Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort

Abstract

Objective: Previous studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex-specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study.

Design: A retrospective cohort study in a UK primary care database.

Patients: We included men and women with available serum testosterone and sex hormone-binding globulin (SHBG) results.

Measurements: We categorized serum concentrations according to clinically relevant cut-off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs).

Results: Serum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone <7 nmol/L (aIRR 2.71, 95% CI 2.34-3.14, P < 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55-2.52, P < 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG <40 and <50 nmol/L, respectively.

Conclusions/interpretation: In this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively.

Keywords: androgens; diabetes; hypogonadism; metabolic diseases; population health; sex hormone-binding globulin; testosterone.

Figure 1

Risk of incident type 2 diabetes (T2DM) according to serum testosterone and sex hormone‐binding globulin (SHBG) concentration categories in men. A, Adjusted Incidence Rate Ratios (aIRRs) for diabetes in 70 541 men with serum testosterone measurements. B, Distribution of 70 541 men across each quintile of serum testosterone concentration. C, aIRRs for serum SHBG concentrations for incident diabetes in 15 907 men. D, Distribution of 15 907 men across each category of serum SHBG concentration. [Correction added on 14 November 2018, after first online publication: in panel D, an error in the data for 40‐49.99 nmol/L has been corrected.]

Figure 2

Risk of incident type 2 diabetes (T2DM) according to serum testosterone and sex hormone‐binding globulin (SHBG) concentrations in women. A, Adjusted Incidence Rate Ratios (aIRRs) for incident diabetes in 81 889 women with serum testosterone measurements. B, Distribution of 81 889 women across each category of serum testosterone concentration. C, aIRRs for serum SHBG concentrations for incident diabetes in 42 034 women with serum SHBG measurements. D, Distribution of 42 034 women across each category of serum SHBG concentration. [Correction added on 14 November 2018, after first online publication: in panel B, missing data for 3–3.49 and ≥3.5 nmol/L have been added.]