A low plasma level of sex hormone–binding globulin strongly predicts increased risk for type 2 diabetes in both men and women, while a high level predicts decreased risk, according to an analysis of two longitudinal studies.
Sex hormone–binding globulin (SHBG) appears to have a predictive ability beyond that of traditional risk factors, including glycosylated hemoglobin and C-reactive protein (CRP), said Eric L. Ding, Sc.D., of Harvard School of Public Health, Boston, and his associates.
The findings were obtained in several different analyses of data from the Women's Health Study, then replicated in several further analyses of data from the Physicians' Health Study II. “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 [SHBG] could be an important target in stratification for the risk of type 2 diabetes and early intervention,” the researchers noted.
The primary function of SHBG was thought to be to bind circulating hormones, and to sequester circulating androgens and estrogens in particular. More recently, SHBG has been implicated in the maintenance of glucose homeostasis, and several variations in the SHBG gene have been associated with insulin resistance.
Dr. Ding and his colleagues studied plasma SHBG levels in a prospective cohort of 12,304 postmenopausal women participating in the Women's Health Study. A subset of 359 of these subjects who had developed type 2 diabetes during 10-year follow-up were matched for age and race with 359 control subjects who had not.
High plasma levels of SHBG at baseline were robustly associated with low risk for developing diabetes, as well as with low body mass index, low likelihood of having hypertension, and favorable lipid profiles and CRP levels.
The results were identical in a replication study involving 170 men participating in the Physicians' Health Study II who had developed type 2 diabetes during 8-year follow-up and 170 matched controls who had not. Study subjects who had SHBG levels in the lowest quartile at baseline were at 10 times the risk for diabetes of those who had SHBG levels in the highest quartile, the investigators wrote (N. Engl. J. Med. 2009 Aug. 5 [doi:10.1056/NEJMoa0804381]).
Moreover, two variants in the SHBG gene, the rs6257 and the rs6259 polymorphisms, were consistently associated with SHBG levels and diabetes risk, they added.
“Our results may provide a potential explanation of the intriguing divergent effects on the risk of diabetes, observed in two randomized trials, of transdermal estradiol (which elevates plasma glucose levels) and oral estrogen (which lowers glucose levels). In direct comparisons, transdermal estradiol does not affect [SHBG] levels, whereas oral-estrogen therapy favorably increases levels of [SHBG],” Dr. Ding and his associates noted.
Dr. Ding is listed on a provisional patent application filed by the University of California at Los Angeles for the use of SHBG for determining risk of type 2 diabetes.