Objective: To investigate whether the prognostic role of testosterone in men with type 2 diabetes is influenced by its carrier, sex hormone binding globulin (SHBG).
Research Design and Methods: 531 men with type 2 diabetes presenting to a diabetes clinic in 2004-2005 were followed prospectively until death, or July 31, 2014, and a survival analysis was performed.
Results: Over a median follow up mean of 8.8 years (interquartile range 7.3-9.1) 175 men (33%) died. In Cox proportional hazard models both higher SHBG (Hazard Ratio (HR) 1.012 [95% Confidence Interval (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) predicted all cause mortality independently of age, body mass index, presence of macro- and microvascular disease, hemoglobin, renal function, insulin use, and HOMA-IR. By contrast, the inverse association of total testosterone (TT) with mortality weakened after adjustments (p=0.11). SHBG remained predictive (P<0.001) both if substituted for or added to TT in the multivariable model. In the fully adjusted model, an increase of SHBG of 10 nmol/L increased mortality by 12% and a decrease in cFT by 10 pmol/L increased mortality by 5%.
Conclusions: In men with type 2 diabetes, high SHBG and low free testosterone levels proved strong predictors of death, independent of competing mortality factors and of patient characteristics influencing the circulating levels of these hormones. Whether SHBG acts via regulation of testosterone, has intrinsic biological roles, or is a marker of poor health requires further study.