstudy.

AB - Objective: Low circulating testosterone levels have beenassociated with increased mortality in men. We hypothesized that the prognosticrole of testosterone in men with type 2 diabetes mellitus (T2DM) is influencedby its carrier protein sex hormone-binding globulin (SHBG). Design: We conducted a prospective cohort study at atertiary referral centre. Methods: In total, 531 men with T2DM presenting to adiabetes clinic in 2004-2005 were followed prospectively until death, or July31, 2014, and a survival analysis was performed. The main outcome measure wasall cause mortality. Results: Over a mean (S.D.) follow up of 7.6 years (2.6) 175men (33%) died. In Cox proportional hazard models both higher SHBG (HazardRatio (HR) 1.012 (95% CI 1.002-1.022), PZ0.02) and lower calculated freetestosterone (cFT) (HR 0.995 (95% CI 0.993-0.998), PZ0.001) were risk factorsfor all cause mortality independently of age, BMI, presence of macro- andmicrovascular disease, duration of T2DM, hemoglobin, renal function, insulinuse, C-reactive protein and homeostatic model of insulin resistance. Bycontrast, the inverse association of total testosterone (TT) with mortalityweakened after these adjustments (PZ0.11). SHBG remained associated withmortality (P7lt;0.001) both if substituted for or added to TT in themultivariable model. In the fully adjusted model, an increase of SHBG by 17.3nmol/l (1 S.D.) increased mortality by 22% and a decrease in cFT by 81 pmol/l(1 S.D.) increased mortality by 45%. Conclusions: The association of SHBG with mortality in menwith T2DM is novel. Whether SHBG acts via regulation of testosterone, hasintrinsic biological roles, or is a marker of poor health requires furtherstudy.

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