OBJECTIVE -Low-level exposure to some persistent organic pollutants (POPs) has recently become a focus because of their possible link with the risk of diabetes.RESEARCH DESIGN AND METHODS -Cross-sectional associations of the serum concentrations of POPs with diabetes prevalence were investigated in 2,016 adult participants in the National Health and Nutrition Examination Survey 1999 -2002. Six POPs (2,2Ј,4,4Ј,5,5Ј-hexachlorobiphenyl, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin, oxychlordane, p,pЈ-dichlorodiphenyltrichloroethane, and trans-nonachlor) were selected, because they were detectable in Ն80% of participants.RESULTS -Compared with subjects with serum concentrations below the limit of detection, after adjustment for age, sex, race and ethnicity, poverty income ratio, BMI, and waist circumference, diabetes prevalence was strongly positively associated with lipid-adjusted serum concentrations of all six POPs. When the participants were classified according to the sum of category numbers of the six POPs, adjusted odds ratios were 1.0, 14.0, 14.7, 38.3, and 37.7 (P for trend Ͻ 0.001). The association was consistent in stratified analyses and stronger in younger participants, Mexican Americans, and obese individuals.CONCLUSIONS -There were striking dose-response relations between serum concentrations of six selected POPs and the prevalence of diabetes. The strong graded association could offer a compelling challenge to future epidemiologic and toxicological research. Diabetes Care 29:1638 -1644, 2006P ersistent organic pollutants (POPs) have become widespread environmental contaminants and now represent a global problem (1). The toxicity of these pollutants in humans and wildlife is enhanced by their persistence in the environment and their bioaccumulation potential in the tissues of animals and humans through the food chain (1). POPs include a variety of man-made chemicals. Some POPs, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and several organochlorines used as pesticides have been highlighted by international organizations as being chemicals of concern (2).Low-level exposure to some POPs has recently been associated with an increased risk of diabetes (3). Prospective cohort studies of subjects exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent dioxin congener of POPs, or other POPs in occupational or accidental settings have reported increased risk of diabetes, modified glucose metabolism, or insulin resistance (4 -10). The U.S. Department of Veterans Affairs added type 2 diabetes to the list of presumptive diseases associated with the exposure to dioxin-containing Agent Orange in Vietnam (11).However, whether similar associations exist in the general population with lifetime exposure to very low doses of a mixture of various POPs is not known. Given that almost everyone has measurable amounts of POPs, the public health significance of a ...

Although oxidative stress has been proposed as a mechanism of lead and cadmium toxicity mostly based on in vitro experiments or animal studies, it is uncertain whether this mechanism is relevant in the pathogenesis of lead- or cadmium-related diseases in the general population with low environmental exposure to lead and cadmium. We examined associations of blood lead and urinary cadmium levels with oxidative stress markers of serum γ-glutamyltransferase (GGT), vitamin C, carotenoids, and vitamin E among 10,098 adult participants in the third U.S. National Health and Nutrition Examination Survey. After adjusting for race, sex, and age (plus serum total cholesterol in the case of serum carotenoids and vitamin E), blood lead and urinary cadmium levels both showed graded associations, positive with serum GGT and inverse with serum vitamin C, carotenoids, and vitamin E (p for trend < 0.01, respectively). These associations were consistently observed among most subgroups: non-Hispanic white, non-Hispanic black, men, women, all age groups, non-drinkers, drinkers, nonsmokers, ex-smokers, current smokers, and body mass index (< 25, 25–29.9, and ≥30). The strong association of blood lead and urinary cadmium levels with oxidative stress markers in this population suggests that oxidative stress should be considered in the pathogenesis of lead- and cadmium-related diseases even among people with low environmental exposure to lead and cadmium.

OBJECTIVE -Recently, we reported increased cardiovascular disease mortality among supplemental vitamin C users with type 2 diabetes in a prospective cohort study. Because vitamin C may cause oxidative stress in the presence of redox active iron, we hypothesized that nontransferrin-bound iron (NTBI), a form of iron susceptible to redox activity, may be present in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -We measured serum NTBI levels using highperformance liquid chromatography in 48 patients with known diabetes (at least 5 years duration since diagnosis), 49 patients with newly diagnosed diabetes, and 47 healthy control subjects (frequency matched on age and sex).RESULTS -NTBI was commonly present in diabetes: 59% in newly diagnosed diabetes and 92% in advanced diabetes. Mean NTBI values varied significantly between the three groups, with the highest values being observed in patients with known diabetes and the lowest in the control subjects (0.62 Ϯ 0.43 vs. 0.24 Ϯ 0.29 vs. 0.04 Ϯ 0.13 mol/l Fe). Serum total iron or percent transferrin saturation were very similar among the three groups, yet NTBI was strongly associated with serum total iron (r ϭ 0.74, P Ͻ 0.01) and percent transferrin saturation (r ϭ 0.70, P Ͻ 0.01) among the patients with known diabetes.CONCLUSIONS -Consistent with our hypothesis, these data demonstrate the common existence of NTBI in type 2 diabetic patients with a strong gradient with severity. Prospective cohort studies are required to clarify the clinical relevance of increased NTBI levels. Diabetes Care 29:1090 -1095, 2006R ecently, we reported that supplemental vitamin C intake in excess of 300 mg/day increased cardiovascular disease (CVD) mortality among postmenopausal women with type 2 diabetes in a prospective cohort study (1). This finding was unexpected in that it is contrary to the general belief that supplemental vitamin C intake is beneficial for patients with type 2 diabetes because they tend to have lower serum vitamin C levels (2,3). One explanation for this finding is that vitamin C may interact with redox active iron in patients with type 2 diabetes (4,5).Although the prooxidant reaction of vitamin C occurs readily in vitro, its relevance in vivo has been a matter of some controversy, the main point of contention being the availability of redox active iron in vivo (6). Levels of redox active iron are thought to be low due to their sequestration by various metal-binding proteins such as transferrin (7). It is generally believed that non-transferrin-bound iron (NTBI) possesses redox activity but only appears in serum when transferrin is fully iron saturated (8). However, recent studies have demonstrated that NTBI can be detected when transferrin is not fully saturated, leading to a revision of the original understanding that NTBI results from a simple spillover phenomenon (9 -11). Interestingly, a disturbance of iron metabolism and/or iron overload has recently been suggested as a mechanism of the pathogenesis of both diabetes and CVD complications (12,13).The ...

Serum gamma-glutamyltransferase (GGT) concentration, within its normal range, has recently been proposed as a reliable marker of oxidative stress. Oxidative stress plays a central pathogenic role in many metabolic and/or cardiovascular diseases, incidences of which have recently increased in South Korea. Since serum GGT has strong associations with these diseases and their risk factors, the authors hypothesized a corresponding secular trend of increasing serum GGT levels in South Korea. Study subjects were 8,072 male workers at a large steel company who were aged 24-44 years at baseline and had received annual physical examinations from 1996 to 2003. The secular trend was a 0.1066-units/liter increase in ln(GGT) level per calendar year (a 180% increase during the 7-year follow-up period) (p < 0.01). Adjustment for body mass index, alcohol consumption, smoking, exercise, and cholesterol level as time-dependent covariates did not change the results. Although cholesterol is commonly used as a marker of epidemiologic transition, there was a less dramatic secular trend in ln(serum cholesterol) level, and it disappeared after adjustment for the secular trend in serum GGT. These findings suggest that serum GGT concentration can be used as a sensitive marker of epidemiologic transition, and they portend a continuing rise in incidences of metabolic and/or cardiovascular diseases in this population in the coming years.

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