Diabetes and Toxicant Exposure

Abstract

The worldwide prevalence of obesity has near tripled between 1975 and 2016. Diabetes was the direct cause of an estimated 1.6 million deaths in 2015. Diabetogens, otherwise known as toxicants that cause insulin resistance in animal models and humans as a result of pancreatic β-cell damage include the persistent organochlorine pesticides trans-nonachlor, oxychlordane, and DDE -the main metabolite of DDT, as well as another class of persistent organic pollutants, polychlorinated biphenyls (PCBs). Other toxicants that are now considered diabetogens: BPA, arsenic, phthalates, perfluorinates (PFOS), diethyl hexyl phthalate (DEHP), and dioxin (TCDD) are commonly found in the blood and urine in the CDC NHANES populations and presumed to also be commonly found in the U.S. population as a whole. A review of the literature on the risk for diabetes in epidemiologic studies considering these toxicants, challenges for clinicians using lab testing for these diabetogens, and the necessary interventions for lowering body burden of persistent toxicants are discussed.

Both obesity and diabetes, have now become metabolic diseases of pandemic proportions. The worldwide prevalence of obesity nearly tripled between 1975 and 2016.¹ Diabetes, a chronic disease affecting 422 million people worldwide in 2014, was the direct cause of an estimated 1.6 million deaths in 2015.²

At least 10.3 million Americans carry a diagnosis of diabetes mellitus. Another 5.4 million are estimated to have undiagnosed diabetes. Approximately 95% of patients with diabetes have the type 2 variety.³

Another 35% of people ≥ 20 years of age are believed to be prediabetic, a precursor to the development of type 2 diabetes (T2D) and a riskfactor for micro and macrovascular diseases.⁴ The prevalence of prediabetes is increasing worldwide and experts have projected that more than 470 million people will have prediabetes by 2030. Prediabetes is associated with the simultaneous presence of insulin resistance and β-cell dysfunction-abnormalities that start before blood glucose level changes are detectable.

The current criteria for the diagnosis of prediabetes, includes a HgA_1C of 5.7% – 6.4%, a fasting blood sugar of 100 to 125 mg/dl or a 2 hour oral glucose tolerance test blood sugar of 140 mg/dl to 199 mg/dl.⁵

Vascular disease is a hallmark in diabetes and the American Heart Association has termed T2D “a form of cardiovascular disease”.⁶ Diabetics are also at high risk for nonalcoholic fatty liver disease, up to 70 to 75% of those with T2D have some stage of NAFLD and are also at higher risk of developing nonalcoholic steatohepatitis (NASH) and a 2 to 4 fold higher risk of developing serious liver-related complications (cirrhosis, liver failure, and hepatocellular carcinoma).^7,8

Until this century, the etiology of T2D was thought to be directly related to obesity as a determining major risk factor, along with a strong genetic predisposition, aging, and lack of exercise. But the research reviewed in this article and gaining wide support in the scientific and medical community does not support the obesity/genetics equals diabetes premise.

Although 80% of T2D patients are obese, approximately 75 to 80% of obese people never develop T2D.⁹ Insulin resistance, a prediabetic state, varies widely among obese individuals- up to 6-fold and the data from genome-wide association studies have shown that genetic variants explain only about 10% of the phenotypic variability. Obesity or genetics are insufficient to explain the current tsunami of insulin resistance and T2D.¹⁰

Persistent Organic Pollutants (POPs)

Organochlorine Pesticides (OP) and Polychlorinated Biphenyls (PCB)

Although standard causation of aging, genetics, obesity, and inactivity are still the case in conventional medical circles, the publication in 2006, of a groundbreaking analysis of the toxicant body burden of the US population revealed a different story. Dr. Duk Hee Lee and her team looked at 2,016 adults in the 1999 to 2002 dataset from US NHANES and assessed the relationship of six persistent organic pollutants (POPs): two dioxins, one polychlorinated biphenyl (PCB), and three metabolites of organochlorine pesticides to determine their possible relationship with type 2 diabetes.¹²

What she and her team found was a significant positive relationship between the assumed body burden of these POPs and the diagnosis of diabetes. The identified toxicants: trans-nonachlor, oxychlordane, p,p -dichlorodi-phenyldichloroethylene (DDE-the main metabolite of DDT), and PCB153 were chosen because they had been identified in at least 80% of the participants tested. The study then compared those with the highest level of toxicants (the 90th percentile) to those at the lowest level of toxicant exposure (defined as non-detectable levels). The results were odds ratios of approximately 4-12 for T2D for those with the highest level of POPs. When participants were classified by a measure summarizing the combined exposure to all six POPs, the risk for T2D rose to 10-40. There were four toxicants that appeared to determine the magnitude of the association: trans-nonachlor, oxychlordane, p,p -DDE, and PCB-153, all of which are found as current contaminants in the water and food supply. Oxychlordane is also found in indoor air as chlordane was used as termiticide control in the building industry until 1988 but has been detectable in indoor air at elevated levels as late as 2007.¹³

These three pesticides and one PCB were strongly associated with risk for diabetes even when the researchers compared those in the 25th percentile to those in the 75th percentile. This means they compared the 25% of the population with the highest levels to the 25% of those with the lowest but detectable levels. Even here, those in the top 25% had a 2.5x higher risk for T2D.

Even though the association between POPs and diabetes was stronger among more obese persons, there was also a clear positive association between POPs and T2D among normal-weight people (BMI of 25 or less). The most striking finding in this study was that obesity was not associated with T2D among persons in the lowest quartile of the POPs group summary. So those who did not have a body burden of POPs, regardless of their BMI, did not have an increased risk of T2D. Although they were not recognized as such in her study, these individuals are now termed the “metabolically health obese” who, despite meeting traditional BMI criteria for obesity, do not demonstrate high risk metabolic profiles for either diabetes or cardiovascular disease. These findings could only mean that POPs may play a more critical role in the pathogenesis of T2D than the adipose tissue itself, a fact that had no acceptance in the scientific community at the time the article was published.

Lee and others continued to publish further evidence for the role of POPs in T2D and also agreed that no single POP was related to increased risk but that groups of POPs could consistently predict risk for diabetes.^14-23 These included DDE, PCBs, organochlorine pesticides (including hexachlorobenzene) and dioxins- a class of POPs that is accepted as a cause of T2D by the Dept of Veterans Affairs in those who had been exposed to Agent Orange (2,4-D and dioxin) used as a defoliant in the Vietnam War. Especially in high-risk groups, like Mexican Americans, organochlorine pesticide exposure was consistently associated with T2D.

Eight years after Lee published her original paper, the Endocrine Society (international member group of endocrinologists and researchers) published their “Second Scientific Statement on Endocrine-Disrupting Chemicals” known as ED-2 where they identified the diabetogen hypothesis.²⁴ They acknowledged that specific endocrine disruptors circulating in plasma are able to produce insulin resistance, whether they accumulated in adipocytes or not, and could be considered a risk factor for metabolic syndrome and T2D. Any toxic chemical that kills pancreatic β-cells or disrupts their function has been termed a diabetogen and this mechanism of action- direct injury to or dysfunction of β-cells is consistent as an effect of all diabetogens.^25,26

Separate from the actions of endocrine-disrupting obesogens, diabetogen’s specific mechanism of action does not involve adipocytes or stem cells. But some endocrine disrupting chemicals that are diabetogens are also obesogens; BPA and DDT are two examples listed in ED-2. They are both known to cause adipocyte damage and can contribute to obesity both pre and post conception by increasing the number of adipocytes, increasing the size of adipocytes or altering the endocrine pathways responsible for the control of adipose tissue development.²⁷

The Endocrine Society Statement also acknowledged that diabetogens could be responsible for the condition of “metabolically obese despite normal weight” (MONW), indicating a growing subset of individuals that despite a normal BMI, have metabolic syndrome with insulin resistance and hypertriglyceridemia and run the same risks for cardiovascular disease and diabetes as their obese counterparts with metabolic syndrome.²⁴

The additional diabesogens included in EDC-2 Scientific Statement were BPA, arsenic, phthalates, perfluorinates (PFOS), diethyl hexyl phthalate (DEHP), dioxin (TCDD), and the mixture of BPA, TCDD, PCB-153 and DEHP. With the exception of arsenic and per fluorinates, where much more research is needed, they are reviewed below.

Significant evidence has also been published for organophosphate pesticides (OP) use and the risk for T2D. In the large Agricultural Health Study in 31 787 farmers, long-term exposure to handling OPs was significantly diabetogenic for seven OP: chlorpyrifos, coumaphos, diazinon, dichlorvos, phorate, terbufos and trichlorfon.²⁸ This relationship has been confirmed in multiple studies looking at use of OP and diagnosis of T2D.²⁹

Although the exposure for farmers is significantly different than mothers or children who are not occupationally exposed, one study of non-occupationally exposed pregnant mothers has shown a positive correlation between OP metabolites in the mother’s urine at onset of pregnancy and babies’ insulin levels at birth.³⁰

Contamination of conventionally grown food with the pesticides identified in the Agricultural Health Study has been verified for many food items by the USDA. For example, chlorpyrifos has been found as a residual pesticide on 51 different fruits, vegetables or other food items from the years 1999 to 2012.³¹

Triclosan/Triclocarban

Triclosan and triclocarban are biocides currently found in over 2000 consumer products, including soaps, toothpastes, detergents, clothing, toys, carpets, plastics, and paints as anti-odor, antibacterial additives.³² Triclosan and triclocarban are found in the urine of over 75% of the U.S. population according to the NHANES database for 2013 to 2014.³² Triclosan/triclocarban were banned from all hand-wash sanitizing products in 2016 because the FDA said that the manufacturer of triclosan had failed to prove the product was safe. Because soaps that make antibacterial claims are considered over-the-counter drugs they are under the regulatory control of the FDA. The remaining 2000 consumer products that contain triclosan/triclocarban are not under the regulation of the FDA and are still in commerce. Triclosan and triclocarban are accepted endocrine disrupting chemicals, specifically as human reproductive toxicants.³²

A very recent evaluation of 900 participants in the NHANES 2013-2014 Database looked at urine triclosan/triclocarban detection in relationship to both impaired glucose tolerance and T2D. They found that in women (after adjusting for age, ethnicity, BMI, education, ratio of family income to poverty, smoking, exercise and hypertension) a positive association remained between triclocarban exposure and the odds of T2D (OR = 1.79).³³

Phthalates

Phthalates are plasticizers found in personal care products, fragrances, cleaning products, food packaging, high-fat animal products, toys, house dust and vinyl flooring.³⁴ Their main route of exposure appears to be through food contamination via plastic packaging.³⁵

Phthalates are known endocrine disruptors (obesogens and reproductive toxicants) and evidence from animal studies suggests they interfere with adipocyte biology and glucose metabolism through effects on peroxisome proliferator-activated receptors (PPARs). Phthalates, specifically DEHP, which has been shown to be related to risk for T2D in NHANES data, also appear to increase levels of oxidative stress, which is a known pathway for the development of insulin resistance in humans.³⁶

Evidence in human studies has been mixed. Positive associations of urine phthalate levels in T2D was evident in the Nurses Health Study II where younger nurses (mean age 45.6) with high levels of urine phthalates were twice as likely to have T2D as those with the lowest levels of urine phthalates. However this association did not show up in the older nurses in the Nurses’ Health Study (mean age 65.6). Nurses with high levels of DEHP and butyl phthalate were 3 times more likely to have T2D, but again, only in the NHS II younger nurses cohort.

In a meta-analysis of all published human studies prior to 2014, the odds risk for T2D in those with the highest levels of urinary phthalate compared to the lowest level was significant- 1.5 times more likely to have T2D.³⁷

BPA

BPA is a high production volume chemical- meaning it is produced or imported into the U.S. in over 1 million pounds per year. BPA exposure includes thermal receipts, dental composites and sealants, hard plastic water bottles and municipal water supply pipes made of polycarbonate plastic, and food packaging materials. Ingestion of contaminated food may contribute more than 90% of general BPA environmental exposure.³ And BPA is also detected in waste water, drinking water, air and dust particles and has been found in 86% of house dust samples at levels ranging from 0.2 to 17.6 μg/g.^38-39 It is also found in the urine 93-95% of the U.S. population according to the NHANES database.⁴⁰

BPA is also a well-established endocrine disrupting toxicant and acts as an obesogen, xenoestrogen and diabesogen. This assumption is supported by data from cross-sectional and epidemiological studies showing a relationship between BPA levels and metabolic diseases: obesity, insulin resistance, type 2 diabetes, hypertension, and both cardiovascular and nonalcoholic fatty liver disease.^41-43

BPA effects pancreatic B-cells resulting in the impairment of insulin and glucagon secretion. BPA also triggers inhibition of cell growth and apoptosis and acts on muscle, liver and adipose cells to trigger an insulinresistant state.^44,45

In a meta-analysis of clinical studies on BPA and cardiometabolic disease risk, assessing all studies published before mid-2014, urinary concentrations of BPA were associated with T2D risk; comparing the highest to lowest urinary levels, those with the highest urinary levels had an increased odds ratio of 1.47.⁴⁵ BPA urine levels also indicated increased risk for obesity (1.67), hypertension (1.41), and waist circumference (1.48) all hallmarks of cardiometabolic syndrome.

BPA CLARITY, a project begun by the NIEHS (National Institute of Environmental Health Sciences)/NTP (National Toxicology Project) and the FDA and now involving over 10 major academic research centers, has attempted to establish data on BPA and endocrine toxicity and has provided evidence of significant adverse effects at the lowest dose examined (2.5 μg/kg body weight per day), far lower than the maximum safe daily oral BPA dose over the lifetime (50 μg/kg body weight per day) established by the EPA and FDA.^47,48

Conclusion: The Path Forward

The current conundrum regarding toxicant exposure and diabetes must be directly addressed and a proposal for immediate action must be created, consensus reached and communicated to all healthcare providers. Legislation to eliminate bisphenols and phthalates from commerce is eventually unavoidable. Green chemistry has already provided plant-based plastics that do not have endocrine disruptor properties and will not be just another regrettable substitution. The following suggestions are offered as a beginning:

Avoidance

A US monitoring study published in 2010 revealed that DDT, as well as endosulfan and aldrin, are still largely present in food, and consumed daily.⁴⁹ Conventionally grown food imported into the U.S. continues to be contaminated with organochlorine pesticides. One hundred and sixty metric tons of DDT is still being produced for agricultural use, and other organochlorine pesticides, like aldrin and dieldrin have suspected use in multiple countries outside the US.^50,51 Because these imported, conventionally grown (non-organic) fruits, vegetables, and other food items (grains, legumes) may contain organochlorine pesticide residues, the only guaranteed method of avoidance is to recommend a diet of USDA-certified organic food.

An article published in 2018 assessed organic food purchased with risk for T2D from NHANES 2007-2010. After adjustment for age, gender, race/ethnicity, family history of diabetes, socioeconomic status, and dietary and lifestyle factors, and BMI- the OR of diabetes associated with those individuals who purchased organic food in the previous month was 0.80, or 20% less likely to have a diagnosis of T2D.⁵²

POPs have contaminated animal and human food webs across the planet. PCBs volatilize and move on air currents to contaminate soil and grasses globally. Because animal foods (meat, dairy products, and eggs) contain significantly higher levels of POPs than plant foods, a plant-based diet is the option to prevent further exposure.⁵³ There is no clear evidence that organically-raised dairy products contain fewer POPs than conventionally raised dairy animals and in some studies the opposite is true.⁵⁴

For phthalates and BPA- endocrine disruptors that are non-persistent and have very short half-lives and daily repeated exposure, avoidance is the only option. Research has shown that minimizing packaged foods and canned foods can cut mean urine BPA levels by 66% and DEHP metabolite levels by 53-56%.³⁸ Those in the study who were the most diligent in avoiding packaged and canned foods and storing or heating in plastic were able to reduce their BPA and DEHP levels by 76% and 93-96% respectively. Guidance for patient education can be found through the NIEHS website, https://www.niehs.nih.gov/research/supported/assets/docs/j_q/phthalates_the_everywhere_chemical_handout_508.pdf and from the Endocrine Society, https://www.endocrine.org/topics/edc/talking-edcs and for BPA, https://www.niehs.nih.gov/health/topics/agents/sya-bpa/index.cfm/. An 2018 article with patient guidance for persistent and non-persistent toxicant avoidance includes patient handouts on how to avoid endocrine disrupting chemical exposure: Ruiz D, Becerra M, Jagai JS, Ard K, Sargis RM. Disparities in Environmental Exposures to Endocrine-Disrupting Chemicals and Diabetes Risk in Vulnerable Populations. Diabetes Care. 2018;41(1):193–205. Full text access: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741159/.

Assessment

Clinical laboratories provide toxicant panels for all of the toxicants mentioned above. However, they use irrelevant reference ranges when relating exposures to potential disease states. Endocrine disruption effects can be nonmonotonic, meaning, low doses may be more toxic than moderate or high doses. Even using the NHANES database values to attempt to identify the top 95th percentile values may be misleading for clinicians in this area. For those of us who have not memorized the literature on endocrine disruption and diabetes (all of us) we need guidance on which levels of exposure may be diabetogenic. Low levels of POPs may have stronger diabetogenic effects than high levels. This was pointed out in the analysis of the CARDIA study in which 5115 young individuals had POPs levels drawn at year 2 of the study and were followed for another 18 years.⁵⁵ The highest risk for T2D was observed in the second quartiles of trans-nonachlor, oxychlordane, mirex, PCB 153 and PBB 153. As the researchers suggested, and other similar studies have shown, POPs may have an inverted U shape effect, meaning that after a certain point as exposure increases, effects and risk of disease diminish and disappear.⁵⁶

As well, endocrine disruption occurs at low levels, as evidenced in Lee’s groundbreaking 2006 paper where those in the 2nd quartile of PCB 153 blood levels had an increased risk of T2D (OR 2.5). In other words, those with 14.3 ng/gm lipid of PCB 153 in their bloodstream had a 2.5 times increased risk for T2D compared with those whose levels were nondetectable. In this analysis the odds ratios continue to go up as PCB levels increase for the 25th to 90th percentiles. The problem is that, as an example, a widely used toxicologic lab panel serum PCB 153 levels lists the 95th percentile as the apparent upper limit of 97.1 ng/gm lipid. So those identified in Lee’s research from the 25th to the 90th percentile would be missed and considered “normal”.⁵⁷

Laboratory assays also need to be revised to include new chemicals substitutions. We need to be assured that when we test for bisphenol A, we are also seeing the replacement bisphenols (S and F) in our patient’s urine. They too have endocrine disrupting activity that may be even more impactful than BPA. One cohort study found that in U.S. children BPA levels are dropping as BPS and BPF levels rise and that both BPS and BPF were more strongly correlated with abdominal obesity and general obesity than was BPA. This is an example of two truly regrettable substitutions.⁵⁸

And finally, a paper published a few months ago by Gerona and colleagues points out that the current assay methodologies for BPA may seriously underestimate BPA exposure by as much as 19 to 44 times because they do not account for the glucuronide and sulfate forms of BPA found in urine, which are the conjugation metabolites that eliminate BPA from the body.^59,60 If this number is off by a factor of 19 then the geometric mean would far exceed the level of BPA implicated in T2D. They also commented that the current assays for parabens, benzophenone, triclosan and phthalate metabolites also rely on indirect methods that may underestimate exposure to these toxicants.⁶¹

Lowering Body Burden

There are strategies to increase POP excretion from the body. Although POPs are excreted through feces, a substantial amount of POPs excreted through bile are reabsorbed through enterohepatic recirculation. Experimental animal studies and human studies of women from the Yusho PCB exposure event in Japan suggest that dietary fiber may be an efficient intervention to absorb POPs in the gut and increase their excretion via feces.^62,63 The use of both cholestyramine and rice bran fiber in patients exposed to PCB and dibenzofuran from rice bran cooking oil was able to increase excretion of PCBs by 50 to 190%.⁶⁴

Antioxidants such as vitamin C appear to increase excretion of POPs. A study of 15 healthy women showed that 1000 mg/day of ascorbic acid for 2 months significantly reduced serum levels of six PCBs and two organochlorine pesticides: PCB-74, PCB-118, PCB-138, PCB-153, PCB-180, and PCB-187, DDE, and DDT.⁶⁵

Given the data on DDT/DDE and PCB153 consistently associated with T2D, a cost-effective intervention such as this should be commonly applied. It remains to be seen if higher doses of 2 or 3 grams daily would decrease blood levels of these suspect diabetogens to an even greater degree.

Sauna therapy protocols have also shown evidence for increased excretion of PCBs for occupationally-exposed workers.⁶⁶ However, conflicting evidence exists for the most common non-occupational exposure PCB congeners (specifically 153, 138) that do not appear to be effectively excreted in sweat.⁶⁷ So it is not clear that sauna therapy would be an effective intervention for those with diet-related PCB body burdens.

Interventions To Mitigate Damage

In 2014, Lee concluded that current human exposures to POPs induce mitochondrial dysfunction through GSH depletion leading to insulin resistance and T2D. However, the restorative mechanism of increasing GSH synthesis, she was clear, has been shown to reverse these adverse effects.⁶⁸

Bernard Hennig has been publishing research on using diet to reverse POP-induced damage for over a decade and has shown that In animal models, diets enriched with polyphenols and omega-3 polyunsaturated fatty acids have been shown to reverse the toxicant-induced inflammation that leads to vascular damage, a hallmark of cardiometabolic disease.⁶⁹

Dioxin-like PCBs and other POPs exert their diabetogenic effects because they bind to the aryl-hydrocarbon receptor (AhR) found within vascular endothelial cells and increase reactive oxygen species (ROS) through cytochrome P450 1A1 (CYP1A1)-mediated uncoupling.⁷⁰

Oxidative stress from PCB-induced inflammation leads to activation of transcription factor NFκB and cytokine release of IL-6, VCAM, and MCP-1 creating a leaky endothelial vascular membrane increasing inflammation in both the vascular lining and in the intracellular environment (including mitochondria).

Based on this model, interventions to address the mechanisms of damage for endocrine disrupting chemicals include the polyphenols resveratrol, epigallocatechin gallate (EGCG), and quercitin as well as sulforaphane which have been shown to activate Nrf2, prevent activation of NFκB, IL-6, VCAM MCP-1, and decrease free radical production as well as mitigating aryl-hydrocarbon receptor-induced damage by PCBs and other toxicants.^71-73 In short, minimize the damage these toxicants cause.

All of these strategies have to be employed for any successful prevention or reversal of disease related to diabetogen exposure, and will necessitate diet and lifestyle changes as well. However, as public awareness of both the diabetes epidemic and the role of endocrine disruption grows, these interventions will become less of a culture change and more the necessary norm.

Figure 1.

US Synthetic Chemical Production and Diabetes Prevalence¹¹

Figure 2.

Mexican Americans diabetics (1), Mexican Americans diabetics without nephropathy (2), Mexican Americans diabetics with nephropathy (3), U.S. diabetics without nephropathy (4) 1-6 Elevated: DDT, DDE, beta hexachlorocyclohexane, oxychlordane, trans-nonachlor and heptachlor epoxide.^13,14

Biography

Lyn Patrick, ND, has been in private practice in Arizona and Colorado since graduating from Bastyr University in 1984. She is currently past president of the Naturopathic Academy of Environmental Medicine and faculty for the American College for Advancement in Medicine (ACAM) chelation training program and the Metabolic Medical Institute Fellowship. She speaks internationally on the subject of environmental medicine, endocrine disruption, metals toxicity, and nonalcoholic fatty liver disease. Previously, Dr Patrick acted as contributing editor for Alternative Medicine Review, a peer-reviewed P ubMed-indexed integrative medical journal.