THE DIABETES EPIDEMIC

The last several decades have witnessed a dramatic deterioration in human metabolic health, with the rapidly increasing prevalence of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus.^1,2 In 2011, 366 million people worldwide had diabetes, and this number is projected to reach a staggering 552 million by 2030.³ The tremendous burden of diabetes contributes significantly to health care spending, amounting to $174 billion in the U.S. alone.⁴ To address the individual and societal burdens of diabetes, efforts to uncover its causes and develop interventions to limit its development are critical.

The rise in worldwide diabetes prevalence has paralleled the dramatic increase in global obesity rates. The reasons underlying increases in body mass are incompletely understood and are not fully explained by diet and physical inactivity.⁵ Nor is diabetes completely accounted for by obesity; among U.S. adults, nearly 20 percent of those with diabetes are neither overweight nor obese.⁶ It is time to develop a more holistic view of the causes of diabetes. Interestingly, rates of both T1DM and T2DM correlate with the dramatic increase in synthetic chemical production since World War II.⁷ Indeed, several epidemiology studies have shown that adults exposed to a mixture of lipophilic and persistent chemicals have a higher T2DM rate than controls.^8,9 Furthermore, animal studies suggest that chemical exposure can promote the development of a diabetic phenotype (reviewed in Neel and Sargis 2011, Sargis et al 2012, and Batista et al 2012). Collectively, these findings suggest that exposure to a specific class of environmental chemicals, endocrine-disrupting chemicals (EDCs), which interfere with hormone action,¹² may contribute to the diabetes epidemic and should be considered targets for intervention to limit development of the disease (see Table: Chemical Exposures Associated with Diabetes in Human Studies for a list of chemicals associated with diabetes in epidemiological studies).

Table.

Chemical Exposures Associated with Diabetes in Human Studies

T2DM or Insulin Resistance	Sources of Exposure
Persistent organic pollutants22,23	Food (animal fats, fish)22,23
Dioxin24	Agent Orange (Vietnam war)24
Arsenic25	Drinking water, food (fruit juice, rice)26
Bisphenol A (BPA)27–29	Polycarbonate plastics, canned food, thermal paper, dental sealants28,30
Phthalates31,32	PVC plastics, cosmetics, medical equipment31
Traffic-related air pollution33	Residential proximity to traffic33
Agricultural pesticides34	Applying pesticides34
Brominated flame retardants35	Consumer products, furniture, electronics35
Cadmium36	Food (oysters, oilseeds, offal), tobacco37
T1DM or Autoimmunity
Nitrite/nitrate/nitrosamines38,39	Processed meat, drinking water, cosmetics39
Air pollutants ozone and sulfate40	Ambient air40
PCBs41	Food (animal fats, fish)22
Mercury42	Fish42
Tricholorethylene43	Drinking water, occupational43
GDM or Impaired Glucose Tolerance During Pregnancy
Agricultural pesticides44	Applying/mixing pesticides44
Arsenic45	Drinking water45

Diabetes as a Disease of Development

While existing epidemiological studies that evaluated EDCs and T2DM only examined the body burden of chemicals during adulthood, the risk of developing T2DM clearly starts during development (in utero and in early postnatal life)^13,14 and continues throughout life, with puberty and pregnancy being additional sensitive periods for environmental effects. In animal models, in utero exposure to EDCs results in metabolic derangements in the offspring, including increases in fat mass¹⁵ and disturbances in glucose homeostasis.¹⁶ For the developing fetus, there is the potential for two insults to metabolic programming, namely disturbances in maternal energy homeostasis and direct effects of transplacental EDC exposure. To better understand the development and progression of diabetes in patients, clinicians should become aware of the potential diabetogenic nature of chemical exposures, the sensitive periods for their effects, and the precise sources of human exposure. Clinicians will then be able to provide anticipatory guidance to their patients regarding the adverse effects of chemical exposures on metabolic health.

Bringing the Clinic to the Forefront of Environmental Diabetology

Clinicians are critical in the detection and treatment of diabetes, but they also play an important role in disease prevention by becoming engaged in understanding how diabetes can arise from the pernicious chemical cocktail to which an individual is exposed. Through careful examination of a patient’s history, a clinician may be able to identify individuals likely to have had a chemical exposure that contributed to their diabetes, such as slender individuals diagnosed with T2DM without a strong family history of the disease, or those with clear exposure to a known diabetogenic chemical (e.g., Agent Orange). Importantly, these chemical exposures should be considered as one of many contributing factors, in addition to diet and physical inactivity, in the pathogenesis of diabetes.

While the data linking chemical exposure to T1DM lags behind that for T2DM (see Table), specific exposures could be contributing to the observed increase in T1DM through either direct beta cell toxicity or via modulation of the immune system. Indeed, there are chemicals with EDC activity that could directly affect beta cell development and also have immunomodulating effects. We suggest that physicians maintain a high level of suspicion concerning chemicals as etiologic agents in T1DM. The seasonality and geographical clustering of T1DM cases have suggested to investigators that viruses may play an important role in the development of this disease. It is, however, equally likely that chemical exposures unique in timing or location could also trigger the disease. It may be necessary for the Centers for Disease Control and Prevention (CDC) to develop an environmental detective service to specifically track T1DM incidence, including investigating geographical and seasonal clustering, akin to current approaches for infectious disease outbreaks, in order to identify specific chemical exposures that promote development of the disease.

An additional paradigm of metabolic disruption that may help identify chemical-mediated metabolic disruption is gestational diabetes (GDM) (Table). Studying links between EDCs and GDM has the advantage that all women should receive assessments of glucose homeostasis during pregnancy. Further, the inherent insulin resistance of pregnancy may make pregnant women acutely sensitive to chemical disruptions in metabolic homeostasis. A greater appreciation for the contribution of chemicals in the pathogenesis of GDM is critical given the potential long-term metabolic impact on the children of those with the disease. Addressing exposure to EDCs during pregnancy may also have additional health benefits for the offspring, unrelated to the mother’s metabolic state, including limiting the deleterious effects mediated by EDCs interfering with other hormonal axes.

To understand the role EDCs play in the pathogenesis of clinical diabetes, physicians should be equipped with skills to obtain thorough occupational and environmental histories. Several publications provide guidance on obtaining such a history,^17,18 and recent publications for health care providers have outlined potential reproductive consequences of chemical exposures;^19,20 however, more must be done to facilitate physicians’ assessments of chemical contributions to metabolic diseases. As in most diseases, clinical suspicion is the fundamental tool for establishing a diagnosis. Clinicians’ awareness of potential links between environmental exposures and diabetes could provide critical insights into the contribution of pollutants to metabolic diseases. Through interactions at clinical meetings, publications, or eventually a centralized, Internet-based notification system, clinicians will be able to share potential cases of environmentally mediated diabetes with public health professionals to prompt further study. Where this is not possible or not yet established, referral to an academic center with physician-scientists interested in environmental health is critical. Together, clinicians and scientists may provide the “smoking gun” evidence necessary to implement policies aimed at reducing exposure to EDCs.

Bringing Environmental Science to the Clinic

Critical to appreciating the role of chemical exposures in diabetes is a better understanding of which chemicals pose the greatest risk and during which developmental periods that risk is highest Of particular interest to the clinical community is the possibility that environmental pollutants may modify the efficacy of diabetes treatments. This unexplored area of environmental diabetology requires significant study. Chemical exposures may also play an additive or synergistic role in the pathogenesis of diabetes complications as suggested for organochlorine pesticides and peripheral neuropathy.²¹ Of critical interest is whether reducing exposure to EDCs prevents or mitigates the severity of diabetes. Given that many potential diabetogenic chemicals are lipophilic, accumulate in body fat, and are released during weight loss, this is clearly an area of concern. Interactions and collaborations between basic science researchers and clinicians will be fundamentally important for addressing many of these lingering issues. Capitalizing on the insights of clinicians in close contact with their patients could greatly aid researchers in the study of environmental diabetology. Formal mechanisms could facilitate communication between these often disparate groups, such as centralized databases, translational publications, and conferences.

While entirely eliminating exposures to EDCs may be impossible, some exposures can be reduced via lifestyle interventions across the lifespan and especially during pregnancy, lactation, and early childhood (for example, by avoiding animal fats; mercury-contaminated fish; and EDCs in plastics, cans, cosmetics, etc.). (For specific suggestions, see Sathyanarayana et al 2012, Sutton et al 2012.) The emerging links between chemical exposures and diabetes warrant efforts to decrease and potentially eliminate exposure to diabetogenic pollutants whenever possible, likely resulting in additional health benefits.

Synthesizing the Chemical-Diabetes Story

In conclusion, emerging scientific evidence implicates EDCs as potential contributors to the diabetes epidemic. Bringing an appreciation of this association to the clinic will be critical for identifying new risks that threaten patient health and developing novel strategies for preventing and treating diabetes. To reach this point, clinicians must appreciate the emerging importance of EDCs in the development of T1DM and T2DM, and researchers must aggressively fill the gaps in our scientific knowledge to improve clinical care. Working together, we may be able to seize this unique opportunity to reverse the disturbing trends in global metabolic health.