Sex hormone-binding globulin and risk of type 2 diabetes in women and men
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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.
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Particular single nucleotide polymorphisms (SNPs) for SHBG confer increased risk for type 2 diabetes.
“Particular single nucleotide polymorphisms (SNPs) for SHBG confer increased risk for T2D (102, 104).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [102]
For carriers of rs6257 and rs6259, a decrease and an increase of SHBG were observed, respectively.
“Finally, for carriers of two other SNPs, rs6257 and rs6259, a decrease and, respectively, an increase of SHBG was observed [75].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [75]
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- Authors
- Ding, E. L., Song, Y., Manson, J. E., Hunter, D. J., Lee, C. C., Rifai, N., Buring, J. E., Gaziano, J. M., & Liu, S.
- Affiliations
- Harvard University (US)
- University of California, Los Angeles (US)
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-09-17
- Volume
- 361
- Issue
- 12
- Pages
- 1152-1163
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2774225
- OpenAlex
- W1966222552
- Cited by
- 726
- References
- 42
- Citations by year
- 2026: 32 · 2025: 34 · 2024: 42 · 2023: 33 · 2022: 41 · 2021: 51 · 2020: 34 · 2019: 36 · 2018: 33 · 2017: 44 · 2016: 36 · 2015: 48 · 2014: 48 · 2013: 50 · 2012: 65
- FWCI
- 39.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl043851-10)
- National Heart, Lung, and Blood Institute (R01HL080467, R01‐HL043851, R01 HL026490, HL080467, R01HL034595)
- National Cancer Institute (R01CA040360, R01 CA034944, CA-097193, R01CA097193, CA 047988, CA 40360, R01CA047988)
- National Institute of Diabetes and Digestive and Kidney Diseases (L30 DK084809, K01DK078846, DK066401, R01DK066401)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- sex hormone-binding globulin, type 2 diabetes, diabetes risk, postmenopausal women, men, insulin resistance, sex differences, genetic association, Mendelian randomization, plasma biomarkers, Women's Health Study
- MeSH terms
- Diabetes Mellitus, Type 2, Female, Genotype, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, ROC Curve, Sex Hormone-Binding Globulin, Biomarkers, Linkage Disequilibrium, Multivariate Analysis, Linear Models, Case-Control Studies, Postmenopause, Polymorphism, Single Nucleotide
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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