Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Women and Men

By E. Ding, Yiqing Song, JoAnn E. Manson, D. Hunter, Cathy C. Lee, N. Rifai, J. Buring, J. Gaziano, Simin Liu. New England Journal of Medicine, 2009

664 citations recorded by the source corpus.

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.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Reproductive Medicine

View Paper: https://www.semanticscholar.org/paper/8304a1b18bad90056b3a2485d1ea23a1536c3a21

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Citations in the corpus

Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study (2012, background): “…randomisation analysis—ie, that the genotype should be associated with an intermediate biomarker (ﬁ gure 1), should not be associated with confounding factors (appendix pp 24–46), and should exert its eﬀ ect on the clinical outcome only through the speciﬁ c intermediate biomarker (appendix p 22).”
Insulin-sensitive obesity. (2010, background): “Low SHBG serum concentrations have previously been shown to significantly predict the risk of type 2 diabetes in both women and men (11).”
Heart Disease and Stroke Statistics—2016 Update: A Report From the American Heart Association (2016, neutral): “● ● An overview of the costs of various strategies for primary prevention of CVD determined that the estimated costs per year of life gained were between $9800 and $18 000 for statin therapy, $1500 for nurse screening and lifestyle advice, $500 to $1250 for smoking cessation, and $20 to $900 for pop”
The role of estrogens in control of energy balance and glucose homeostasis. (2013, background): “However, they also exhibited increased free serum T concentration and decreased SHBG concentrations.”
Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus (2016, background): “Additionally, low sex hormone-binding globulin (SHBG) levels may indicate diabetes-risk potentially mediated via SHBG gene polymorphisms (60, 61).”
Heart Disease and Stroke Statistics—2015 Update: A Report From the American Heart Association (2009, neutral): “The share increases as absolute income levels decline.(115) ● Among 153 forms of fruits and vegetables priced with 2008 Nielsen Homescan data, price and calorie per portion of 20 fruits and vegetables were compared with 20 common snack foods such as cookies, chips, pastries, and crackers.”