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Xenobiotic Diabetogenesis: Chemical Exposure as a Major Contributor to the Epidemic of Diabetes Mellitus and Disorders of Insulin Resistance, From Molecular Mechanisms to Clinical Implications
 
Dr Alex Vasquez

This article was originally published in Naturopathy Digest in 2007
naturopathydigest.com/archives/2007/apr/diabetes.php

Introduction
Evidence has been consistently accumulating over the past few years implicating chemical exposure as a plausible and important cause of insulin resistance and diabetes mellitus. In this article, I will survey current literature and explain the causes, mechanisms, and clinical implications of the toxin-diabetes link, and I will expand some of my previous work on chemical exposure and clinical detoxification methods[1],[2] as specifically related to the genesis and treatment of diabetes.[3] By the time they finish reading this article, chiropractic and naturopathic doctors should appreciate the role of chemical exposure in the genesis and perpetuation of insulin resistance, understand the mechanisms of chemical accumulation and detoxification, and have an awareness of some of the methods used to alleviate and prevent chemical-induced disease.
 
Chemical Exposure and Type-2 Diabetes in Humans
Numerous animal models have irrefutably established the ability of specific chemicals and toxic metals to destroy pancreatic beta-cells and thus reduce insulin production to such an extent that hyperglycemia and diabetes result; these models establish that toxin exposure can result in a form of type-1 “low insulin” diabetes. However, the largest burden of hyperglycemic diabetes (distinguished from diabetes insipidus) in industrialized nations is associated not with insufficiency of insulin as in type-1 diabetes but rather with the hallmark findings of excess insulin, peripheral insulin resistance, and associated clinical presentations that include overweight/obesity, hypertension, hyperglycemia and dyslipidemia. The current dominant paradigm of type-2 diabetes and its synonyms and closely related conditions including insulin resistance, adult-onset diabetes, metabolic syndrome, and syndrome X is that the condition results from excess caloric intake and an insufficiency of exercise in patients with one or more genetic predispositions. Medical treatment generally consists of inadequate dietary-lifestyle advice and the use of one or more prescription drugs. However, the diet-exercise-gene-drug model of diabetes is clearly incomplete; other factors, including micronutrient status (particularly vitamin D, cholecalciferol[4]) and hormonal milieu also clearly influence adiposity and insulin receptor sensitivity. Exposure to and accumulation of toxic chemicals, either from occupational exposure or chronic background exposure to these chemicals which pervade our environment appears to be a hitherto underappreciated factor influencing insulin receptor sensitivity and the risk and prevalence of diabetes mellitus; a sampling of primary research is provided in the following section.


In 1997, Henriksen et al[5] showed that military veterans exposed to dioxin showed increased prevalence of glucose abnormalities, insulin abnormalities, and diabetes prevalence and faster development of diabetes compared to veterans of the same era who had lower levels of dioxin in their blood. In 1999, Calvert et al[6] showed that among workers occupationally exposed to a highly toxic form of dioxin, those with the highest blood levels of dioxin showed higher average levels of blood glucose. In 2000, Longnecker and Michalek[7] showed that among 1,197 veterans Air Force Veterans with no history of chemical exposure and normal serum levels of dioxins, patients with higher levels of dioxins showed an increased prevalence of diabetes. In 2003, Fierens et al[8] reported that diabetic patients showed significantly increased serum levels of dioxins, coplanar PCBs, and 12 PCB markers compared to unaffected control patients, and the level of chemical accumulation in diabetics was very significant; diabetic patients showed a 62% higher level of PCB toxins than healthy patients, and higher levels of toxins were associated with a higher risk of diabetes in a dose-dependent manner. In 2006, Fujiyoshi et al[9] showed that higher levels of dioxin correlated with higher levels of systemic inflammation (as measured by NF-kappaB activity, which I have reviewed elsewhere[10]) and higher levels of blood glucose and increased risk of clinical diabetes; the results of this study are particularly alarming because serum levels of toxins that correlated with increased risk of insulin resistance were comparable to levels found in the general population and which are generally considered “normal”, assuming that chemical exposure and accumulation could ever be considered normal. This research shows that background “every day” environmental exposure to dioxins and other chemical increases the risk of diabetes and insulin resistance even among patients with no occupational or accidental acute exposure to these chemicals. Also in 2006, Vasiliu et al[11] showed that women with higher levels of polychlorinated biphenyls showed increased risk of diabetes. Further in 2006, Lee et al[12] showed a "striking dose-response relations between serum concentrations of six selected POPs [persistent organic pollutants] and the prevalence of diabetes" among a sample of more than 2,000 American citizens; note that this study is unique in that it analyzed a group of chemicals rather than a single or a small number of chemicals as performed in most of the previous studies. In 2007, Lee et al[13] published a follow-up study which again showed a clinically significant correlation between body burden of toxic chemicals and the incidence of insulin resistance and risk of diabetes.
Given the strong and consistent link between diabetes and the accumulation of toxic chemicals, two causal possibilities exist: either chemical accumulation causes diabetes, or diabetes causes chemical accumulation. While the former is more likely, the latter would not exclude clinicians and patients from the need to take action on this data because of the inherent risks associated with chemical accumulation. Toxic chemicals such as the ones associated with diabetes in the aforementioned studies are the same chemicals associated with induction of Parkinson’s disease, and current evidence does indeed show increased risk of Parkinson’s disease among diabetic patients.
 
Molecular Mechanisms of Xenobiotic Diabetogenesis
Toxic chemicals (xenobiotics) can cause insulin resistance and clinical diabetes mellitus by several different mechanisms. The aryl hydrocarbon receptor (hereafter: hydrocarbon receptor) is generally viewed as the molecular mechanism by which dioxin-like chemicals exert their adverse biological actions.[14] Stated simply, a leading hypothesis suggests that dioxin-like chemicals stimulate the hydrocarbon receptor to suppress glucohomeostatic activity of PPAR-gamma (peroxisome proliferator activated receptor gamma). PPAR-gamma is an intranuclear receptor that powerfully modulates insulin sensitivity and glucose utilization; indeed PPAR-gamma is the main target of the drug class of thiazolidinediones (TZDs) which are used in diabetes mellitus and other disorders of insulin resistance.[15] PPAR-gamma activation promotes insulin sensitivity and thus has a clear anti-diabetic effect by increasing the number of GLUT-4 receptors on the surface of muscle and adipose cells. Conversely, inhibition of PPAR-gamma (by toxin activation of the hydrocarbon receptor) causes a reduction in the number of GLUT-4 transporters which are required to move glucose from the serum into the intracellular space of muscle and adipose tissue. Thus, the molecular mechanism and biologic plausibility by which toxic chemicals can lead to insulin resistance is clearly and firmly established based on in vitro studies, animal experiments, and the consistent data reported in humans. Furthermore, secondary effects such as the estrogen-like action of many toxic chemicals may further complicate and exacerbate the diabetogenic effect of these toxins via upregulation of adipose accumulation. Increased adiposity from whatever cause correlates with increased serum levels of estrogens because adipose tissue expresses the aromatase enzyme which converts androgens into estrogens. Furthermore, adipose tissue is pro-inflammatory via the elaboration of cytokines (adipokines) which induce systemic inflammation and downregulate insulin sensitivity by decreasing the number of insulin receptors in adipose and muscle cell membranes. Many of the toxic chemicals that correlate with increased risk for diabetes have been shown in other studies to adversely affect thyroid function, directly leading to clinical and subclinical hypothyroidism and the resultant reduction in metabolic rate and propensity for weight gain and increased adiposity. Once established, the hyperglycemia of diabetes results in increase urinary excretion of nutrients such as magnesium, which is essential for peripheral insulin sensitivity and hepatic detoxification of xenobiotics; thus diabetes-induced magnesium deficiency can impair xenobiotic detoxification and thus contribute to an exacerbation of chemical accumulation. Lastly, some clinicians have proposed that increased adiposity may be a defensive means by which the body attempts to protect itself from chemical exposure, since increased fat stores will serve to dissipate and dilute absorbed chemicals and thus lessen their toxic effects. Anecdotal reports of rapid and effective weight loss have been observed in some patients following the implementation of clinical detoxification procedures, such as those outlined by the current author[16] and detailed by others, notably Walter Crinnion ND as cited below.

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"The production of chemicals has been shown to be closely associated with the rise of diabetes prevalence in the USA."  Dr Hong Lee

"Dear fellow diabetes investigators, I think we have a very good answer to the question of ‘why is there a diabetes epidemic in my country?’ It is due to the contamination of our environment by POP during industrialization." Dr Hong Lee

Diabetes Treatment by Routine Methods: Unintentional DetoxificationI propose here that some of the commonly used methods for treating diabetes actually derive their benefits at least in part from their ability to enhance excretion of toxic chemicals. Exercise increases lipolysis which liberates fat-stored xenobiotics from adipose tissue, resulting in higher serum levels of toxins which thus increases urinary excretion of these toxins. Furthermore, the hyperventilation induced by exercise promotes respiratory alkalosis and the resultant alkalinization of the urine increases excretion of weakly acidic poisons. Relatedly, increased intake of fruits and vegetables promotes systemic and urinary alkalinization and thereby facilitates urinary excretion of poisons. Given evidence that systemic inflammation (in human studies of endotoxinemia) suppresses hepatic detoxification of xenobiotics, then the glucohomeostatic benefits of exercise, phytonutrient-rich diets, vitamin D3, fatty acid supplementation, and lipoic acid may be derived in part from the ability of these interventions to reduce systemic inflammation and thus facilitate (via derepression) xenobiotic biotransformation. The fiber of fruits and vegetables binds to chemicals which have undergone detoxification/biotransformation and which have been excreted in the bile; high-fiber diets reduce the recycling of toxins excreted into the gut. Magnesium supplementation improves insulin sensitivity, enables hepatic detoxification, and promotes urinary alkalinization. Fruits, vegetables, fiber, exercise, and magnesium supplementation all promote increased frequency of bowel movements to reduce enterohepatic recycling of (de)conjugated toxins. “Statin” cholesterol-lowering drugs (designed to inhibit the HMG-CoA reductase enzyme) activate the pregnane X receptor which upregulates xenobiotic detoxification and results enhanced toxin excretion. Cholestyramine, a drug that binds cholesterol in the gut and that is used in the treatment of diabetic hypercholesterolemia, also binds toxic chemicals excreted in the gut and can be used as effective therapy in patients with chronic chemical poisoning.[17] Therefore, the anti-diabetic, hypocholesterolemic, and insulin-sensitizing clinical effects of many commonly employed therapeutics may result directly and in part from the enhanced elimination of xenobiotics; this is a hitherto unappreciated mechanism of action for these treatments.

Diabetes Treatment by Detoxification: Proposal for