Abstract
Many studies have shown that in addition to the free-fraction of sex hormones, the sex hormone-binding globulin (SHBG)-bound fraction is able to directly mediate biological effects. Recent evidence suggests that low circulating SHBG concentrations are also associated with impaired glucose control and insulin resistance. Further, SHBG polymorphisms have been associated with insulin resistance. However, it is uncertain whether these low SHBG concentrations can predict the risk of developing type-2 diabetes (T2DM). In this prospective study, the association of plasma SHBG concentration and two SHBG polymorphisms (rs6257 and rs6259) with the risk of T2DM was investigated in postmenopausal women over 45 y not on hormone-replacement therapy. After a 10-y follow-up, 359 cases of newly diagnosed T2DM were selected together with 359 matched controls from a Women's Health study cohort. A replication study was conducted in men selected from the Physician's Health Study II (170 cases with newly diagnosed T2DM after an 8-y follow-up, and 170 matched controls).
Higher SHBG concentrations were strongly associated with a reduced risk of T2DM among women and men in both simple and multivariable analyses (adjusted for many variables including body mass index, family history of diabetes, blood pressure, glycated haemoglobin). Carriers of an rs6257 variant allele (CC or CT) had a 10% lower SHBG concentration than wild-type homozygotes (TT) and a higher risk of T2DM. Conversely, carriers of an rs6259 variant allele (AA or AG) had a 10% higher SHBG concentration and a lower risk of T2DM. Mendelian randomization analyses in women and men (using rs6257 and rs6259 alleles) revealed that SHBG may have a causal role in the risk of T2DM.
The authors conclude that SHBG may play an important role in the development of T2DM at both genomic and phenotypic levels and that SHBG could be an important target in stratification for the risk of T2DM and early intervention.