Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus.
OBJECTIVE
Low circulating testosterone levels have been associated with increased mortality in men. We hypothesized that the prognostic role of testosterone in men with type 2 diabetes mellitus (T2DM) is influenced by its carrier protein sex hormone-binding globulin (SHBG).


METHODS
We conducted a prospective cohort study at a tertiary referral centre.


METHODS
In total, 531 men with T2DM presenting to a diabetes clinic in 2004-2005 were followed prospectively until death, or July 31, 2014, and a survival analysis was performed. The main outcome measure was all cause mortality.


RESULTS
Over a mean (S.D.) follow up of 7.6 years (2.6) 175 men (33%) died. In Cox proportional hazard models both higher SHBG (Hazard Ratio (HR) 1.012 (95% CI 1.002-1.022), P=0.02) and lower calculated free testosterone (cFT) (HR 0.995 (95% CI 0.993-0.998), P=0.001) were risk factors for all cause mortality independently of age, BMI, presence of macro- and microvascular disease, duration of T2DM, hemoglobin, renal function, insulin use, C-reactive protein and homeostatic model of insulin resistance. By contrast, the inverse association of total testosterone (TT) with mortality weakened after these adjustments (P=0.11). SHBG remained associated with mortality (P<0.001) both if substituted for or added to TT in the multivariable model. In the fully adjusted model, an increase of SHBG by 17.3 nmol/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 men with T2DM is novel. Whether SHBG acts via regulation of testosterone, has intrinsic biological roles, or is a marker of poor health requires further study.
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia.
Aye N
AN
Tint
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia.
Rudolf
R
Hoermann
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia.
Henry
H
Wong
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia.
Elif I
EI
Ekinci
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia.
Richard J
RJ
MacIsaac
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia.
George
G
Jerums
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia.
Jeffrey D
JD
Zajac
Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia Department of Endocrinology and DiabetesAustin Health, 145 Studley Road, Heidelberg, Victoria 3084, AustraliaDepartment of MedicineUniversity of Melbourne, Victoria, AustraliaDepartment of Endocrinology and DiabetesSt Vincent's Hospital, Melbourne, Victoria, Australia mathisg@unimelb.edu.au.
Mathis
M
Grossmann
D000368:Aged; D002318:Cardiovascular Diseases; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012738:Sex Hormone-Binding Globulin / Q000032:analysis*; D013739:Testosterone / Q000097:blood*
D012738:Sex Hormone-Binding Globulin; D013739:Testosterone