Objective: Coffee consumption has been inversely associated with type 2 diabetes risk, but its mechanisms are largely unknown. We aimed to examine whether plasma levels of sex hormones and sex hormone-binding globulin (SHBG) may account for the inverse association between coffee consumption and type 2 diabetes risk.

Research Design and Methods: We conducted a case-control study nested in the prospective Women's Health Study. During a median followup of 10 years, 359 postmenopausal women with newly diagnosed type 2 diabetes were matched with 359 controls by age, race, duration of follow-up, and time of blood draw.

Results: Caffeinated-coffee was positively associated with SHBG but not with sex hormones. Multivariable-adjusted geometric mean levels of SHBG were 26.6 nmol/L among women consuming ≥4 cups/day of caffeinated-coffee and 23.0 nmol/L among non-drinkers (P for trend = 0.01). In contrast, neither decaffeinated-coffee nor tea was associated with SHBG or sex hormones. Multivariable-adjusted odds ratio (OR) of type 2 diabetes for women consuming ≥4 cups/day of caffeinated-coffee compared with non-drinkers was 0.47 (95% CI, 0.23 – 0.94; P for trend = 0.047). The association was largely attenuated after further adjusting for SHBG (OR=0.71; 95% CI, 0.31 – 1.61; P for trend = 0.47). In addition, carriers of rs6259 minor allele and non-carriers of rs6257 minor allele of SHBG gene consuming ≥2 cups/day of caffeinated-coffee had lower risk of type 2 diabetes in directions corresponding to their associated SHBG.

Conclusions: Our findings suggest that SHBG may account for the inverse association between coffee consumption and type 2 diabetes risk among postmenopausal women.