In this prospective study of postmenopausal women, caffeinated coffee and caffeine intakes were positively associated with plasma SHBG levels. Also, we observed an inverse association between intake of caffeinated coffee and caffeine and risk of type 2 diabetes. The associations were largely attenuated after adjustment for SHBG levels. Finally, carriers of the rs6259 minor allele and noncarriers of the rs6257 minor allele who reported high intake of caffeinated coffee had a lower risk of type 2 diabetes in directions corresponding to their associated plasma SHBG levels. These findings suggest that SHBG may account for the inverse association between caffeinated coffee and type 2 diabetes risk.
The inverse associations of caffeinated coffee and caffeine intake with type 2 diabetes risk observed in our study are consistent with findings from previous studies (1
). Several possible explanations have been put forth to explain the protective effect of coffee consumption on type 2 diabetes risk, including effects on insulin sensitivity and β-cell function by varying coffee components such as magnesium, potassium, chlorogenic acid, and caffeine (2
). To date, however, little is known about the underlying mechanisms. Evidence from a systematic review suggests the sex differences in the inverse association between coffee and type 2 diabetes risk (2
). Moreover, both observational and experimental data indicate the important roles of sex hormones in the development of type 2 diabetes (6
). SHBG is synthesized primarily in the liver and binds androgens with high affinity and estrogens with low affinity, thereby regulating the biologically active fraction of sex hormones (21
). Recently, it has been shown that the plasma membranes of a variety of cells are able to bind SHBG specifically and with high affinity, and SHBG mediates sex hormones signaling at the cell membrane through the SHBG receptors (9
). This discovery of the function of SHBG as a mediator of a steroid-signaling system has drawn much interest to the biological effects of SHBG. We first reported that lower levels of SHBG may be causally associated with type 2 diabetes risk using Mendelian randomization analyses (10
), findings of which have been replicated by a large consortium of case-control studies (22
). Taken together, we hypothesized that caffeinated coffee consumption may lower the risk of type 2 diabetes possibly by altering SHBG metabolism.
We found that caffeine and caffeinated coffee intakes were positively associated with plasma SHBG levels, which is consistent with earlier studies (4
). Little or no association between decaffeinated coffee and plasma SHBG levels suggest that caffeine may be a key component of coffee responsible for determining plasma SHBG levels. Moreover, our findings of little or no relations between caffeine-related beverage consumption and sex hormones suggest that caffeine may increase the level of plasma SHBG without directly altering sex hormones levels. Caffeine and other major components of coffee (cafestol and kahweol) alter expression and activity of liver enzymes (26
). Because SHBG is synthesized and metabolized primarily in the liver (21
), coffee intake may affect SHBG metabolism in the liver and influence the plasma levels of SHBG (5
Coffee may increase plasma SHBG levels, resulting not only in affecting the biological actions of sex hormones by binding to circulating androgens and estrogens but also in exerting direct metabolic effects (9
). Our findings thus provide a new explanation for the potential protective effect of coffee consumption on the type 2 diabetes risk. Notably, we found that carriers of the rs6259 minor allele and noncarriers of the rs6257 minor allele who reported high intake of caffeinated coffee had a lower risk of type 2 diabetes in directions corresponding to their associated plasma SHBG levels. These findings may further support the notion that SHBG may account for the potential protective effect of caffeinated coffee on type 2 diabetes. In contrast, the role of specific sex-steroids in relation to the coffee-diabetes relation remains to be determined.
The strengths of our study include its prospective study design with 10-year follow-up with comprehensive assessment of baseline variables, blood samples, and SHBG genotypes. Nevertheless, our study has several limitations. First, cross-sectional analyses of coffee consumption and plasma SHBG may be a concern, although it is not likely that endogenous sex hormones or SHBG would influence the consumption. Second, we cannot exclude the possibilities of residual confounding from unmeasured or incompletely measured covariates even though we have adjusted for many major risk factors for type 2 diabetes. Third, misclassifications of dietary intakes and biomarker measures are inevitable. For example, there may be measurement errors of plasma sex hormones and SHBG because of the limitations of stored samples. However, because case subjects were identified prospectively and case-control pairs were matched and handled in an identical fashion in the same analytical run, any potential misclassifications should affect case and control subjects equally. Therefore, such misclassifications were likely to be nondifferential, which would lead to an underestimation of the associations. Fourth, there is a concern about the possibility of residual confounding from unmeasured time-dependent confounders when a standard method is performed to adjust for both an exposure and a measured intermediate variable. However, we consider it is less likely that such residual confounding would substantially explain our findings, because our observed associations appear to be consistent with the observed genetically determined SHBG levels when stratifying by SHBG genotypes. Finally, our study only included postmenopausal women, which may limit the generalizability of our findings to premenopausal women or men.
In conclusion, our results suggest that SHBG levels may account for the potential protective effect of habitual coffee consumption against type 2 diabetes risk among postmenopausal women. A better understanding of the underlying mechanisms requires further investigation in both observational and experimental settings.