Chemical Exposure as a Major Contributor to the Epidemic of Diabetes Mellitus and Disorders of Insulin Resistance: From Molecular Mechanisms to Clinical Implications
By Alex Vasquez, DC, ND, Editor
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.
This article surveys current literature and explain the causes, mechanisms and clinical implications of the toxin-diabetes link; and expands upon some of my previous work on chemical exposure and clinical detoxification methods,1,2 specifically related to the genesis and treatment of diabetes.3 By the time naturopathic doctors finish reading this article, they 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, cholecalciferol4) 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 an 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 Michalek7 showed that among 1,197 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 percent 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 elsewhere10), 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 "everyday" environmental exposure to dioxins and other chemicals increases the risk of diabetes and insulin resistance, even among patients with no occupational or accidental acute exposure to these chemicals. In 2006, Vasiliu, et al.,11 indicated that women with higher levels of polychlorinated biphenyls showed an increased risk of diabetes. Also in 2006, Lee, et al.,12 showed "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.
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 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 that 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 increased 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 contribute to an exacerbation of chemical accumulation. Finally, 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, which serves to 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 author1 and detailed by others, notably Walter Crinnion, ND.19
Diabetes Treatment by Routine Methods: Unintentional Detoxification
I 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. The result is increased 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, thereby facilitating 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 that have undergone detoxification/biotransformation and that 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 in enhanced toxin excretion. Cholestyramine, a drug that binds cholesterol in the gut and 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.16 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 Large-Scale Clinical Trials
Given the strength and direction of the research indicating that xenobiotic exposure and chemical accumulation is a major contributor to the epidemic of type 2 diabetes mellitus and other disorders of insulin resistance, all of us as researchers, clinicians and health care consumers are potentially on the verge of a major paradigm shift in regard to our view of these disorders and their clinical management. If chemical exposure and accumulation contribute to insulin resistance, health care professionals will have ethical and professional obligations to address these underlying problems in patients who present with insulin resistance. Detoxification protocols, rather than endless and additive drug prescriptions to suppress the symptoms of the problem, could become the standard of care if such protocols are shown safe and effective for restoring glucohomeostasis. However, given the ubiquitous nature of xenobiotic exposure and the numeric infinity and methodological complexity of measuring levels of xenobiotics in individual patients, doctors and patients alike will be fighting an uphill battle against the constant onslaught of toxins. Both groups will have to start with an understanding of the body’s inherent detoxification processes and the means by which these defense mechanisms can be supported in their respective roles. Given that we already have molecular mechanisms, animal research and human data linking xenobiotic exposure to the genesis and perpetuation of insulin resistance, the only piece of the diabetes-xenobiotic puzzle that is missing is a large-scale clinical trial of effective therapeutic detoxification in patients with diabetes.
If such a trial were to be skillfully designed and successfully implemented, and was able to demonstrate amelioration of insulin resistance by interventions that are, to the extent possible, specific to the detoxification process (rather than directed toward enhancement of insulin sensitivity), then an authentic breakthrough in the management of the rising pandemic of diabetes mellitus would be achieved. Further, such a breakthrough would open the door to other trials in xenobiotic-associated diseases, particularly Parkinson’s disease, autism17 and many of the systemic autoimmune diseases, such as systemic lupus erythematosus.1 In order to design and implement such trials, clinician researchers must start from an understanding of the biochemical and physiologic means by which detoxification occurs and the means by which such process can be supported and expedited to effect rapid elimination of toxins. An overview of important concepts will be provided in the following section. Citations to research will be limited here due to space restrictions; excellent reviews of this subject include the works of Liska18 and Crinnion.19 What follows is an extended excerpt from my previous work on the role of therapeutic detoxification in the treatment of musculoskeletal inflammation. (See Chapter 4 of Integrative Rheumatology1 for the complete list of 95 references to the following section.)
The Biochemistry and Physiology of Detoxification: A Rationale for Clinical Therapeutics
Studies using blood tests and tissue samples from Americans across the nation have consistently shown that all Americans have toxic chemical accumulation, whether or not they work in chemical factories or are exposed at home or work.20,21 We cannot escape from the chemical consequences of living in a world with tens of thousands of synthetic chemicals. According to limited analyses, the average American has accumulated at least 18 different chemicals,22 and analyses that are more detailed show that even more chemicals and metals have been accumulated.23 Common sources of these chemicals include pesticides, synthetic fertilizers, herbicides, fungicides, industrial pollution, car exhaust, solvents, paints, perfumes, plastic food/drink containers, non-stick cookware, Styrofoam, trichloroethylene from dry cleaning, rubber, carpet, plastics, glues, propellants, petroleum fuels such as gasoline, detergents, and other "cleaners." Clinical consequences of chemical toxicity are diverse, can affect nearly every organ system, and may be predicted to some extent by the pattern of chemical exposure since some chemicals have characteristic sequelae. Most of these chemicals are fat-soluble and can readily enter the body via respiratory, gastrointestinal, and transdermal routes. Once in the bloodstream, chemicals are either detoxified (inactivated and/or solubilized) by the liver and then excreted via urine or bile, or to a lesser extent, exhaled from the lungs or excreted via sweat.
Chemicals that are not excreted from the body are stored in the tissues, particularly lipid-rich organs such as the liver, adipose and brain. Molecular turnover and recycling (particularly lipolysis) liberate fat-stored xenobiotics, providing another opportunity for either detoxification or additional toxicity. The main route for detoxification is the liver, which hydrosolublizes xenobiotics via oxidation ("phase one") and conjugation ("phase two"). Generally speaking, oxidation reactions are dependent on the cytochrome P-450 system, which can be inhibited by various drugs (e.g., ketoconazole, erythromycin, ritonavir, cimetidine, omeprazole, ethanol), foods such as ethanol and grapefruit juice, bacterial endotoxin from bacterial overgrowth of the bowel, and/or by genetic defects known as single nucleotide polymorphisms ("SNiPs"), which reduce xenobiotic clearance. Similarly, conjugation reactions can be inhibited by a low-vegetable diet, SNiPs, and insufficiencies of conjugation moieties such as glutathione, glycine, glutamine, taurine, ornithine, sulfur, and methyl groups. If oxidation is too slow, then xenobiotics are insufficiently detoxicated and insufficiently processed for conjugation, leading to xenobiotic accumulation. If oxidation is too fast relative to conjugation, then reactive intermediates are formed which are commonly more toxic than the original xenobiotic.
Optimally, oxidized and conjugated xenobiotics are excreted in the urine or expelled in the bile. Supranormal hydration and urinary alkalinization enhance renal clearance of weakly acidic xenobiotics and drugs, whereas dehydration and urinary acidity impair toxin excretion, generally speaking. Conjugated toxins expelled in the bile can be deconjugated by bacteria so that the toxin is reabsorbed, a phenomenon commonly referred to as "enterohepatic recycling" or "enterohepatic recirculation." Such recirculation is obviously less likely if gastrointestinal status and diet have been optimized to minimize the presence of deconjugating bacteria and to maximize fiber intake and laxation for the adsorption and expulsion of intraluminal toxins. Therapeutic colonics and enemas can be employed to stimulate bile flow from the liver24,25 and to remove bile-secreted toxins from the gut before deconjugation and reabsorption occur. Bile formation and expulsion are further stimulated by botanical medicines such as beets, ginger, curcumin/turmeric,26 Picrorhiza, milk thistle, Andrographis paniculata, and Boerhaavia diffusa.
Respiratory exhalation of toxins is enhanced by deep breathing and exercise, and hyperventilation promotes respiratory alkalosis which elevates urine pH and promotes excretion of weakly acidic drugs and xenobiotics as previously mentioned. Dermal excretion of toxins via sweat and expedited lipolysis are stimulated via low-temperature saunas and regular aerobic exercise. Xenobiotic oxidation can be promoted (cautiously) by reducing endotoxins from the gut and by the use of botanicals such as Hypericum perforatum which induce several isoforms of cytochrome P-450 via activation of the pregane X receptor. Xenobiotic conjugation is likewise promoted via nutrigenomic induction stimulated by cruciferous vegetables and their derivatives such as indole-3-carbinol (I3C) and dimethylindolylemethane (DIM). The plant-based diet is employed to provide fiber for bowel cleansing and the urinary alkalinization that is necessary for optimal urinary excretion of toxins, the majority of which are weak acids and are thus excreted more efficiently in alkaline urine. Sodium bicarbonate can also be used to induce urinary alkalinization. The diet must contain high-quality protein and can be supplemented with amino acids to support amino acid and glutathione conjugation. Serum, urine and adipose samples can be analyzed to determine the intensity and diversity of chemical accumulation.
For most patients, chemical accumulation is so diverse that they may not display abnormally high levels of a specific chemical; their clinical manifestations are rather a manifestation of a wide plethora of different chemicals, which individually may be only modestly increased. Detoxification characteristics can be assessed from genotypic and phenotypic perspectives using appropriate laboratory tests. Phenotype can be assessed by serum and urine measurements of post-challenge detoxification of benzoate, caffeine, acetylsalicylic acid, and acetaminophen. Amino acid status can be quantified and qualified via serum or urine amino acid analysis. Stool testing assesses digestion, absorption, and microflora status. Clinical implementation of therapeutic detoxification follows a physical examination and basic laboratory assessment (minimally including CBC, metabolic panel, and urinalysis). Stool testing for dysbiosis is always reasonable when working with patients with fatigue and/or autoimmunity;27 however, this and the other detoxification-related tests often can be deferred and/or used selectively.
The Paleo-Mediterranean diet provides ample high-quality protein, alkalinization, fiber, and phytonutrients to which may be added supplements of protein, amino acids (especially NAC, glycine and glutamine), and vitamins and minerals. Antioxidant teas and fresh fruit and vegetable juices are consumed to increase frequency of urination and promote urinary alkalinization due primarily to the content of potassium citrate. Exercise and low-temperature saunas promote sweating and xenobiotic-mobilizing lipolysis. Bile flow is further stimulated by consumption of beets, ginger, curcumin/turmeric, Picrorhiza, milk thistle, Andrographis paniculata and Boerhaavia diffusa. These interventions work in concert to enhance xenobiotic removal and cleanse the tissues of accumulated toxins. Intervention can be acute or periodic, but must be maintained for the long-term in order to resist the reaccumulation destined to result from the chemical onslaught that is inescapable in our polluted world.
Clinicians should now have an appreciation of the emerging research that links chemical accumulation to the development of diabetes. The molecular mechanisms have been explained, and the basic science and clinical research have been reviewed, and major considerations for the design and implementation of therapeutic detoxification programs have been presented. Formal clinical trials must be pursued, while at the same time, individual clinicians explore the use of detoxification in their diabetic patients.
About the Author: Dr. Alex Vasquez is a researcher and lecturer for Biotics Research Corporation, and is author of more than 50 articles and letters in magazines and journals such as Arthritis & Rheumatism, Journal of the American Medical Association, The Lancet, British Medical Journal, Annals of Pharmacotherapy, Journal of Manipulative and Physiological Therapeutics, Integrative Medicine, and Alternative Therapies in Health and Medicine.
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Date Last Modified - Friday, 17-Oct-2008 12:10:55 PDT