Low Testosterone: A Risk Marker Rather Than a Risk Factor for Type 2 Diabetes

Context: Low serum T levels have been associated with type 2 diabetes (T2D) and cardiovascular disease. However, it is unresolved whether low T is a risk factor or rather a risk marker for these conditions. Objective: The objective of the study was to investigate serum levels of total T, SHBG, free T, estradiol, LH, and FSH and the subsequent risk of T2D and/or cardiovascular disease. Design, Setting, and Participants: A prospective cohort study consisting of 5350 men from the general population aged 30-70 years at baseline, examined between 1982 and 2001 and followed with complete registry follow-up until December 2011, ie, up to 29 years of follow-up. Main Outcome Measures: T2D outcomes defined as the first diagnosis of T2D and cardiovascular outcomes defined as first diagnosis of either ischemic heart disease or stroke (ischemic and hemorrhagic stroke). Results: In Cox proportional hazards models, a significantly negative association between T quartile and the risk of T2D was seen. Similarly, men with SHBG in the highest quartile had a decreased risk of developing T2D (nonsmokers: hazard ratio 0.30, 95% confidence interval 0.14-0.63; smokers: hazard ratio 0.40, 95% confidence interval 0.20-0.78). Similar trends were seen for free T, however, insignificant in the fully adjusted analysis. No associations were seen for estradiol, LH, and FSH. A less consistent pattern was seen for the hormones in relation to CVD outcomes; nonsmoking men showed a pattern of higher levels of total T, SHBG, and LH being negatively associated with ischemic heart disease and less pronounced for stroke, whereas in smokers higher levels of total T, free T, and LH were positively associated with the two CVD outcomes. Conclusions: The observed negative associations of T and SHBG with T2D, but no association to LH and free T, indicates that low T in men who develop T2D is a marker of the disease rather than primary hypogonadism being a causal risk factor.