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Diabetes Risk Linked to Sex Hormone Protein
Posted: Wednesday, August 12, 2009
A new study found that people with low blood levels of a protein that regulates sex hormones are at higher risk of diabetes, and genetics may play a role in determining both the levels and the risk.
Men and women with the lowest blood levels of sex hormone-binding globulin (SHBG) were 10 times more likely to develop Type 2 diabetes than those with the highest levels of the protein (P<0.001 for trend), according to the study.
The association held up after adjusting for a range of factors, including weight, smoking status, exercise, and high blood pressure, Simin Liu, MD, ScD, of the University of California Los Angeles, and colleagues wrote.
They also found that blood levels of SHBG had a genetic component, with carriers of two single-nucleotide polymorphisms (SNPs) -- rs6259 and rs6257 -- having 10% higher and lower levels of SHBG, respectively, than people who carried the most common allele (P=0.005 for rs6259, P=0.004 for rs6257).
Variants of both SNPs were also associated with risk of Type 2 diabetes with rs6259 lowering risk and rs6257 raising risk.
"These strong and consistent findings obtained with the use of multiple analytical 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," the investigators said.
Researchers have long known that SHBG binds to sex hormones circulating in the blood to regulate their action, but since the mid-1990s evidence has emerged to suggest that they also mediate other aspects of metabolism and cellular function.
Clinical studies have indicated that low levels of SHBG were associated with impaired control of blood glucose and that even when sex hormones are bound to SHBG they are associated with risk of diabetes. However, few long-term prospective studies have directly examined the role of SHBG in the development of Type 2 diabetes, particularly in women.
So Liu and colleagues measured the plasma levels of SHBG in 718 postmenopausal women participating in the Women's Health Study, a National Institutes of Health project focusing on prevention of cardiovascular disease and cancer in women. Half of the women had recently been diagnosed with Type 2 diabetes and the other half served as controls.
In addition to measuring blood levels of SHBG, the researchers checked the participants for rs6259 and rs6257, two polymorphisms of the gene that encodes SHBG that are strongly associated with blood levels of the protein.
The researchers also replicated the study in an independent cohort of men (170 newly diagnosed with diabetes and 170 controls) from the Physicians' Health Study II, a long-running study on cardiovascular disease and cancer.
Participants in the study were placed into four groups based on their SHBG levels.
Compared with the women who had the lowest levels of the protein (5.8 to 24.7 nmol/liter), the odds ratios of Type 2 diabetes for the other three groups from lowest to highest levels were as follows (P<0.001 for trend):
· Quartile 2 (24.8 to 34.6 nmol/liter): 0.16 (95% confidence interval 0.08 to 0.33)
· Quartile 3 (34.7 to 44.3 nmol/liter): 0.04 (95% CI 0.01 to 0.12)
· Quartile 4 (44.4 to 122.4 nmol/liter): 0.09 (95% CI 0.03 to 0.21)
For the men, the associations were similar, with an odds ratio of 0.10 (95% CI 0.03 to 0.36) for diabetes in the group with the highest blood levels of SHBG compared with the group with the lowest levels (P<0.001 for trend). In addition to the links between the two SHBG SNPs and blood levels of the protein, Mendelian randomization analyses showed that the odds of Type 2 diabetes dropped as levels of SHBG increased.
Each standard deviation increase in plasma levels of the protein resulted in a 0.28 reduction in the odds ratio for diabetes in women (95% CI 0.13 to 0.58) and 0.29 in men (95% CI 0.15 to 0.58).
The researchers noted that the statistical power of their study was limited by its size, especially with regard to the genetic associations, but that the links between blood levels of SHBG, the two SHBG SNPs, and diabetes were consistent between the two study cohorts.
"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," they wrote.
"Two germ-line variants in the SHBG gene were also identified as being directly associated with both blood plasma levels of sex hormone-binding globulin and the risk of Type 2 diabetes."
Note that patients who carry variants of the gene for sex hormone-binding globulin may be at varying risk for Type 2 diabetes.
Note that blood levels of sex hormone-binding globulin may be predictive of Type 2 diabetes risk.
Source: Diabetes In Control: Liu S, et al "Sex hormone-binding globulin and risk of Type 2 diabetes in women and men" New Engl J Med 2009: DOI: 10.1056/NEJMoa0804381.
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