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Previous Volume 361:1152-1163 September 17, 2009 Number 12 Next

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ABSTRACT

Background 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.

Methods We performed a nested case–control study of postmenopausal women in the Women's Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). 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 (170 with newly diagnosed type 2 diabetes and 170 controls).

Results Among women, higher plasma levels of sex hormone–binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone–binding globulin levels (P=0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P=0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone–binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone–binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone–binding globulin may have a causal role in the risk of type 2 diabetes.

Conclusions Low circulating levels of sex hormone–binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.

Source Information

From the Departments of Nutrition (E.L.D., D.J.H.) and Epidemiology (E.L.D., J.E.M., D.J.H., J.E.B.), Harvard School of Public Health; the Division of Preventive Medicine (E.L.D., Y.S., J.E.M., J.E.B., J.M.G.), Channing Laboratory (E.L.D., J.E.M., D.J.H.), and the Division of Aging (J.M.G.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; the Department of Laboratory Medicine, Children's Hospital and Harvard Medical School (N.R.); and Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs (VA) Boston Healthcare System (J.M.G.) — all in Boston; and VA Greater Los Angeles Healthcare System (C.C.L.); the Department of Epidemiology, Program on Genomics and Nutrition and Center for Metabolic Disease Prevention, UCLA School of Public Health (C.C.L., S.L.); the Department of Medicine, UCLA David Geffen School of Medicine (C.C.L., S.L.); and Jonsson Comprehensive Cancer Center, UCLA (S.L.) — all in Los Angeles.

Drs. Ding and Song contributed equally to this article.

This article (10.1056/NEJMoa0804381) was published on August 5, 2009, at NEJM.org.

Address reprint requests to Dr. Liu at the Center for Metabolic Disease Prevention, UCLA, CHS 73-265, Box 951772, 650 Charles E. Young Dr., Los Angeles, CA 90095-1772, or at siminliu{at}ucla.edu.

Full Text of this Article

Related Letters:

Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes
Stefan N., Schick F., Häring H.-U., Nestler J. E., Semple R., Savage D. B., O'Rahilly S., Liu S., Ding E., Song Y.
Extract | Full Text | PDF  
N Engl J Med 2009; 361:2675-2678, Dec 31, 2009. Correspondence

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