Iron is a transition metal that can easily become oxidized and thus act as an oxidant in the body . The general effect of catalytic iron is to convert poorly reactive free radicals, such as H2O2, into highly reactive ones, such as the hydroxyl radical . A recent review paper has reported influences of iron metabolism on Type 2 diabetes based on experimental and epidemiological studies . The possible mechanisms are as follows: firstly, increased accumulation of iron affects insulin synthesis and secretion in the pancreas and interferes with the insulin-extracting capacity of the liver; secondly, iron deposition in muscle decreases glucose uptake because of muscle damage; and thirdly, conversely, insulin stimulates cellular iron uptake through increased transferrin receptor externalization . Thus, insulin and iron might act synergistically, contributing, in a vicious cycle, to insulin resistance and diabetes .
Although obesity is the most important risk factor for Type 2 diabetes, in this large prospective cohort study of women, we found evidence for an independent positive association between dietary heme iron and risk of diabetes, initially diagnosed after menopause and therefore most likely of the Type 2 form. In addition, the association was stronger in those who consumed higher amounts of alcohol. Non-heme iron, which comprises 91% of total dietary iron, similar to another US study , showed a different relation. Non-heme iron was inversely associated with Type 2 diabetes among non-drinkers, but this apparent advantage disappeared among drinkers.
Even though most dietary iron comes from non-heme sources, heme iron absorption is about five to ten times greater than non-heme iron absorption. The absorption of heme iron is less sensitive to body iron stores and not influenced by other dietary factors . Some population studies showed a positive association between meat intake or heme iron and serum ferritin, a marker of stored body iron, but the association of non-heme iron intake with serum ferritin was negligible [16, 25], although the findings have not been totally consistent [26, 27, 28].
In this cohort, 91% of total dietary iron was from non-heme sources. Therefore, even considering the low absorption rate of non-heme iron, the absolute amount of available non-heme iron might be similar to that of available heme iron. Currently, there is no evidence that the two types of iron play a different role after absorption in the human body. Other nutrients and unknown components of the main food sources of non-heme iron, such as grains, fruits, and vegetables might explain any beneficial effect of non-heme iron among non-drinkers. Such a prudent diet, characterized by higher consumption of vegetables, fruit, fish, poultry, and whole grains, is associated with a lower risk of Type 2 diabetes . The inverse association between non-heme iron and Type 2 diabetes remained even after adjusting for vegetable fat and cereal fibre, which are known beneficial nutrients contained in the main food sources of non-heme iron [30, 31]. However, these specific dietary factors probably explain only part of the effect of diet on glucose metabolism; a direct effect of dietary non-heme iron is consistent with a disappearance of the inverse association of non-heme iron with Type 2 diabetes among drinkers. The beneficial effect of other dietary components might be countered by a harmful effect of non-heme iron, which was expected to mostly exert its effect, if any, among drinkers.
Supplemental iron showed a positive trend with Type 2 diabetes incidence among women who took more than or equal to 30 mg/d and the association became stronger among heavier drinkers, in agreement with our hypothesis. We used 30 mg/d as a cut-off point because, in elderly participants in the Framingham Heart Study cohort , the risk of having high iron stores was higher in subjects who took more than or equal to 30 mg/d supplemental iron than in nonusers. We note that the use of supplemental iron might not increase risk in the presence of iron-deficiency anaemia; however, the baseline iron status of these Iowa women is not known.
It is generally believed that light or moderate alcohol consumption can be helpful for preventing Type 2 diabetes [33, 34]. In this study, alcohol (mean consumption: 4.5 g/d) also showed an inverse association with Type 2 diabetes. However, we hypothesized that alcohol consumption could interact with iron because the regular consumption of alcohol can disrupt normal iron metabolism in humans, resulting in the excess deposition of iron in the liver . This could happen irrespective of mechanisms relating the beneficial effect of light or moderate alcohol consumption to the development of Type 2 diabetes. A possible harmful effect of alcohol related with iron metabolism might be only a small part of alcohol’s various effects. Thus, a net effect of low or moderate alcohol consumption seems to be beneficial in the risk of diabetes. However, in this study, alcohol consumption was chosen as one of possible situations that can disturb iron metabolism. We speculate that there might be other conditions related with iron metabolism, even though at present they are unknown. Therefore, our results should be interpreted as showing that high iron intake might increase the risk of diabetes under certain situations that can disturb iron metabolism. Our result should not be interpreted to stop drinking alcohol.
The underlying mechanism of the association between alcohol consumption and abnormal iron metabolism is largely unknown; however, it is likely that the two major proteins of iron metabolism, ferritin and transferrin, are intimately involved in the process . The relation between alcohol consumption and disturbance of iron metabolism has mostly been observed among alcoholics ; however, recent studies have reported that, even in general populations, there is a positive dose-response relationship between the amount of alcohol consumed and serum ferritin level [15, 16, 17]. For example, those who consumed 10 g/d of alcohol had higher ferritin levels than non-drinkers . Therefore, the effect of alcohol on iron metabolism seems to start at a lower level than what was believed. Based on these observations, we hypothesized that, if there were an effect of iron intake on the risk of Type 2 diabetes, it would be a stronger association among drinkers.
The main food source of heme-iron is red meat ; other meat constituents besides iron might explain our findings. Indeed, the association between red meat and Type 2 diabetes was positive and very similar to that for heme iron: as alcohol consumption increased, the positive association became stronger. Some studies have reported a positive association between meat or processed meat intake and Type 2 diabetes [31, 35]. Saturated fat intake or nitrites were the main interests in these papers, but saturated fat intake was not associated with Type 2 diabetes in most large prospective studies [31, 35, 36], and the relevance of nitrites or nitrite-derived nitrosamines for Type 2 diabetes is unclear .
This study was limited by the lack of biological samples. In addition, measurement of diet and diabetes was imperfect. The reproducibility and validation of the food-frequency questionnaire used in Iowa Women’s Health Study was evaluated in 44 study participants . The reproducibility of total dietary iron was similar to that of macronutrients (r=0.47–0.81), whereas the validity compared with five 24-h dietary recalls was very low (r=0.07 unadjusted for total energy; −0.09 adjusted for total energy). The absolute amount of dietary iron intake measured by the food frequency questionnaire was only half of that of the five 24-h dietary recalls. Most dietary iron is in the form of non-heme iron and an important source of non-heme iron is iron-fortified commercial foods such as breakfast cereal. Thus, a choice of a specific brand or type during the period of dietary recall survey might greatly influence the absolute amount of dietary iron intake, and therefore result in a very low validity because the food frequency questionnaire had limited information on breakfast cereal. Non-heme and heme iron were not reported separately, but the two types of dietary iron might show a different reproducibility and validity because their main food sources, and their validities, are different. Main food sources of heme iron are very limited compared with non-heme iron. Therefore, validity of heme iron might be much higher than those of non-heme iron. For example, the validity of heme iron might be similar to that of saturated fat, which has similar food sources with heme iron. Differential validity of measurement between non-heme and heme iron might explain the observed difference in association with incident Type 2 diabetes.
Incident cases of Type 2 diabetes were ascertained by self-report. A validation study of self-reported diabetes was conducted on 85 cohort participants in 1988 after the first follow-up survey. Subjects tend to over-report having diabetes; of 44 women who reported having diabetes at baseline, 28 (64%) were confirmed as having diabetes by their physician . All 41 women who reported not having diabetes at baseline were confirmed as not having diabetes. Non-validated positive reports could nonetheless reflect some level of diabetes. One study  found that several people with non-validated positive reports of diabetes had some history of glycosuria. Furthermore, the fasting glucose criterion for diabetes was more than or equal to 140 mg/dl in 1988, but has subsequently been lowered to less than or equal to 126 mg/dl. Thus, some women who falsely reported a diagnosis of diabetes might still have some level of underlying disease, such as impaired glucose tolerance. The ascertainment of diabetes in the present study was sensitive enough to confirm associations with other known risk factors for Type 2 diabetes. Assuming that the error in diabetes ascertainment was independent and nondifferential, the present findings would only be strengthened by more accurate ascertainment of disease.
In summary, although obesity is the most important risk factor for Type 2 diabetes, our results suggest that a high dietary heme iron intake and/or supplemental iron is associated with an increased risk of Type 2 diabetes, especially among drinkers. Further studies with biochemical indicators of body iron stores would be desirable to further evaluate this possible interaction among Type 2 diabetes, dietary iron and alcohol intake.