Sex hormone-binding globulin may explain sex differences for glucose homeostasis and incidence of type 2 diabetes: The KORA study

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Background: Research has indicated that sex hormone-binding globulin (SHBG) is associated with glucose homeostasis and may play a role in the etiology of type 2 diabetes (T2D). While it is unclear whether SHBG may mediate sex differences in glucose control and subsequently, incidence of T2D. Methods: We used observational data from the German population-based KORA F4 study (n =1937, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1387). T2D was initially assessed by self-report and validated by contacting the physicians and/ or reviewing the medical charts. Mediation analyses were performed to assess the role of SHBG in mediating the association between sex (women vs men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis). Results: After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower fasting glucose levels compared to men (b = -4.94 (mg/dl), 95% CI: -5.77, -4.11). SHBG levels were significantly higher in women than in men (b = 0.47 (nmol/l), 95% CI:0.42, 0.51). Serum SHBG may mediate the association between sex and fasting glucose levels with a proportion mediated (PM) of 30% (CI: 22-41%). Also, a potential mediatory role of SHBG was also observed for sex differences in incidence of T2D (PM= 95% and 63% in models 1 and 2, respectively). Conclusions: Our novel findings suggest that SHBG may partially explain sex-differences in glucose control and T2D incidence.