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.