Circulating sex hormone–binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.

We performed a nested case–control study of postmenopausal women in the Women's Health Study who were not using hormone therapy. Plasma levels of sex hormone–binding globulin were measured; two polymorphisms of the gene encoding sex hormone–binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians' Health Study II.

As expected, women in whom type 2 diabetes developed generally had more adverse risk profiles at baseline than those who remained free of the disease. Cross-sectional analyses at baseline revealed that higher levels of sex hormone–binding globulin were associated with lower BMI, a lower likelihood of having a history of hypertension, and more favorable lipid-profile and CRP levels. Elevated levels of sex hormone–binding globulin were strongly and consistently associated with a reduced risk of type 2 diabetes in both simple and multivariable analyses.

There are four main findings regarding sex hormone–binding globulin and the risk of type 2 diabetes from these two prospective studies. First, the risk of type 2 diabetes among participants with sex hormone–binding globulin levels in the highest quartile appeared to be only one tenth the risk among those with levels in the lowest quartile. Second, the rs6257 and rs6259 SHBG polymorphisms were consistently associated with plasma levels of sex hormone–binding globulin and were predictive of risk of type 2 diabetes in directions corresponding to their effects on plasma sex hormone–binding globulin levels. Third, the strong relation between plasma levels of sex hormone–binding globulin and risk of type 2 diabetes was confirmed both in standard multivariable analyses and in mendelian randomization analyses in which suitable genetic variants were used as randomization instruments. Finally, plasma levels of the globulin appeared to have a predictive ability for the risk of type 2 diabetes beyond that of traditional risk factors, including glycated hemoglobin and CRP.

In conclusion, our prospective studies of postmenopausal women and men showed that higher levels of circulating sex hormone–binding globulin were strongly associated with a decreased risk of type 2 diabetes. Two germ-line variants in the SHBG gene were also identified as being directly associated with both plasma levels of sex hormone–binding globulin and the risk of type 2 diabetes. These strong and consistent findings, obtained with the use of multiple analytic approaches and subgroup analyses in two independent cohorts, support the notion that sex hormone–binding globulin may play an important role in the development of type 2 diabetes at both the genomic and phenotypic levels and that sex hormone–binding globulin could be an important target in stratification for the risk of type 2 diabetes and early intervention.

Source:  sumarized from the original article in the New England Journal of Medicine Volume 361:1152-1163,  September 17, 2009, Number 12.