In this prospective cohort study, we found a modest inverse association between zinc intake and risk of type 2 diabetes in U.S. women after adjustment of established and potential confounders. In addition, a higher zinc–to–heme iron ratio was associated with a significantly lower risk of type 2 diabetes.
The close relationship between zinc and insulin action was first documented by Scott (1
) in early 1930s, when zinc was found to be an integral component of crystalline insulin. Over the years, studies have shown that zinc ions play important roles in the biosynthesis, storage, and action of insulin (2
). Interestingly, certain zinc complexes, per se, showed insulinomimetic effects, including attenuating hyperglycemia and increasing lipogenesis, when these complexes were orally or intraperitoneally administrated to mice (6
). Studies on mechanisms underlying the effects of zinc on insulin signaling are limited. But current evidence suggested that enhancement of tyrosine kinase phosphorylation in insulin signal transduction (18
) and improved binding of insulin to its receptor may be involved (3
). Another line of evidence indicated that zinc could act as an antioxidant as well. Zinc may protect insulin and β-cells from being attacked by free radicals by playing a structural role of antioxidant enzymes, such as copper, zinc, and superoxide dismutase (CuZnSOD) (19
), by competing with redox-active transitional metals, such as iron (19
), or by stimulating expression of metallothionein (21
), a free-radical scavenger (22
Despite this evidence, human data regarding this association are sparse (9
). To our knowledge, the current study provided the first prospective epidemiologic data suggesting an inverse association between zinc intake and risk of type 2 diabetes. In the U.S. diet, the primary sources of zinc include cereals, meats, and dairy products, as well as supplements (23
). In the current analysis, the magnitude of associations for the highest quintile was similar for total and dietary zinc intake despite the fact that the median level of the former was nearly twice as high as the latter, indicating that zinc supplementation may not further decrease the risk of type 2 diabetes in people with high dietary zinc intake. Indeed, in the current analysis, zinc intake from supplements was associated with a lower risk of type 2 diabetes only among those who had low levels of dietary zinc intake and vice versa. The average intake levels in our participants have reached the recommended dietary allowance, which is 8 mg/day for women (11
). The bioavailability of zinc is higher for zinc supplements than for zinc from foods, but when dietary intake levels are adequate, additional zinc intake from supplements may not confer further benefits (11
In the current study, a higher dietary zinc–to–heme iron ratio was significantly associated with a lower diabetes risk. Although it is clear that nonheme iron can inhibit inorganic zinc absorption, few studies have examined the interplay between heme iron and organic zinc in foods (13
). It is possible that heme iron, for which absorption is through separate pathways and is less regulated than inorganic nonheme iron (24
), may inhibit dietary zinc absorption but has weaker effects on highly bioavailable supplemental zinc absorption. Another possible mechanism for zinc-heme iron interaction is that zinc may compete with iron ions for chelation by the organic ligand cysteine and thus inhibit the production of hydroxyl radicals in human body (20
). Heme iron contributes to high body iron stores, which has been demonstrated to be a risk factor for type 2 diabetes (25
One of the strengths of this prospective study design was that dietary data were collected before the occurrence of disease so that disease status could not influence the self-report of diet. We further stopped updating the dietary data after report of chronic diseases that might change the diet of the participants. By calculating the cumulative average of dietary intakes, we minimized the measurement errors caused by change of diet over time (17
). Several limitations are worth discussion as well. Although we adjusted for a multitude of established and potential lifestyle and dietary confounders, we cannot entirely exclude the possibility that residual confounding may explain the observed associations. In addition, despite that the FFQs were validated against multiple diet records, assessment of zinc intake was still inevitably subject to some measurement error. However, since the dietary intakes of zinc were assessed prospectively, such measurement error is more likely to be random and thus attenuate the true associations. Because the vast majority of participants in the current study were white nurses, it is important to examine whether the results can be generalized to women of other ethnicities or professions in future studies. Finally, we observed these significant associations only after using cumulative average of diet and stopping diet updates after participants developed chronic diseases. Our previous analyses have shown that the use of cumulative averages yielded stronger estimates than the use of baseline diet only or simply updated diet (17
), probably because the cumulative averages reduce measurement errors and also reflect long-term diet.
In summary, the current study provided novel evidence that zinc intake may be associated with a lower risk of type 2 diabetes in U.S. women. Our results also suggest that a diet with high zinc–to–heme iron ratio is significantly associated with lower risk of type 2 diabetes. These findings are considered preliminary, and, thus, further studies are warranted to confirm these findings.