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T
ype 2 diabetes is becoming more Hand reported a higher dioxin level in
prevalent throughout the world, diabetic patients compared with nondia- zofurans (PCDFs) during an average of
and although a number of conven- betic subjects (2). Longnecker et al. (3) nine months’ exposure to the contami-
tional risk factors have already been iden- revealed a 30% higher level of total PCBs nated oil. Most (83%) of the blood levels
tified, they can only partly explain such in diabetic (primarily type 1) pregnant ranged from 11 to 150 ppb. The current
high levels of incidence. Polychlorinated women than in nondiabetic subjects re- 24-year follow-up study of the Yucheng
biphenyls (PCBs) and dioxins are persis- cruited in 1959 –1966. Similar conclu- cohort provides a good opportunity to ex-
tent organic pollutants (POPs) with long sions were drawn from the National amine the hypothesis that raised levels of
half-lives in the human body, and they Health and Nutrition Examination Survey PCBs and dibenzofurans (DFs) might be
may act as endocrine disruptors and ex- (NHANES) (4) and other population associated with an increased risk of dia-
hibit endocrine system effects (1). The studies in Belgium (5), Michigan (6), and betes. Though obese people have been en-
study of veterans of Operation Ranch Seveso, Italy (7). These data raised great couraged to reduce body weight by
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● calorie restriction, serum levels of total
PCBs have been shown to increase in the
From the 1Division of Environmental Health and Occupational Medicine, National Health Research Insti-
tutes, Miaoli, Taiwan; the 2Institute of Environmental Medicine, College of Public Health, China Medical 6 –9 months following the weight-loss
University Hospital, Taichung, Taiwan; the 3Department of Basic Medical Sciences, National Cheng-Kung program (13). Studying the effects of
University Medical College, Tainan, Taiwan; the 4Department of Health Business Administration, Hung- POPs on the degree of risk of type 2 dia-
Kuang University, Taichung, Taiwan; and the 5Department of Environmental and Occupational Medi- betes is clearly relevant to managing both
cine, National Taiwan University College of Medicine, and National Taiwan University Hospital, Taipei,
Taiwan.
diabetes and obesity in modern societies.
Corresponding author: Yueliang Leon Guo, leonguo@ntu.edu.tw.
Received 26 December 2007 and accepted 13 May 2008.
Published ahead of print at http://care.diabetesjournals.org on 16 May 2008. DOI: 10.2337/dc07-2449. RESEARCH DESIGN AND
© 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly METHODS — Beginning in 1992 and
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
using the addresses listed for the 2,061
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby victims in the Yucheng registry obtained
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. from the Taiwan Provincial Department
Table 1—General characteristics of the Yucheng cohort and their matched reference group aged >30 years in 1993
Men Women
Yucheng Reference group P Yucheng Reference group P
n 155 152 — 223 218 —
Age in 1993 (years) 59.6 ⫾ 11.5 58.9 ⫾ 11.5 ns 52.2 ⫾ 10.6 51.6 ⫾ 10.5 ns
⬍55 62 (40.0) 63 (41.5) — 155 (69.5) 158 (72.5) —
55–64 37 (23.9) 40 (26.3) — 29 (13.0) 26 (11.9) —
ⱖ65 56 (36.1) 49 (32.2) — 39 (17.5) 34 (15.6) —
BMI (kg/m2) 24.1 ⫾ 3.1 24.0 ⫾ 3.1 ns 24.3 ⫾ 8.5 23.5 ⫾ 3.4 ns
Education (years) 7.2 ⫾ 4.1 7.2 ⫾ 3.7 ns 6.6 ⫾ 4.1 7.3 ⫾ 4.2 ns
Current smoker 85 (55.2) 93 (62.0) ns 2 (0.9) 1 (0.5) ns
Alcohol drinking 41 (26.8) 34 (22.8) ns 4 (1.8) 1 (0.5) ns
Occupation
ratios (ORs) for diabetes prevalence therapy, which rose to 6.6 (P ⬍ 0.05) af- that the exposure happened before onset
among the exposed, relative to reference ter further adjustment for BMI. For both of diabetes. However, caution should be
subjects, and multivariable logistic re- sexes, there was a slight but nonsignifi- exercised in interpreting the data because
gression was used to evaluate the ORs cant increase in the risk of developing hy- members of the Yucheng cohort group
with adjustments for potential confound- pertension and cardiovascular disease. were accidentally exposed to PCBs and
ing factors. For women, we did not carry We compared the rate at which diabetes PCDFs for nearly a year via a diet of con-
out further adjustments for cigarette developed in subjects that exhibited taminated oil. These results might not ap-
smoking (with only three smokers) and chloracne with the rate in which it devel- ply to the background population, and
alcohol intake (with only five drinkers) in oped in those free of chloracne and found further investigations are needed to con-
deriving a reliable model. We used JMP a highly significant age-adjusted OR of trol for the effects of different PCBs de-
5.0.1 software for all the analyses (SAS 4.6 (95% CI 1.9 –11.4) and AOR of 5.5 rived from sources other than those of the
Institute, Cary, NC). (2.3–13.4) in women but not in men (Ta- 1978 –1979 poisoning. A recent report
ble 3). The same pattern was found for using the NHANES data showed signifi-
RESULTS — Table 1 shows very simi- hypertension (AOR 3.5 [95% CI 1.7– cant association between non– dioxin-
lar distributions in age, sex, BMI, educa- 7.2]) and cardiovascular disease (3.0 like PCBs and increased risk of insulin
tion, lifestyle, and occupation between [1.5– 8.6]). resistance in nondiabetic subjects, partic-
the Yucheng cohort and the background- ularly those with a larger waist circumfer-
exposed reference group. Mean PCBs in CONCLUSIONS — We found that ence (18). For those in the upper quartile
the Yucheng subjects were about 40- to diabetes was twice as prevalent in of PCB 170 exposure, compared with the
50-fold those of the reference group. Men Yucheng women who had been exposed nondetectable reference group, the OR
appeared to be older than women by to PCBs and PCDFs during the 1978 – increased to 4.1 (P ⬍ 0.01). In the
around 7 years. We suspected that men 1979 poisoning as it was in the reference Yucheng cohort, a total of 33 PCB conge-
younger than 35 years old were too busy population in the long-term cohort study. ner profiles showed that PCB 170 consti-
working to get registered for special care The AOR significantly increased to 2.5 for tuted 13% of all PCB concentrations (16).
in 1979 –1980. those requiring therapy for diabetes and In addition to PCB 170, PCB 180 (which
The Yucheng subjects had a very high to 5.5 for those with chloracne, a condi- represented 14% of 33 PCBs), PCB 153
risk of developing chloracne compared tion symptomatic of POP poisoning. This (13%), and PCB 156 (13%) each repre-
with the reference group (Table 2). The correlation between POPs and diabetes is sented over 12% of the total PCBs. This
AOR (OR adjusted for age and BMI in consistent with the findings from cross- implies that certain PCB congeners might
women and age, BMI, cigarette smoking, sectional studies in Belgium (5) and the be associated with an increased risk of di-
and alcohol drinking in men) of diabetes U.S. (2,4,11,17,25). In the current study, abetes occurrence.
for the Yucheng cohort relative to the ref- most excess body burdens of PCBs and We further report that Yucheng
erence group remained significant in PCDFs were present in women with an women diagnosed with chloracne have a
women (OR 2.1; P ⬍ 0.05) after adjusting average age of 25 years, when type 2 dia- significantly increased risk of developing
for age and BMI. We found an age- betes most likely had not yet occurred. hypertension and cardiovascular disease.
adjusted OR of 6.4 (P ⬍ 0.05) in women The cumulative incidence associated with This increased risk of hypertension may
aged ⬎65 years who received diabetes PCB and DF exposure provides evidence partly result from diabetes complications
Data are n (%) unless otherwise indicated. *Age adjusted. †P ⬍0.05; ‡P ⬍ 0.001.
Cardiovascular disease
Hypertension without therapy
Hypertension with therapy
Table 2—Prevalence or ORs of reported diseases ever diagnosed by a physician in Yucheng, stratified by sex, in Taiwan from 1979 –2003
Aged ⱖ65
Aged 55–64
Aged ⬍55
Aged ⱖ65
Aged 55–64
Aged ⬍55
lence of increased blood pressure was
most strongly correlated with PCDFs,
particularly 1,2,3,4,7,8-HxCDF in nondi-
abetic subjects in the NHANES study
(22). This corresponded to data in the
Yucheng cohort, in which 1,2,3,4,7,8-
HxCDF (toxic equivalency factor 0.1) and
2,3,4,7,8-PeCDF (toxic equivalency fac-
tor 0.5) were important congeners, con-
tributing ⬃20 and 50% of the total
dioxins’ toxic equivalent quotients
(TEQs), respectively (16). This suggests
22 (14.2)
40 (26.0)
46 (30.0)
10 (17.9)
22 (14.3)
10 (18.2)
22 (14.4)
66 (42.9)
Yucheng
9 (25.0)
3 (4.8)
9 (25.0)
3 (4.8)
that congeners containing PCDF or poly-
155
chlorinated dibenzo-dioxins might be as-
sociated with an increased risk of
Reference
17 (11.2)
31 (20.7)
39 (26.0)
17 (11.3)
10 (20.8)
22 (14.7)
9 (18.8)
5 (12.5)
3 (4.8)
5 (12.5)
7 (11.3)
1 (0.7)
17 (7.7)
12 (30.8)
25 (11.3)
51 (23.0)
Yucheng
6 (20.7)
7 (4.6)
223
12 (5.6)
2 (5.9)
0 (0.0)
5 (3.2)
7 (3.2)
5 (14.7)
0 (0.0)
7 (4.5)
0 (0.0)
0.6 (0.1–2.5)
2.5 (1.0–6.7)
2.6 (0.8–9.1)
1.0 (0.3–3.1)
2.2 (1.1–4.7)†
—
—
0.6 (0.1–2.5)
2.5 (1.0–6.5)†
2.6 (0.9–9.3)
1.0 (0.3–3.1)
2.1 (1.1–4.5)†
receptor agonists (19). CYP1A1 and diabetes among all registered Yucheng
5.5 (2.3–13.4)‡
3.5 (1.7–7.2)‡
3.0 (1.5–8.6)‡
CYP1B1 catalyze hydroxylation of the A- subjects (25). Additionally, the women
ring of estradiol (E2) to form the catechol appeared to be younger than the men by
AOR
—
—
—
—
estrogen 2- or 4-hydroxyl estradiol (2- ⬃7 years. One possibility for future study
Table 3—Lifetime prevalence of medical conditions in Yucheng individuals without (negative) or with (positive) reported chloracne aged >30 years, stratified by sex, in 2003
—
cause increased oxidative stress, which for women compared with men; thus,
has been associated with a range of vascu- our study is unlikely to have a biased
lar pathologies, including hypertension conclusion.
Women
and diabetes (21). Further investigations The present study did not include
0.0006
0.0009
0.0035
0.006
0.04
P
0.7
various POP detoxification pathways are such as exercise and total calorie intake,
tor (PPAR) pathway (23). Tetra- sure group. Furthermore, BMI, educa-
chlorinated dibenzo-p-dioxin cotreating tion, and occupational distribution were
estrogens were found to upregulate insu- similar between the exposed and refer-
lin-like growth factor binding protein-1 ence groups. A previous study showed
72.6 ⫾ 114.7
52.3 ⫾ 11.4
24.2 ⫾ 9.5
(IGFBP-1) in MCF-7 cells via the PPAR that lipid contents were similar between
27 (14.4)
22 (11.8)
Negative
11 (5.9)
186
pathway (24). These compounds may the two groups (16). We would expect the
counter the effects of insulin, which same conclusion after adjustments for dif-
downregulates IGFBP-1. Dioxins or diox- ferences in lipids, exercise, and total cal-
in-like chemicals may therefore disrupt orie intake.
glucose homeostasis. In conclusion, an increased cumula-
1.7 (0.7–4.6)
0.6 (0.3–1.1)
0.9 (0.4–2.2)
A hypertriglycemia state, often coex- tive incidence of type 2 diabetes was seen
AOR
—
—
—
isting with hypertriglycerides, might be among Yucheng women who had been
related to delayed degradation and/or ex- exposed to PCBs and PCDFs, particularly
cretion of the lipophilic compounds in di- among those diagnosed with chloracne.
abetic patients. In addition, metabolism In modern societies, the body burden of
1.7 (0.7–4.3)
0.7 (0.4–1.5)
1.3 (0.6–3.2)
of PCB- and DF-related genes, such as PCBs and dioxins clearly needs to be
CYP1A, CYP1B, and CYP11B (19,20), may considered within the framework of di-
OR*
—
—
—
—
P
53.9 ⫾ 53.2
References
11 (11.6)
34 (35.8)
14 (14.7)
24.2 ⫾ 3.0
Negative
subject (8,700 in pooled serum samples tissue: storage and effector site for envi-
[Prof. Yueliang Leon Guo, personal com- ronmental pollutants. Physiol Res 56:375–
munication]). Potential confounding ef- 381, 2007
fects from OCPs are therefore unlikely. 2. Henriksen GL, Ketchum NS, Michalek JE,
Cardiovascular disease
The effects of aging could have influ- Swaby JA: Serum dioxin and diabetes
mellitus in veterans of Operation Ranch
enced this 24-year follow-up study, since Hand. Epidemiology 8:252–258, 1997
members of the exposure group would be
Hypertension
PCBs (ppb)
Age (years)
expected to die sooner from diabetes JW, Zhou H: Polychlorinated biphenyl se-
Diabetes
and/or cardiovascular disease. This influ- rum levels in pregnant subjects with dia-
ence might be slight, as we found that betes. Diabetes Care 24:1099 –1101, 2001
only one man and six women died from 4. Everett CJ, Frithsen IL, Diaz VA, Koop-
n
man RJ, Simpson WM Jr, Mainous AG 1999 –2002. Diabetes Care 29:1638 – tor approach for risk assessment of diox-
3rd: Association of a polychlorinated 1644, 2006 ins and related compounds. J Anim Sci 76:
dibenzo-p-dioxin, a polychlorinated bi- 12. Hsu ST, Ma CI, Hsu SK, Wu SS, Hsu NH, 134 –141, 1998
phenyl, and DDT with diabetes in the Yeh CC, Wu SB: Discovery and epidemi- 20. Wang SL, Chang YC, Chao HR, Li CM, Li
1999 –2002 National Health and Nutri- ology of PCB poisoning in Taiwan: a four- LA, Lin LY, Papke O: Body burdens of
tion Examination Survey. Environ Res year follow-up. Environ Health Perspect polychlorinated dibenzo-p-dioxins, di-
103:413– 418, 2007 59:5–10, 1985 benzofurans, and biphenyls and their re-
5. Fierens S, Mairesse H, Heilier JF, De Bur- 13. Walford RL, Mock D, MacCallum T, La- lations to estrogen metabolism in preg-
bure C, Focant JF, Eppe G, De Pauw E, seter JL: Physiologic changes in humans nant women. Environ Health Perspect 114:
Bernard A: Dioxin/polychlorinated bi- subjected to severe, selective calorie re- 740 –745, 2006
phenyl body burden, diabetes and endo- striction for two years in biosphere 2:
21. Ceriello A: Possible role of oxidative stress
metriosis: findings in a population-based health, aging, and toxicological perspec-
in the pathogenesis of hypertension. Dia-
study in Belgium. Biomarkers 8:529 –534, tives. Toxicol Sci 52:61– 65, 1999
2003 14. Guo YL, Yu ML, Hsu CC, Rogan WJ: betes Care 31:S181–S184, 2008
6. Vasiliu O, Cameron L, Gardiner J, Chloracne, goiter, arthritis, and anemia 22. Lee DH, Lee IK, Porta M, Steffes M, Jacobs
Deguire P, Karmaus W: Polybrominated after polychlorinated biphenyl poisoning: DR Jr: Relationship between serum con-
biphenyls, polychlorinated biphenyls, 14-year follow-up of the Taiwan Yucheng centrations of persistent organic pollut-