This study examined the association between sex hormone-binding globulin (SHBG) levels and risk of type 2 diabetes in women and men. The study found that individuals with the highest SHBG quartile had a 10-fold lower risk of developing type 2 diabetes compared to those in the lowest quartule. Genetic variants of SHBG that were associated with higher SHBG levels also reduced risk of type 2 diabetes. Both observational analyses and Mendelian randomization analyses confirmed the strong relationship between plasma SHBG levels and lower risk of type 2 diabetes, independent of other risk factors. The results suggest SHBG levels may help predict risk of type 2 diabetes beyond traditional risk factors.

1. Original Article (NEJM-8/5/09)
Presented by Zainab Basheer (Research volunteer)


2. Sex Hormone–Binding Globulin and Risk of
Type 2 Diabetes in Women and Men
Eric L. Ding, Sc.D., Yiqing Song, M.D., Sc.D., JoAnn E.
Manson, M.D., Dr.P.H., David J. Hunter, M.B., B.S.,
Sc.D., Cathy C. Lee, M.D., Nader Rifai, Ph.D., Julie E.
Buring, Sc.D., J. Michael Gaziano, M.D., M.P.H., and
Simin Liu, M.D., Sc.D.

3. Background
 Circulating SHBG levels are inversely associated
with insulin resistance, but whether these levels
can predict the risk of developing type 2
diabetes is uncertain.

4. Methods
 Study Population
 The Women's Health Study begun in 1993
 39,876 female >28,345 >12,304 were postmenopausal and were
not using hormone-replacement therapy at the time of blood
collection .
 10 yr f/u period, 366 cases new DM 2
 Using risk set sampling , 359 case patients and 359 matched
controls were selected .
■ Physicians' Health Study II of men begun in 1997
 14,641 US male physicians> 11,130
 8 yr f/u period, 170 new DM 2
 Using risk set sampling ,170 cases and 170 matched controls
were selected

5. Methods (con)
Laboratory Procedures
 Plasma levels of sex hormone–binding globulin were measured
with the use of a chemiluminescent immunoassay validated for
plasma sex hormone–binding globulin
 Genotyping of SHBG polymorphisms of women and replication
genotyping of men were conducted in two separate labs using
PCR amplification. Five SNPs were genotyped in women namely
rs6257 , rs6258 , rs6259 , rs6260 , rs9282845
 Two informative SNPs, rs6257 and rs6259, were included in the
study

6. Methods(con)
■ Statistical analysis
 The distributions of plasma SHBG levels among
controls into quartiles and compared baseline
characteristics across the quartiles
 Simple and multivariable models in women,
 Simple and multivariable models in men
 Sensitivity models

7. Methods (con)
 In mendelian randomisation analyses
 SHBG variants seem to satisfy 3 main criteria :-
1) Genotypes should be robustly associated with the intermediate
phenotype
2) No confounding factors b/w the intermediate phenotype and
disease outcome
3) It’s effect on the clinical outcome only thru the specific
intermediate phenotype
■ The mendelian randomization estimate reflects the potential
causal effect of SHBG levels on the risk of type 2 diabetes

8. Results

9. Results

10. Results

11. Results

12. Results

13. Results

14. Discussion
 The risk for type 2 DM in participants with highest
SHBG quartile is 1/10 compared to the ones with
lowest SHBG quartile
 Variants of SHBG SNP’ rs6257 & rs6259 were
associated with a risk of type 2 DM depending on their
respective effects on SHBG levels.
 The strong relation b/w plasma SHBG levels and type
2 DM confirmed both in multivariable analyses and in
mendelian randomization analyses.

15. Discussion
 SHBG plasma levels appeared to have a
predictive ability for the risk of type 2 DM
beyond that of traditional risk factors, including
HbA1c & CRP
£ Limitation
Statistical power < 600 newly diagnosed type 2
DM in the 2 cohorts
Biomarkers, plasma SHBG levels were modestly
correlated with adiposity

16. 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.

17. Thank you