The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic
- 1Committee on Molecular Pathogenesis and Molecular Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois
- 2Kovler Diabetes Center, Committee on Molecular Metabolism and Nutrition, Institute for Endocrine Discovery and Clinical Care, Department of Medicine, University of Chicago, Chicago, Illinois
- Corresponding author: Robert M. Sargis, rsargis{at}medicine.bsd.uchicago.edu.
Article Figures & Tables
Figures
- FIG. 1.
Sources and targets of metabolic disruptors.
- 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.
Strategies for addressing environmental disruption of metabolism.
Tables
- TABLE 1
Epidemiological data linking EDC exposure to diabetes
Reference EDC Population Association with diabetes Notes Morgan et al., Arch Environ Contam Toxicol 1980;9:349–382 Pesticides 2,620 pesticide exposed workers from 1971–1977 Cause-of-death questionnaires addressed to survivors indicated possible association between DDT exposure and diabetes Lai et al., Am J Epidemiol 1994;139:484–492 Arsenic 891 Taiwanese residents exposed to arsenic in 1988 Abnormal OGTT, medical histories of diagnosed diabetes, and use of diabetes treatments significantly associated with arsenic exposure Dose-response relationship between arsenic exposure and diabetes prevalence Henriksen et al., Epidemiology 1997;8:252–258 TCDD 989 Air Force veterans of Operation Ranch Hand exposed to TCDD Glucose abnormalities, diabetes diagnosis, and use of diabetic medications associated with TCDD exposure Significant hyperinsulinemia in exposed nondiabetic subjects Pesatori et al., Occup Environ Med 1998;55:126–131 TCDD Large Italian cohort (>230,000) localized in the exposure zones of the 1976 Seveso accident Mortality 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;106:645–653 TCDD, HCD International 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 diabetes Strongest 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;56:270–276 TCDD 281 former workers at two U.S. chemical plants Cross-sectional study significantly associated individuals with the highest serum lipid–adjusted TCDD concentrations with higher serum glucose levels Cranmer et al., Toxicol Sci 2000;56:431–436 TCDD 69 individuals in Jacksonville, AR, living within 25 miles of the Vertac waste site Higher 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;153:1031–1044 TCDD 15-year follow-up to the 1976 Seveso accident Mortality study associated an increase in reported diabetes with TCDD exposure in women Beard et al., Environ Health Perspect 2001;111:724–730 Pesticides 1999 Australian pesticide sprayers employed from 1935–1996 Mortality study and surviving morbidity questionnaire determined increased mortality due to diabetes associated with pesticide exposure Diabetes more commonly self-reported with occupational herbicide use Fierens et al., Biomarkers 2003;8:529–534 17 PCDD/Fs, dioxins, 4 PCBs, 12 PCB markers 257 environmentally exposed Belgians Quantification of serum fat from a population-based study determined significantly increased levels of dioxins, PCBs, and PCB markers in diabetic patients Diabetes risk significantly increased for individuals in the top decile of dioxin concentrations Glynn et al., Environ Health Perspect 2003;111:349–355 7 PCBs, 5 OC pesticides 205 Swedish women Association study of lifestyle/medical factors and serum PCB levels indicated increased prevalence of diabetes with higher serum PCB concentrations Serum PCB concentrations also associated with age, body, BMI, diet, and location of residence Rylander et al., Environ Health 2005;4:28 PCB-153, DDE 380 male and female Swedish fishers with a Baltic Sea marine diet Cross-sectional study significantly associated serum PCB-153 and DDE levels with an increased prevalence of diabetes Association stronger with PCB-153 for men and with DDE for women Lee et al., Diabetes Care 2006;29:1638–1644 6 POPs detected in >80% of population 2,016 adults from the 1999–2002 NHANES Prevalence of diabetes associated with increased lipid-adjusted serum concentrations of dioxins, PCBs, and organochlorines Stronger correlations with younger age, obesity, or Mexican American heritage Vasiliu et al., Epidemiology 2006;17:352–359 PCBs, PBBs 1,384 individuals from the Michigan PBB cohort Enrollment questionnaires and serum samples associated serum PCB levels with an increased prevalence of diabetes in women Exposed overweight and obese men and women had an increased prevalence of diabetes Codru et al., Environ Health Perspect 2007;115:1442–1447 101 PCBs, DDE, HCB 352 adult Native Americans (Mohawk) Standardized questionnaire and fasting serum samples positively associated the highest tertile of serum HCB levels with diabetes Nonsignificant associations with PCBs and DDE with diabetes; mirex levels inversely associated with diabetes Cox et al., Environ Health Perspect 2007;115:1747–1752 OC pesticides 1,303 adult Mexican Americans from the 1982–1984 HHANES Self-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;103:413–418 HxCDD, PCB, DDT 1,830 adults from the 1999–2002 NHANES Diabetes 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;115:876–882 Phthalates U.S. men from the 1999–2002 NHANES Insulin 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;50:1841–1851 OC pesticides, PCBs 721 nondiabetic participants from the 1999–2002 NHANES Fasting glucose levels and metabolic syndrome significantly associated with increased levels of OC pesticides PCBs were significantly associated with waist circumference. OC pesticides significantly associated with elevated triacylglycerides Lee et al., Diabetes Care 2007;30:1596–1598 PCDD/Fs, PCBs, OC pesticides 1,721 individuals from the 1999–2002 NHANES Prevalence of diabetes strongly associated with serum concentrations of PCBs and OC pesticides PCDDs and PCDFs weakly associated with diabetes Lang et al., JAMA 2008;300:1303–1310 BPA 1,455 U.S. adults from the 2003–2004 NHANES Urinary BPA concentrations associated with diabetes prevalence in a dose-dependent manner Lim et al., Diabetes Care 2008;31:1802–1807 5 PDBEs, PBB 637 adults from the 2003–2004 NHANES Serum concentrations of various brominated flame retardants correlated with increased prevalence of diabetes with varying dose dependency PBDE-153 showed an inverted U-shaped association with metabolic syndrome Jørgensen et al., Diabetologia 2008;51:1416–1422 General POPs 692 Greenland Inuits sampled from 1999–2002 living on a marine diet Significant inverse association between POPs and stimulated insulin concentrations and HOMA-B No association between POP concentration and glucose intolerance or insulin resistance Wang et al., Diabetes Care 2008;31:1574–1579 PCBs, PCDFs 1,054 Taiwanese poisoned with PCB-laced rice-bran oil during late 1970s Blind 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;117:1076–1082 PCBs, DDE Population of sport fish consumers in the Great Lakes region from 1990s-2005 Serum concentrations of DDE positively associated with increased diabetes prevalence No association with total PCB levels Park et al., J Prev Med Public Health 2010;43:1–8 OC pesticides 50 South Korean nondiabetic subjects with metabolic syndrome Community-based health surveys and HOMA-IR measurements associated OC pesticide exposure with metabolic syndrome Strong dose dependence between heptachlor epoxide and HOMA-IR Ukropec et al., Diabetologia 2010;53:899–906 PCBs, HCB, DDE, DDT, HCH 1,220 PCBRISK survey participants from Eastern Slovakia Abnormal OGTTs and fasting glucose levels associated with serum levels of POPs suggesting dose-dependent increased risk of diabetes and prediabetes No 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
Author EDC Model system Disruption of glucose homeostasis Weber et al., Toxicology 1991;66:133–144 TCDD Wild-type male Sprague Dawley rats Injection 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;47:65–73 TCDD Wild-type male C57BL/6 and DBA/2J mice A 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;119:139–144 DEHP Wild-type female Wistar Kyoto rats Administration 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;114:106–112 BPA Wild-type male Swiss albino OF1 mice Administration 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;15:2942–2950 Penta-BDE Wild-type male Sprague Dawley rats Daily 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:e2069 BPA Wild-type male Swiss albino OF1 mice and ERα and ERβ KO mice Administration 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;229:1019 TCDD Wild-type male C57BL/6 and AhR KO mouse Oral 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;118:465–471 General POPs Wild-type male Sprague Dawley rats Administration 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;33:261–268 TCDD Wild-type male Sprague Dawley rats Diabetic 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;26:79–85 TBT Wild-type male KM mice Oral 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
In this Issue
July 2011, 60(7)
The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic
