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Perspectives in Diabetes

The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic

  1. Brian A. Neel1 and
  2. Robert M. Sargis2⇓
  1. 1Committee on Molecular Pathogenesis and Molecular Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois
  2. 2Kovler Diabetes Center, Committee on Molecular Metabolism and Nutrition, Institute for Endocrine Discovery and Clinical Care, Department of Medicine, University of Chicago, Chicago, Illinois
  1. Corresponding author: Robert M. Sargis, rsargis{at}medicine.bsd.uchicago.edu.
Diabetes 2011 Jul; 60(7): 1838-1848. https://doi.org/10.2337/db11-0153
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  • FIG. 1.
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    FIG. 1.

    Sources and targets of metabolic disruptors.

  • FIG. 2.
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    FIG. 2.

    U.S. synthetic chemical production and diabetes prevalence. Synthetic chemical production in the U.S. from 1939 to 1994 was obtained from the U.S. Tariff Commission reports (72). Production from 1995 to 2008 was extrapolated using the annual index of chemical production published by Chemical & Engineering News from 1989 to 2008 (73,74), with kilograms calculated from linear regression analysis of overlapping data from 1989 to 1994 (r2 = 0.948). Diabetes prevalence was obtained from the Centers for Disease Control and Prevention (75).

  • FIG. 3.
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    FIG. 3.

    Strategies for addressing environmental disruption of metabolism.

Tables

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  • TABLE 1

    Epidemiological data linking EDC exposure to diabetes

    ReferenceEDCPopulationAssociation with diabetesNotes
    Morgan et al., Arch Environ Contam Toxicol 1980;9:349–382Pesticides2,620 pesticide exposed workers from 1971–1977Cause-of-death questionnaires addressed to survivors indicated possible association between DDT exposure and diabetes
    Lai et al., Am J Epidemiol 1994;139:484–492Arsenic891 Taiwanese residents exposed to arsenic in 1988Abnormal OGTT, medical histories of diagnosed diabetes, and use of diabetes treatments significantly associated with arsenic exposureDose-response relationship between arsenic exposure and diabetes prevalence
    Henriksen et al., Epidemiology 1997;8:252–258TCDD989 Air Force veterans of Operation Ranch Hand exposed to TCDDGlucose abnormalities, diabetes diagnosis, and use of diabetic medications associated with TCDD exposureSignificant hyperinsulinemia in exposed nondiabetic subjects
    Pesatori et al., Occup Environ Med 1998;55:126–131TCDDLarge Italian cohort (>230,000) localized in the exposure zones of the 1976 Seveso accidentMortality study using Poisson regression to assess relative risk determined substantial TCDD exposure correlated to increased diabetes mortality in women
    Vena et al., Environ Health Perspect 1998;106:645–653TCDD, HCDInternational study of 36 cohorts from 12 countries (1939–1992) (>25,000)Job record data and company questionnaires with biological and environmental measurements suggested possible correlation of TCDD exposure with diabetesStrongest association found when first exposure was 10–19 years previous to assessment and with duration of exposure of 10–19 years
    Calvert et al., Occup Environ Med 1999;56:270–276TCDD281 former workers at two U.S. chemical plantsCross-sectional study significantly associated individuals with the highest serum lipid–adjusted TCDD concentrations with higher serum glucose levels
    Cranmer et al., Toxicol Sci 2000;56:431–436TCDD69 individuals in Jacksonville, AR, living within 25 miles of the Vertac waste siteHigher fasting plasma insulin levels associated with individuals in the top 10% of TCDD concentrations (>15 ppt)No associations with TCDD and glucose levels, obesity, or total lipids
    Bertazzi et al., Am J Epidemiol 2001;153:1031–1044TCDD15-year follow-up to the 1976 Seveso accidentMortality study associated an increase in reported diabetes with TCDD exposure in women
    Beard et al., Environ Health Perspect 2001;111:724–730Pesticides1999 Australian pesticide sprayers employed from 1935–1996Mortality study and surviving morbidity questionnaire determined increased mortality due to diabetes associated with pesticide exposureDiabetes more commonly self-reported with occupational herbicide use
    Fierens et al., Biomarkers 2003;8:529–53417 PCDD/Fs, dioxins, 4 PCBs, 12 PCB markers257 environmentally exposed BelgiansQuantification of serum fat from a population-based study determined significantly increased levels of dioxins, PCBs, and PCB markers in diabetic patientsDiabetes risk significantly increased for individuals in the top decile of dioxin concentrations
    Glynn et al., Environ Health Perspect 2003;111:349–3557 PCBs, 5 OC pesticides205 Swedish womenAssociation study of lifestyle/medical factors and serum PCB levels indicated increased prevalence of diabetes with higher serum PCB concentrationsSerum PCB concentrations also associated with age, body, BMI, diet, and location of residence
    Rylander et al., Environ Health 2005;4:28PCB-153, DDE380 male and female Swedish fishers with a Baltic Sea marine dietCross-sectional study significantly associated serum PCB-153 and DDE levels with an increased prevalence of diabetesAssociation stronger with PCB-153 for men and with DDE for women
    Lee et al., Diabetes Care 2006;29:1638–16446 POPs detected in >80% of population2,016 adults from the 1999–2002 NHANESPrevalence of diabetes associated with increased lipid-adjusted serum concentrations of dioxins, PCBs, and organochlorinesStronger correlations with younger age, obesity, or Mexican American heritage
    Vasiliu et al., Epidemiology 2006;17:352–359PCBs, PBBs1,384 individuals from the Michigan PBB cohortEnrollment questionnaires and serum samples associated serum PCB levels with an increased prevalence of diabetes in womenExposed overweight and obese men and women had an increased prevalence of diabetes
    Codru et al., Environ Health Perspect 2007;115:1442–1447101 PCBs, DDE, HCB352 adult Native Americans (Mohawk)Standardized questionnaire and fasting serum samples positively associated the highest tertile of serum HCB levels with diabetesNonsignificant associations with PCBs and DDE with diabetes; mirex levels inversely associated with diabetes
    Cox et al., Environ Health Perspect 2007;115:1747–1752OC pesticides1,303 adult Mexican Americans from the 1982–1984 HHANESSelf-reported diabetes significantly associated with lipid-adjusted serum DDT levels and serum glucose levels were elevated in individuals exposed to trans-nonachlor and HCH
    Everett et al., Environ Res 2007;103:413–418HxCDD, PCB, DDT1,830 adults from the 1999–2002 NHANESDiabetes significantly associated with serum PCB 126, DDT, and HxCDD levels. PCB 126 and DDT levels significantly associated with undiagnosed diabetes (HbA1c >6.1%)
    Stahlhut et al., Environ Health Perspect 2007;115:876–882PhthalatesU.S. men from the 1999–2002 NHANESInsulin resistance measured by HOMA-IR was associated with three phthalates (MBP, MBzP, MEP)Four phthalates (MBzP, MEHHP, MEOHP, MEP) associated with increased waist circumference
    Lee et al., Diabetologia 2007;50:1841–1851OC pesticides, PCBs721 nondiabetic participants from the 1999–2002 NHANESFasting glucose levels and metabolic syndrome significantly associated with increased levels of OC pesticidesPCBs were significantly associated with waist circumference. OC pesticides significantly associated with elevated triacylglycerides
    Lee et al., Diabetes Care 2007;30:1596–1598PCDD/Fs, PCBs, OC pesticides1,721 individuals from the 1999–2002 NHANESPrevalence of diabetes strongly associated with serum concentrations of PCBs and OC pesticidesPCDDs and PCDFs weakly associated with diabetes
    Lang et al., JAMA 2008;300:1303–1310BPA1,455 U.S. adults from the 2003–2004 NHANESUrinary BPA concentrations associated with diabetes prevalence in a dose-dependent manner
    Lim et al., Diabetes Care 2008;31:1802–18075 PDBEs, PBB637 adults from the 2003–2004 NHANESSerum concentrations of various brominated flame retardants correlated with increased prevalence of diabetes with varying dose dependencyPBDE-153 showed an inverted U-shaped association with metabolic syndrome
    Jørgensen et al., Diabetologia 2008;51:1416–1422General POPs692 Greenland Inuits sampled from 1999–2002 living on a marine dietSignificant inverse association between POPs and stimulated insulin concentrations and HOMA-BNo association between POP concentration and glucose intolerance or insulin resistance
    Wang et al., Diabetes Care 2008;31:1574–1579PCBs, PCDFs1,054 Taiwanese poisoned with PCB-laced rice-bran oil during late 1970sBlind morbidity follow-up interviews and chloracne diagnoses significantly associated PCB exposure with an increased prevalence of diabetes in women
    Turyk et al., Environ Health Perspect 2009;117:1076–1082PCBs, DDEPopulation of sport fish consumers in the Great Lakes region from 1990s-2005Serum concentrations of DDE positively associated with increased diabetes prevalenceNo association with total PCB levels
    Park et al., J Prev Med Public Health 2010;43:1–8OC pesticides50 South Korean nondiabetic subjects with metabolic syndromeCommunity-based health surveys and HOMA-IR measurements associated OC pesticide exposure with metabolic syndromeStrong dose dependence between heptachlor epoxide and HOMA-IR
    Ukropec et al., Diabetologia 2010;53:899–906PCBs, HCB, DDE, DDT, HCH1,220 PCBRISK survey participants from Eastern SlovakiaAbnormal OGTTs and fasting glucose levels associated with serum levels of POPs suggesting dose-dependent increased risk of diabetes and prediabetesNo association between HCB and HCH levels and diabetes
    • HCB, hexachlorobenzene; HCD, higher chlorinated dioxins; HCH, hexachlorocyclohexane; HHANES, Hispanic Health and Nutrition Examination Survey; HOMA-B, homeostasis model assessment of β-cell function; HxCDD, hexachlorodibenzo-p-dioxin; MBP, monobutyl phthalate; MBzP, monobenzyl phthalate; MEOHP, mono(2-ethyl-5-oxohexyl) phthalate; MEP, monoethyl phthalate, NHANES, National Health and Nutrition Examination Survey; OC, organochlorine; OGTT, oral glucose tolerance test; PBB, polybrominated biphenyls; PCDDs, polychlorinated dibenzodioxins; PCDFs, polychlorinated dibenzofurans; PDBE, polybrominated diphenyl ethers.

  • TABLE 2

    Animal studies demonstrating EDC-induced changes in glucose homeostasis

    AuthorEDCModel systemDisruption of glucose homeostasis
    Weber et al., Toxicology 1991;66:133–144TCDDWild-type male Sprague Dawley ratsInjection of 25 μg/kg TCDD resulted in decreased activity of PEPCK and G-6-Pase after 2 and 8 days of treatment, respectively.
    Liu et al., Mol Pharmacol 1995;47:65–73TCDDWild-type male C57BL/6 and DBA/2J miceA single dose of 116 μg/kg i.p. TCDD resulted in the significant decrease in glucose transport in adipose tissue and brain after 24 h that was sustained for at least 30 days. The effect was AhR mediated.
    Gayathri et al., Indian J Med Res 2004;119:139–144DEHPWild-type female Wistar Kyoto ratsAdministration of 75 μg/kg DEHP every other day for 14 days resulted in a decrease in serum insulin and cortisol as well as liver glycogen; blood glucose was increased. The effects were reversible upon stopping treatment.
    Alonso-Magdalena et al., Environ Health Perspect 2006;114:106–112BPAWild-type male Swiss albino OF1 miceAdministration of a single 10 μg/kg dose of BPA produced a rapid rise in plasma insulin and a corresponding decrease in plasma glucose; however, 4-day treatment with 100 μg/kg/day of BPA impaired glucose tolerance on an intraperitoneal glucose tolerance test and reduced the hypoglycemic effect of insulin in an insulin tolerance test.
    Hoppe and Carey, Obesity 2007;15:2942–2950Penta-BDEWild-type male Sprague Dawley ratsDaily gavage of 14 mg/kg penta-BDE for 4 weeks resulted in a 30% increase in isoproterenol-stimulated lipolysis and a 59% decrease in insulin-stimulated glucose oxidation in adipocytes.
    Alonso-Magdalena et al., PLoS One 2008;3:e2069BPAWild-type male Swiss albino OF1 mice and ERα and ERβ KO miceAdministration of 100 μg/kg BPA twice per day for 4 days resulted in a significant increase in β-cell insulin content that was ERα dependent. Isolated islets treated with 1 nmol/L BPA had an increase in insulin content.
    Sato et al., Toxicol Appl Pharmacol 2008;229:1019TCDDWild-type male C57BL/6 and AhR KO mouseOral administration of 500 ng/kg TCDD once a day for 18 days resulted in significantly increased CYP1A1 expression in the liver and changes in energy metabolism gene expression that was AhR-mediated.
    Ruzzin et al., Environ Health Perspect 2010;118:465–471General POPsWild-type male Sprague Dawley ratsAdministration of a crude fish oil diet for 28 days resulted in systemic insulin resistance, visceral fat accumulation, and hepatosteatosis. Several genes regulating hepatic lipid metabolism were altered. Isolated POP classes impaired insulin-stimulated glucose uptake in 3T3-L1 adipocytes.
    Fried et al., Drug Chem Toxicol 2010;33:261–268TCDDWild-type male Sprague Dawley ratsDiabetic rats (high-fat diet/streptozotocin treatment) dosed with 12.8 μg/kg TCDD had significantly reduced serum glucose levels by day 8 of treatment.
    Zuo et al., Environ Toxicol 2011;26:79–85TBTWild-type male KM miceOral administration once every 3 days for 45 days of 0.5–50 μg/kg TBT resulted in body weight gain, hepatic steatosis, hyperinsulinemia, hyperleptinemia, and a reduction in hepatic adiponectin levels in a dose-dependent fashion.
    • BDE, bromodiphenyl ether; DEHP, di(2-ethylhexyl)-phthalate; G-6-Pase, glucose-6-phosphatase.

  • TABLE 3

    Challenges in endocrine/metabolic disruption of glucose homeostasis

    Challenges related to the chemicals
     Number of structurally diverse compounds to which humans are exposed
     Measurement of chemicals in metabolically-relevant tissues
     Lack of clear structure-function relationships
      Multiple mechanisms of action for a single chemical
      Effects mediated by a chemical’s metabolites
       Chemical breakdown differing by route of exposure
      Interactions among chemicals
       Additive, antagonistic, and synergistic effects
      Interactions between chemicals and endogenous metabolites
     Persistence of chemicals
     Ubiquity of exposure to some chemicals
    Challenges related to exposed individuals
     Interindividual genetic susceptibility to EDCs
      Differences in EDC target genes
      Differences in genes regulating EDC metabolism
     Coexisting diabetes risk factors
      Obesity, high-fat diet, sedentary lifestyle, family history
     Medical comorbidities
     Pharmaceutical agents/medications
     Hormonal status
      Women versus men
      Prepubertal versus reproductive age versus postmenopausal
      Eugonadal versus hypogonadal
    Challenges related to experimental design and approaches
     Cross-sectional versus longitudinal epidemiological design
     Single chemical approaches versus analyses of mixtures
      Additive, antagonistic, and synergistic effects
     Nonmonotonic dose-response relationships
     Failure of cell culture or animal models to recapitulate human physiology
     Background hormonal milieu of experimental animals
     Effect of timing of exposure
      in utero or early postnatal versus adult exposure
     Transgenerational effects
     Phytochemical content of animal feed
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The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic
Brian A. Neel, Robert M. Sargis
Diabetes Jul 2011, 60 (7) 1838-1848; DOI: 10.2337/db11-0153

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The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic
Brian A. Neel, Robert M. Sargis
Diabetes Jul 2011, 60 (7) 1838-1848; DOI: 10.2337/db11-0153
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