Sugar Toxicity: A Silent Epidemic

A View from the Trenches of Daily Primary Integrative Medical Praxis

by David A. Edwards, MD, HMD; Jean Malik, MD, APH; Edna Espig, CNA, CHA; Renoir Morillo, BSN, CHA; Erika Bryant, EECP Tech; and Jesusa

Ludahl

Sugar is the generalized name for sweet, short-chained soluble carbohydrates. Carbohydrates are composed of carbon, hydrogen and oxygen (basically carbon + water). The term sugar refers loosely to a number of different types of carbohydrates, including monosaccharides (glucose, fructose), disaccharides (sucrose, lactose), oligosaccharides, and polysaccharides (common components of glycoproteins and glycolipids). The most biologically important and well known monosaccharide is glucose. Glucose is the main source of energy fueling aerobic metabolism – a fundamental necessity of living mammalian cells. The most common disaccharide is sucrose (glucose + fructose) or common table sugar. Biopolymers (oligo- and polysaccharides) of sugar are common structural forms of carbohydrates in nature. Plants produce sugar and sugar biopolymers through the process of photosynthesis. These biopolymers are converted into structural polysaccharides, such as cellulose and pectin found in plant cell walls. They also may serve as a form of energy storage, such as starch or inulin. In addition, DNA and RNA are polymers of the monosaccharides deoxyribose and ribose respectively and constitute the basis of genetic blueprint and memory for almost all forms of life. The importance of sugar in its various functional and structural forms for life cannot be overstated. However, like oxygen, which is both essential for most life forms and also extremely toxic to life (physiologic function versus toxic free-radical damage), sugar also has a dark side for living tissue.

Studies in animals and humans have suggested that chronic consumption of added sugar contributes to metabolic and cardiovascular dysfunction. There is also growing evidence that added fructose is more damaging than refined glucose in terms of cardiovascular risk Cardiac performance has been shown to be impaired by switching from a low-carbohydrate diet including fiber to a high-carbohydrate diet. Switching from saturated fatty acids to carbohydrates with high glycemic index values shows a statistically significant increase in the risk of myocardial infarction. Other studies have shown the risk of developing coronary heart disease is decreased by adopting a diet high in polyunsaturated fatty acids and low in sugar, but a low-fat, high-carbohydrate diet showed no reduction. This suggests that consuming a diet with high glycemic load (“high glycemic” = causes a rapid rise in blood sugar) is strongly associated with the development of coronary artery disease. The consumption of added sugars has been positively associated with multiple measures known to increase cardiovascular disease risk in adolescents as well as adults. Multiple studies suggest that the impact of refined carbohydrates or high glycemic load carbohydrates is more significant than the impact of saturated fatty acids on cardiovascular disease. In addition, a connection between Alzheimer’s disease and fructose has been suggested, but remains the subject of debate. Finally, the possible addictive effects of refined sugar simply adds to the scientific concern regarding the toxic effects of sugar in the development of cardiovascular disease.

Glycocalyx

One of the lesser-known structural/functional physiologic aspects of sugar is the glycocalyx. The glycocalyx is a polysaccharide sugar polymer coating that surrounds all cell membranes. This “sugar” coating consists of several carbohydrate moieties of structural membrane glycolipids and glycoproteins which serve as a backbone for support and cell-to-cell communication. Pischinger’s matrix theory of rapid cell to cell communication is centered on the functional aspects of the glycocalyx (Pischinger A. Matrix and Matrix Regulation Basis for a Holistic Theory in Medicine. Brussels: Haug International; 1991). This carbohydrate (“sugar”) portion of plasma membranes contributes to cell–cell recognition, communication, and intracellular adhesion. The slime on the outside of a fish is a common example of a glycocalyx. It is essentially a functional “biofilm.” The term glycocalyx was initially applied to the polysaccharide matrix coating epithelial cells, but its functions have been discovered to go well beyond that. The glycocalyx plays a major role in regulation of endothelial vascular tissue, including the modulation of red cell volume in capillaries. It is located on the apical surface of vascular endothelial cells which line the lumen of all blood vessels and may be up to 11 um thick It is present throughout a diverse range of microvascular beds (capillaries) and macrovessels (arteries and veins). The glycocalyx also consists of a wide range of enzymes (eNOS, ACE, SOD3, etc.) and proteins (growth factors, chemokines, antithrombin, etc.) that regulate and protect the endothelium. They serve to reinforce the glycocalyx barrier against vascular and other diseases. Another function of the glycocalyx within the vascular endothelium is to shield the vascular walls from direct exposure to blood flow while serving as a vascular permeability barrier. Its protective functions are universal throughout the vascular system. In microvascular tissue the glycocalyx inhibits coagulation and leukocyte adhesion. It also affects the filtration of interstitial fluid from capillaries into the interstitial space. Research has shown that the glycocalyx is composed of a negatively charged network of proteoglycans, glycoproteins, and glycolipids.

The glycocalyx plays a crucial role in cardiovascular system health. Initial dysfunction of the glycocalyx can be caused by hyperglycemia or oxidized LDL cholesterol. In the microvessels, dysfunction of the glycocalyx leads to internal fluid imbalance and potentially edema. In arterial vascular tissue, glycocalyx disruption causes inflammation and atherothrombosis. Fluid shear stress is also a potential problem if the glycocalyx is disrupted for any reason. This type of frictional stress is caused by the movement of viscous fluid (i.e., blood) along the lumen boundary, damaging the delicate glycocalyx. Minimal ischemic damage to the glycocalyx increases capillary hematocrit. Endothelial (glycocalyx) dysfunction can be tested by a variety of methods. Of all the current tests employed in a research setting, flow mediated dilatation (postocclusive reactive hyperemia; PORH) is the most widely used noninvasive test for assessing endothelial dysfunction. This technique measures endothelial function by inducing reactive hyperemia via temporary arterial occlusion and measuring the resultant relative increase in blood vessel (capillary) diameter via ultrasound or plethysmography. A reduction of small arteriole/capillary compliance is a marker for endothelial (glycocalyx) dysfunction that is associated with both functional and structural changes in the microcirculation and is predictive of subsequent morbid events. These changes can be distinguished from large artery (macrocirculation) stiffness and obstruction by the use of pulse volume recording (PVR).

Endothelium

The endothelium is a thin layer of squamous endothelial cells that line the inner surface of blood and lymphatic vessels, forming an interface between circulating blood or lymph fluid in the lumen and the vessel wall. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph fluid are known as lymphatic endothelial cells. Endothelium is mesodermal in embryonic origin. Vascular endothelial cells line the entire circulatory system, from the heart (“endocardium”) to the smallest capillaries. These cells have unique functions in vascular biology. Both blood and lymphatic capillaries are composed of a single layer of cells called a monolayer. All endothelial cells are coated with glycocalyx biopolymers. Endothelial dysfunction is a hallmark for vascular disease, and is often regarded as a key early event in the development of cardiovascular disease. Impaired endothelial function has been related to hypertension and vascular thrombosis and is seen in patients with coronary artery disease, diabetes mellitus, and hypercholesterolemia. Endothelial dysfunction is a systemic pathological state of the inner lining of blood vessels and can be broadly defined as an imbalance between vasodilating and vasoconstricting forces acting on endothelial cells. Endothelial dysfunction has been shown to be of prognostic significance in independently predicting vascular events including stroke and myocardial infarction. Endothelial dysfunction can result from and contribute to several disease processes (hypertension, diabetes) and can also result from environmental factors such as smoking and exposure to air pollution. Thus, endothelial dysfunction is a major pathophysiological mechanism of vascular disease. Endothelial dysfunction is synonymous with glycocalyx dysfunction.

Macro vs. Microcirculation

There are actually two “functionally interrelated” blood circulatory or vascular systems found in the human body: the macrocirculation and the microcirculation. The macrocirculation consists of the larger “conduit” arteries that conduct blood to the major organs. Included among these arteries are the aorta (chest and abdomen), carotid (neck), femoral (legs), coronary (heart) arteries, and others. These are the blood vessels commonly treated with surgery and angioplasty (balloon therapy/stenting). The acute treatment of these large conduit “macro” vessels is commonly the focus of cardiologists, vascular surgeons, the news media, websites, and television shows. These treatments are routinely used and “sold” by scientific (more properly called statistical) “evidenced-based” medical practitioners. These macrovessels are the arteries said to be chronically “plugged up” (arterial plaque buildup) from the common “statistical” risk factors promoted by “evidence-based” scientific medicine: cholesterol, “bad” genes, high blood pressure, smoking, and so on. Please note that no one who speaks from scientific authority has ever said that cholesterol or smoking actually “causes” plaque. No, that’s not what has been said, but commonly that is what is heard. What is being “said” is these factors are statistically associated with plaque, but science still does not know what actually causes arterial plaque to form.

Arterial plaque occurs in localized, “specific” sites within macrovessels; but, oddly enough, the statistical risk factors, which occur throughout the entire vascular system, theoretically should affect all macroarteries in the same way. Despite this, one commonly sees plaque blocking 90% of one coronary heart artery and no evidence of any blockage in the heart artery right next to the blocked one in the same patient. Isn’t just as much cholesterol passing through each artery? Why the difference in presence and/or size of plaque? No one, and certainly no one in “evidence-based” scientific medicine, knows. They simply “know” statistical risk factors that are associated (statistically) with the presence of plaque. Scientific “evidence-based” statistical treatment and/or prevention consists of advising lifestyle changes (weight reduction, exercise, stress control, etc.) or prescribing pharmaceutical drugs (statin drugs, ACE inhibitors, ARB blockers, beta blockers, aspirin, Plavix, etc.), angioplasty, or surgery. The typical advice in mild to moderate plaque buildup is to reduce or lower weight, lower cholesterol, lower blood pressure, reduce inflammation, and increase blood thinning – all strategies that have been “statistically” (“evidence-based”) demonstrated to reduce the risk and severity of macrovascular disease. Interestingly, these statistically based approaches are not effective in all patients, simply a “statistically significant” number of patients. Therefore, many patients following the correct “evidence-based” scientific diet and life style and using appropriate “evidence-based” medications or surgery will continue to demonstrate advancing plaque buildup over time. Advanced or high grade plaque buildup (80%–100%) is mechanically (surgery, angioplasty) repaired as if it is simply defective plumbing, but this mechanical therapy does not correct the actual cause. That’s about it, “scientifically speaking,” for macrocirculation treatment from a scientific, “evidence-based” perspective.

Microcirculation is turning out to be radically “different.” Microcirculation is also referred to in scientific medical literature as the capillary circulation, terminal circulation, or end-circulation. These are the tiny blood vessels (capillaries and capillary networks) that actually supply oxygen and nutrients and remove carbon dioxide and other metabolic waste from the vital organs (i.e., heart, brain, kidney, liver, etc.). Incredibly, it now appears from a scientific perspective that microcirculatory disease is primarily related to the biological toxicity of sugar, not fat as in macrocirculatory theory. The “joke” of Mother Nature on modern medical science is that substances that are absolutely “essential” to life (oxygen, sugar) also turn out to be extremely toxic to life. Nature has placed a hidden “tax” on aerobic-based (oxygen-carbohydrate-sugar) metabolic energy efficiency. Thus, metabolically utilizing (“burning”) oxygen and sugar for efficient production of energy comes at a potentially high metabolic price: free radical toxicity and protein glycation or glucotoxicity. By way of analogy, oxygen toxicity can be thought of in simple terms as being similar to “rusting” of molecules in the tissue or organ that these molecules make up (free-radical pathology). Sugar toxicity is being discovered to act by causing “glycation,” or “caramelization” of essential structural and functional proteins, including the glycocalyx or endothelium. This process can be thought of in simple terms as causing protein “wrinkling.” Another simple analogy would be that of melting caramel over an apple and the caramel-sugar “coating” then hardens or stiffens, thus slowly, but progressively “caramelizing” the microcirculatory endoskeleton of the affected vital organ (i.e., heart, brain, kidney, etc.). When this process involves living tissue it occurs with subtle but devastating physiological consequences over time. The “nonenzymatic” (meaning in the absence of the enzyme insulin) attaching of a sugar to a protein is currently thought to destroy (glycate or caramelize) proteins. Protein glycation is currently generally assumed to be nonreversible. This assumption is actually no longer scientifically correct.

The most widely scientifically recognized clinical condition involving abnormal tissue glycation leading to clinical microcirculatory disease is diabetes. This is the biochemical, structural, and regulatory basis of the commonly encountered condition of diabetic gangrene. Once a “black toe or foot” develops in diabetes, there is no bypass vascular operation, angioplasty, or drug that will help. There is only amputation of the dead tissue and usually problems with wound healing due to the subclinical microvascular disease in the remaining “viable” tissue. Diabetes is a condition that exists in the annals of “evidence-based” scientific medicine by definition and is, “by definition,” irreversible. Diabetes is defined as a blood sugar that goes “too high …” that exceeds the statistically derived “normal” height or peak of blood sugar seen in an “average” population. The definition includes establishing the “normal” and “abnormal” blood sugar levels during fasting, after eating, or during a laboratory glucose tolerance test. This definition of diabetes focuses on how high the blood sugar goes. It turns out that glycation from glucotoxicity also occurs from glucose (sugar) being in prolonged contact with tissue. Thus, the newly described “metabolic syndrome” (also called dysmetabolic syndrome, syndrome X, or insulin resistance), which also exists by definition (and is “by definition” reversible), involves the inability of potentially toxic sugar to exit or, in more technically correct scientific terminology, be “disposed of” from the blood into the cellular metabolism as quickly as possible. Thus, diabetes, by definition, is about how high blood sugar goes and metabolic syndrome, by definition, is also about how long sugar remains in the blood (impaired glucose disposal).

The pathological effect of microcirculatory protein glycation is a stiffening of the capillaries throughout the affected organ – actually a caramelization of the microvascular skeleton within the organ involved. This process involves both abnormal biochemistry (protein glycation) and structural circulatory regulation changes (increased microvascular resistance). The gradual glycation of protein molecules (“endothelium”) lining the small capillary microcirculation stiffens those microvessels so that they cannot pulsate with the heartbeat. In addition, glycation of the proteins on the red blood cell stiffens their external membranes, making it more difficult for the stiffened red cells to pass through the caramelized capillary beds one at a time. The resultant structural problem is the inability of the microcirculation to pulsate open with the kinetic (pumping) force of the heartbeat, coupled with the red blood cells’ inability to bend, twist, and deform to slip through these stiffened capillaries one at a time. A capillary that is pulsed open during cardiac systole is 10 microns in diameter. During diastole, the capillary reduces to 5 microns in diameter. A red blood cell is 8 microns in diameter. Thus, the caramelized capillary cannot dilate effectively, and the older caramelized red cell has reduced flexibility. This situation results in small capillary “infarcts or strokes” in the affected Microcirculatory vessel directly involving the affected organ or tissue (i.e., brain, heart, kidney, etc.).

Over time (years to decades) the collective effects of this process appears clinically. Interestingly, the clinical syndrome that appears depends on which organ(s) is (are) affected. Microcirculatory disease somewhat mimics macrocirculatory disease in that it may “skip” around, affecting different organs or areas of the body differently. Thus, if microcirculatory glycation occurs in the heart there will be a development not of a major clinical “heart attack” (myocardial infarction), but small areas of tissue damage (i.e., slight elevation of enzymes without ECG changes) or, more importantly, the gradual development of diastolic heart failure. This process does not involve the active process of the heart contracting but its inability to relax effectively (diastole) after contraction due to microvascular stiffening of capillaries within the involved heart muscle. Thus, the heart fails to fill effectively and clinical congestive heart failure (CHF; fluid backup into the lungs, legs, etc.) develops. CHF is the now the most common and least curable form or heart disease affecting the American population, with a large proportion being diastolic heart failure. Similarly, if capillary glycation involves primarily the kidney, high blood pressure will develop. Interestingly, diastolic dysfunction, diastolic heart failure, high blood pressure, and sugar toxicity (“metabolic syndrome”) are now “epidemic” among Americans, old and young. If capillary glycation occurs mainly in the brain, a condition called leukoaraiosis or coalescing tiny (lacunar) strokes leading to scaring of the gray matter in the brain occurs, and memory loss/cognitive dysfunction and/or small strokes (lacunar infarcts) will develop. Leukoaraiosis is still being taught in scientific medical schools as “a result of aging” and is of “no medical consequence.” This outdated thinking has been clearly and scientifically disproven. The presence of leukoaraiosis on an MRI or CT brain scan should be taken as direct clinical evidence of abnormal microvascular glycation (endothelial dysfunction). The connection between heart disease, hypertension, and Alzheimer’s syndrome, suggesting a common underlying mechanism (microvascular disease), is now being formally recognized.

Figure 1 depicts a diagrammatic representation of this gradual process of capillary cross-sectional attrition over time from normal capillary flow through a tissue or organ in the upper diagram to an intermediate reduction in the middle and then finally a significant loss of the illustrated microvascular capillary bed on the bottom. The organ or tissue most affected is where the clinical “syndrome picture” will manifest (heart, kidney, brain, etc.) Figure 2 is a photomicrograph of a section of brain clearly demonstrating the loss of the microcirculatory capillary bed in a histologic section of brain from a patient with dementia.

Figure 1

Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 2011 Feb;37(1):64. Reprinted with permission.

Figure 2

Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 2011 Feb;37(1):61. Reprinted with permission.

Interestingly, in addition to the toxic microcirculatory effects of glucose and subsequent endothelial glycation now being described in Alzheimer’s-like senile dementia, scientific evidence also shows that the accumulation of abnormal proteins (β-amyloid and tau protein) in Alzheimer’s disease also causes reduced microcirculation (vasoconstriction) in the brain. β-amyloid protein also reduces endothelium-dependent brain vasodilation. As if to add insult to injury, any temporary lack of oxygen in the brain can also lead to increased production of β-amyloid protein. Thus, it is apparent that microcirculatory compromise plays a very large role in the development of memory loss, cognitive dysfunction, and dementia syndromes, regardless of the actual “official name” of the clinical syndrome. In addition to and as further proof of this situation, the microscopic changes in brain tissue that are thought to be “specific” for Alzheimer’s disease (β-amyloid, tau protein, neurofibrillary tangles) have also been described in patients with heart vascular disease and no evidence of dementia. The increase in body fat that is part of “metabolic syndrome” also contributes to the “bad” situation. Centralized body fat is actually a functioning endocrine organ. Body fat secretes certain pro-inflammatory cytokine hormones (tumor necrosis factor alpha and interleukin-6 , etc.). Thus, increased body fat leads to increased inflammation (a statistical risk factor for macrocirculation disease). Inflammation can be measured using the blood test C-reactive protein or CRP. Thus, many previously recognized “independent risk factors” can now be connected through the understanding of the biologically toxic properties of sugar related to malfunction of cellular insulin receptors.

Insulin Resistance/Metabolic Syndrome

The underlying metabolic basis of glucotoxicity is the inability of the enzyme insulin to activate insulin receptors on cell surfaces (“membranes”) that allow the sugar to move quickly from the blood into the cellular metabolism, where it can be used for energy production (and the production of free radicals!). Thus insulin acts as a “key” that must fit into an insulin receptor or “lock” and open that lock so that potentially toxic sugar can be transported (“disposed of”) quickly and efficiently from the blood into the cellular metabolism. When sugar is not disposed of quickly, several “bad” things begin to happen: (1) glycated microvessels and cellular red corpuscles “stiffen” and lose their ability to pulsate with the heart; (2) the undisposed-of sugar is immediately shunted into centralized body fat production. One of the clinical markers used to define metabolic syndrome is centralized body fat (a large waistline); (3) additional pathological events related to poor glucose disposal include excess sorbitol production leading to nerve damage (diabetic neuropathy) and cataracts. The “defining components” of metabolic syndrome that have been “suggested” or adopted by various scientific groups and societies are high blood pressure, high cholesterol, high triglycerides, high fasting insulin levels, and high fasting blood sugar. Interestingly, all the different criteria put forth by various scientific medical groups (the WHO, American College of Cardiology, American Association of Clinical Endocrinology, etc.) do not include any evidence of direct tissue sugar-protein glycation as criteria for diagnosis. Usually, the presence of three or more of these statistical risk factors “qualifies” as a diagnosis of “metabolic syndrome.” In reality, by the time any individual actually “qualifies” for the formal diagnosis of metabolic syndrome, they are already manifesting significant and late-stage clinical evidence of severe microvascular glycation (i.e., high blood pressure, obesity, heart disease, dementia, etc.).

The main biochemistry involved in the pathology of glucotoxicity is known as the Maillard reaction. This common chemical reaction has been known for over 100 years. The main scientific focus of this reaction usually involves food spoilage and industrial applications. Other than in diabetes mellitus (“sugar diabetes”), there was really little medical scientific interest in the Maillard reaction in medical science or practice. However, with the recent and gradually increasing scientific realization that the cholesterol (“fat” toxicity) theory of cardiovascular disease is at best incomplete, or more likely simply wrong, more scientific interest and resources have been reevaluating the pathophysiological effects of the Maillard (sugar toxicity) reaction. There is also overwhelming scientific evidence rapidly accumulating that in vivo pathological Maillard reactions accumulate both from internal dysmetabolism of sugar and ingesting advanced glycation end products (AGEs) created by excessive heating of food that are toxic in living tissue In addition to the Maillard reaction, the Amadori rearrangement and Schiff base reactions are also part of the complex biochemistry of sugar toxicity.

One major problem faced by clinicians interested in prevention of and early intervention in the manifestations of abnormal tissue glycation is that there is no single test in “evidenced-based” medicine that can “diagnose” metabolic syndrome. Abnormal glycation diseases can be diagnosed using several clinical and laboratory findings, but not by a single laboratory test. A simple blood test called the hemoglobin A1c or glycohemoglobin (HbA1c) test easily and cheaply provides critical clinical information about the ongoing degree of glycation in the body due to inadequate glucose disposal from blood. The “trick” in using this scientific (evidence-based) test as a “new and emerging risk factor for clinical vascular disease” (as it is now being discovered and described in scientific medical journals) is to understand that the laboratory statistical “norms” are not related to individual optimal values. A value for HbA1c above 4.6 should be considered “abnormal” (meaning evidence of accelerated cellular membrane glycation). In most commercial laboratories diabetes is said to be present, by definition, if the value is 6.4 or higher. This is why most diabetics demonstrate severe vascular disease before scientific medicine diagnoses it. Membrane receptor resistance to the hormone Insulin is not acknowledged until late in the process (advanced tissue glycation) or a “high” HbA1c. Objectively testing using PORH for disturbed microcirculatory function and/or pulse volume recordings (PVR; microvascular disease of the vasa vasorum in macrovessels) can also demonstrate the effects of abnormal vascular glycation (loss of microvascular compliance.

As an aside regarding laboratory measurement of insulin or any other “hormone level,” the clinical reality is that no hormone actually works in the blood (or urine, or saliva); hormones do their metabolic work by activating a hormone receptor (i.e., the “key in lock” analogy) located on a specific cell or nuclear membrane. The hormone receptor is usually located on the cell membrane (i.e., insulin receptor) or the nuclear membrane (i.e., thyroid receptor). Thus, in many individuals (“not statistical”) cases the “blood level” (and urine or saliva, for that matter) of a given hormone (i.e., thyroid, insulin, vitamin D, etc.) may be “statistically” normal or even “optimal” and yet the clinical symptoms of the particular hormone “deficiency” may clearly be present. This is a very common clinical phenomenon seen with insulin resistance syndrome. Blood simply acts as a transport medium to get the hormone from where it was made to where it will have its metabolic effect. As stated earlier, the insulin receptor is located on the cell membrane – and some cells have many more insulin receptors than others. This is the functional basis of IPT (insulin potentiation therapy) cancer chemotherapy: to use insulin to activate the insulin receptors on cancer cells. Cancer cells revert to a more primitive cellular metabolism referred to as anaerobic (“without oxygen”) glycolysis (fermentation). Thus, cancer cells have significantly more insulin receptors on their cell surface than noncancer cells. Giving Insulin to cause a drop in blood sugar, and at the low point of the blood sugar very small (15% to 20% of standard, recommended) doses of chemotherapy drugs to allow the cancer cell to preferentially take in the drugs as they are in their insulin activated sugar “feeding frenzy,” creates a physiologic “Trojan horse” approach that significantly minimizes side effects and yet maximizes therapeutic benefit of chemotherapy to actually target the problem cancer cells, thus sparing drug toxicity to normal cells and tissue. The clinical results in cancer can be quite amazing when appropriately employing IPT.

Returning to the discussion of microvascular glycation related stiffening or lack of pulsatile ability of vascular tissue, pulsation of the microcirculation turns out to be critical for all major organ health. This is the simple reason that scientific medicine has not yet developed an effective implantable artificial heart. Pulsatile flow is something that is required in normal physiology. Any experimental animal that is put on a heart bypass pump that uses non-pulsatile or laminar flow dies within days of progressive, multiple organ (kidney, heart, brain) failure due to progressive microvascular dysfunction – called scientifically increased peripheral vascular resistance. Our best technological engineers can make pumps smaller than a dime that can operate in climates as alien as the Martian surface, but they have not yet mastered the essential, life-sustaining properties of biologically imperative pulsatile flow. The main physiologic cause of pathological microvascular stiffness is glucotoxicity. Clinical counterparts of this “laboratory” phenomenon of increased organ microcirculatory stiffness are commonly encountered, but just as commonly, the causal underlying mechanism (microvascular stiffening due to glycocalyx/endothelial caramelization) is usually not clinically recognized and thus crude, noncurative symptomatic drug or surgical therapy follows. One commonly missed clinical example of this phenomenon may be heart and peripheral arterial vascular stunning and hibernation. Integrative medicine employing chelation therapy has demonstrated clinical effectiveness in reversing stunning and hibernation, in both entire organs (heart microcirculation) and extremities (leg macrocirculation/vasa vasorum). The actual cause of the phenomenon of stunning and hibernation is “unknown” in evidence-based medicine, but glucotoxicity of the microcirculation in the corresponding capillary bed of the heart muscle or the vasa vasorum (or microcirculation) of the macrovessel arterial wall may be involved.

Another clinical “symptom pattern” manifestation of insulin resistance is polycystic ovary syndrome (PCOS). The currently accepted treatment for PCOS is either using synthetic hormone birth control pharmaceuticals (BCP) or the off-label use of the antidiabetic drug metformin. Interestingly, birth control helps PCOS symptomatically, although it is known to cause weight gain, high blood sugar and, more importantly, increase vascular resistance. It appears that while improving the clinical picture BCPs seem to be making the manifestations of endothelial dysfunction worse. The clinical and laboratory effects of Metformin in PCOS were found to be clinically superior to BCPs. It is also possible that other chronic degenerative diseases may be related to underlying microvascular pathology. For example, osteoarthritis, which is really osteoarthrosis, since no true inflammation (“-itis”) is involved, may be related to reduced microcirculation to the associated joint and cartilage tissue. This could explain why the simple clinical methods of heat, massage and/or injecting ozone (Prolozone therapy) into the affected joint and/or periarticular tissue results in reduction and elimination of pain by increasing microcirculation. Chronic unexplained pelvic pain in both sexes may be related to regional microvascular disease. Localized “trigger points” in muscles may also be due to localized microcirculatory disturbance. Much like the phenomenon of localized compromise of microcirculation in the brain (dementia), heart (diastolic heart failure), or kidney (hypertension) lead to different clinical patterns resulting from the same underlying pathology, perhaps other degenerative conditions will be found to be related to reduced microcirculation to an affected organ or anatomic/physiologic area.

Cholesterol

Since the 1960s, cholesterol has been the focus of medical science regarding the major cause of cardiovascular disease. This model was based on research demonstrating a statistical connection between elevated blood levels of cholesterol and finding cholesterol products within arterial plaque. While not all patients with sudden vascular accidents (heart attack, stroke) demonstrated elevated levels of blood cholesterol, the cholesterol model was very successful in treating disease in males from the 1960s through the 1990s. The advent of “statin drugs” (HMG-CoA reductase inhibitors) seemed to advance the cholesterol theory of vascular disease to the zenith of scientific medicine. Their effects were initially thought to be produced by lowering cholesterol blood levels; further research began to show additional benefits of statin agents, including marked reduction of inflammation among others. This led to the “routine” use of these pharmaceutical agents in all vascular disease patients, whether or not the blood cholesterol level was elevated. Despite this change in approach, the decline in the level of vascular disease in males leveled off. Also, during the 1990s despite dramatic declines in vascular disease in males, heart disease among women correspondingly and dramatically increased despite application of the same medical model used in males (bypass surgery, arterial angioplasty and drug cocktails including statins, beta-blockers, ACE inhibitors, ARBs, and aspirin). This “cookbook approach” was far less effective in women, which led some to begin questioning the accuracy of the cholesterol model of cardiovascular disease.

Several facts seem to bolster this questioning. A major one is the fact that many women having heart attacks had “normal” cholesterol blood levels. In addition, many men and women with high cholesterol never develop cardiovascular disease. Finally, the erratic way that plaque appeared throughout the circulation, with one artery being affected and others seemingly escaping disease (“skip lesions”), strongly suggested that other mechanisms were at play. In the scientistic and media frenzy about cholesterol and vascular disease for the past 60 years, many overlooked the fact that cholesterol was simply a theory – not a proven fact. Other theories for the cause of vascular disease, including systemic vascular inflammation, occult infection, various immune mechanisms, sugar toxicity, trans fats, and free radical damage, were proposed, but never received the attention (research money, scientific inquiry, etc.) that cholesterol commanded. With the increasing incidence of disease occurring in women beginning in the 1990s, these other theories began to take on more significance. The toxicity of sugar and its recognized relationship to obesity, diabetes, and micro- and macrovascular disease began to challenge and displace the cholesterol theory as a fundamental cause of these common vascular disease syndromes. For example, microcirculatory (capillary) disease involving the microcirculation of the arterial wall (vasa vasorum) can easily explain the phenomenon of atherosclerotic “skip lesions.” In addition, the presence of tissue scarring (wall motion abnormality in the heart and leukoaraiosis of the brain) in the absence of corresponding hemodynamically significant macrovascular disease can be explained by local microvascular compromise.

At the present time old recommendations of reducing dietary cholesterol are being challenged as not useful. In addition, the actual “beneficial effects” of statin drugs is being seriously questioned. It appears that statistical manipulation and corporate profiteering may have played a large hand in the now questioned widespread use of statin drugs. Interestingly, diabetes, blood sugar elevation, liver and muscle damage, and heart failure are known, common, and usually limiting side effects of statin drug use. Recent research suggests that statin drugs may actually cause atherosclerosis (“arteriosclerosis?”) and congestive heart failure. While this research needs to be confirmed, it should prompt serious clinical questioning of the widespread use of statin drugs, especially for “primary prevention,” where no vascular event has actually occurred and the drug is being prescribed based exclusively on an elevated level of blood cholesterol in the absence of evidence of significant arterial plaque formation or symptoms. As with the phenomenon of elevated triglycerides, now recognized as a marker of insulin resistance/metabolic syndrome, it appears that cholesterol may be an effect of the underlying glucose/insulin receptor metabolic dysfunction rather than a cause.

Vitamin D

Like all other steroid hormones, vitamin D (a hormone, not a vitamin) is made in the body from cholesterol. This unfortunate confusion of terms is the root the new scientific interest in the “sunlight vitamin.” The basic concept of “hormone” is a substance made in one area of the body that enters the circulation to have its physiologic effect on another organ or area of the body. Vitamin D3 is naturally made from cholesterol in several steps, beginning with a specific frequency of ultraviolet light from the sun interacting with cholesterol in the skin to form a precursor of provitamin D. This provitamin travels through the blood to the liver and is converted into a second provitamin (25-hydroxy vitamin D3), which is again secreted into blood to be transported to the kidney and converted into the final, metabolically active vitamin D3 (1,25-dihydroxyvitamin D3 or cholecalciferol). In addition to bone and intestine where calcium is absorbed, cellular vitamin D receptors are found in all neural, endocrine, and immune cells, indicating the extreme metabolic and regulatory importance of vitamin D in the optimal function of the neuroendocrine-immune system. Due to the past focus on vitamin D for calcium/bone metabolism, medical science is only recently discovering the widespread effects and physiological disturbances related to low or suboptimal vitamin D levels. Inflammation, and symptoms related to chronic inflammation have been shown to be related to vitamin D function. Low vitamin D has also been implicated in some cases of depression, as well as cardiovascular diseases, cardiometabolic disorders, cancer , and more directly related to glucotoxicity and Microvascular disease, cognitive decline, diabetes/metabolic syndrome, and hypertension.

There are two active forms of vitamin D commonly used medically. Vitamin D3 is the bioidentical form of the hormone normally found in humans and other mammals. Given current research results, this is the only form humans should be taking. Vitamin D2, which is made from ergosterol converted into ergocalciferol, is found in third-kingdom organisms (yeast, algae) and should not be taken by humans. While both forms have similar effects on calcium metabolism and bone (D2 is said to be about 40% the “potency” of D3), they have different effects on the immune system. Vitamin D3 activates human immune precursor cells, while vitamin D2 caused these cells to enter a state of hydrogen peroxide induced cellular apoptosis (programmed cell death). In addition, low vitamin D levels have been shown to affect delayed hypersensitivity response to skin test antigens. Unfortunately, vitamin D2 is what the food industry has been “enriching” in processed foods for decades. Most processed and/or “vitamin D enriched” foods should be avoided or minimized. A vitamin D supplement will be labeled as to which type (D2 or D3) is in the product, but if just the term vitamin D is on the label, it is vitamin D2 (FDA “standard of identity”). The large body of research demonstrating vitamin D’s effects on inflammation , blood sugar and blood pressure, and other manifestations of metabolic syndrome/sugar toxicity suggest that one hormonal effect of vitamin D3 may involve enhancing the activity of the cellular insulin receptor. Similar to the concept of insulin receptor resistivity (insulin resistance/metabolic syndrome), vitamin D also works through activating the vitamin D receptor inside each cell. By optimizing vitamin D3 blood levels to between 50 and 60 ng/dl many clinical manifestations of insulin resistance commonly improve, indicating that vitamin D deficiency/insufficiency is part of the widespread epidemic of metabolic syndrome, insulin resistance, diabetes, hypertension, leukoaraiosis, and obesity.

An interesting concept in the new thinking regarding “low” vitamin D blood levels and chronic disease involves the Marshall protocol. In some chronic inflammatory diseases, such as post (chronic) Lyme syndrome, fibromyalgia, sarcoidosis, multiple chemical sensitivity syndrome, lupus, and rheumatoid arthritis, the blood levels of the provitamin D (25-hydroxy-vitamin D) is found to be low while the level of the active 1,25-dihydroxyvitamin D will be found to be high-normal to high. Marshall believes that this situation is caused by L-form bacteria and other intracellular infectious agents disrupting the function of the intracellular vitamin D receptor which disrupts the innate immune system’s ability to find and destroy the infected cells. Patients with chronic inflammatory diseases in addition to metabolic syndrome/insulin resistance problems may benefit from having both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D blood levels measured together to evaluate for a metabolic disturbance of Vitamin D metabolism. If this situation is found the Marshall protocol advises that vitamin D not be given or supplemented and the vitamin D receptor be “reactivated” using the drug olmesartan (Benicar) and others specific protocol recommendations. Since this concept and its clinical application is “anecdotal,” the patient and treating physician should evaluate the information in light of the underlying clinical reality of each individual patient. Simultaneously evaluating the level of both 25-hydroxy- and 1,25-dihydroxyvitamin D may serve as a biochemical marker that may distinguish pathologic inflammation or chronic infection from chronic degenerative structural/functional microvascular disease.

Diagnosis

The formal definition of metabolic syndrome requires a patient to manifest a minimum of four of the following criteria: centralized obesity, hypertension, elevated fasting blood sugar, fasting insulin level, and/or blood triglyceride level, low HDL cholesterol level and/or high LDL cholesterol. The clinical difficulty with diagnosing metabolic syndrome/sugar toxicity by definition is that by the time one fulfills the “formal” criteria for academic recognition of sugar toxicity, the process has progressed to a point of clinical disease. The “real world” diagnosis of preclinical sugar toxicity depends on a number of factors. There is no single physical finding or test that can accurately “diagnose” sugar toxicity. Pathologic Maillard/sugar toxicity reactions, like free radical chemistry, are fundamental processes in human physiology. There is a biological, biochemical, and pathophysiologic continuum from birth through aging, disease, and ultimately death. Once this fact is acknowledged, it logically follows that the earlier the clinical detection of abnormal protein glycation/sugar toxicity, the more effective intervention will be. Relying on laboratory “normal reference values” and late symptomatic pathological pattern recognition after disease is present is inferior medical practice. The earlier dysmetabolic and microvascular manifestations can be detected, the sooner remedial diet/lifestyle measures can be recommended and/or treatment applied.

Clinical evaluation for sugar toxicity can be divided into physical, metabolic, functional, and/or structural findings. If diagnosis is suspected in a “preclinical” state, before functional or structural metabolic and/or microvascular problems (i.e., hypertension, cognitive decline, cardiovascular syndromes) are clinically apparent, then evidence of physical and/or biochemical deviations from optimal, rather than statistically derived “normal” values are currently the most accurate diagnostic tools available. Physically, the presence of any degree of centralized body fat accumulation should be considered a harbinger of insulin resistance/metabolic syndrome. In addition, the skin may demonstrate “liver” or AGE spots on the hands or elsewhere. The presence of microvascular disease can be determined by several methods. Clinical examination of the feet may reveal delayed capillary filling; a simple bedside test that can detect poor capillary filling reserve is to blanch the capillary bed with manual pressure and observing the time taken for color to return to the blanched capillary bed. Normally this should be 3 seconds or less. Ambient temperature should be comfortable, the extremity being examined should be equilibrated to room temperature, and pharmaceutical agents that may interfere with the test should be accounted for (beta blockers, etc.).

Metabolic markers include elevated fasting blood sugar (>85 mg/dl), elevated fasting insulin levels, and/or a blood hemoglobin A1c of 4.6 or higher. It should be kept in mind that insulin receptor resistivity can be manifested by how long the sugar remains in the blood (impaired glucose disposal), as well as how high the blood sugar goes. HbA1c is a more accurate measure of protein glycation than fasting blood sugar levels. An elevated CRP consistent with low-grade cardiovascular inflammation could also point to sugar toxicity. Elevated homocysteine levels have been related to cerebral microvascular disease. Insulin receptor dysfunction from chronic toxic metal burdening is also a factor. Vitamin insufficiency and/or deficiency and hormone deficiency/insufficiency also contribute to the clinical presentation of metabolic syndrome. Other diagnostic tests can provide objective evidence of sugar toxicity, depending on the “syndrome” or pattern of organ dysfunction present. Cognitive decline is one clinical “syndrome” related to brain sugar toxicity. Memory testing can be done using a number of bedside evaluation methods. In addition, brain CT or MRI scans can confirm the presence of leukoaraiosis. Supraoptic Doppler studies with and without compression can confirm reduced cerebral microvascular flow reserve. Loss of compliance (reduced or absent dicrotic wave) on peripheral PVR reflects intramural microvascular involvement (vasa vasorum) of the macrovessels. Hypertension is diagnosed by clinically measuring blood pressure. Exercise induced diastolic hypertension is a more accurate measure and appears earlier clinically than random, casual measurements. Congestive heart failure can be detected using echocardiography, chest X-ray, and clinical evaluation (gallop rhythm, lung rales, peripheral edema and/or cervical venous engorgement). “Diastolic dysfunction” on echocardiogram is evidence of loss of ventricular compliance due to myocardial microvascular disease. Abnormal myocardial wall motion on nuclear scanning, echo or dye ventriculogram studies in the absence of hemodynamically significant (>80% lumenal obstruction) macrovascular coronary artery disease also denotes loss of arterial compliance secondary to microvascular disease.

Autonomic dysfunction (palpitations, anxiety, insomnia, vertigo/balance problems, temperature regulation, etc.) is a common feature of sugar toxicity/insulin resistance. Similar dysautonomic symptoms may be caused by chronic toxic metal burdens, such as mercury, negatively affecting the sympathetic/parasympathetic homeostasis. The symptoms caused by and diagnosis of dysautonomia can be difficult to detect or manage. In addition to the presence of subjective physical symptoms (anxiety, palpitations, insomnia, etc.), one simple, useful method of diagnosing autonomic dysfunction is microvascular PORH testing. In addition to demonstrating the presence microvascular disease, PORH is an accurate measure of neurological autonomic tone. Other useful methods for detecting autonomic imbalance are Autonomic Response Testing (ART) and electrodermal screening (i.e., electroacupuncture according to Voll [EAV]). Considering that microcirculation serves all organs and tissues of the body, perhaps other chronic degenerative diseases may be due to microvascular disease involving a specific body region, tissue or organ. For example, osteoarthritis/osteoarthrosis (degenerative joint disease) does not involve any inflammation, simply degeneration. Microvascular ischemia developing slowly over years may present as “angina” of the joints, with ischemic/hypoxic degenerative physical changes occurring as the final result. Soft tissue trigger points may be localized areas of microcirculatory dysfunction. Chronic pelvic pain and congestion, such as nonspecific prostate symptoms, may be regional or localized pelvic ischemia/dysregulation due to microvascular disease. Without objective clinical testing availability involving these areas, there is no way to detect the presence of microvascular dysfunction. Thus, early detection of unphysiologic (pathological) glycation using the preclinical tools previously presented and having a high index of suspicion are most important for the patient and clinician.

Treatment

Treatment of sugar toxicity is directed at the metabolic, functional, or structural problems of the individual patient. The current situation regarding commercialized diet and food choices is difficult if not impossible to correct due to the large amount of added sugar (sucrose, glucose, and fructose) in the US food supply. Also, the inability or lack of interest of government regulators to address the epidemic magnifies the problem. The use of sewer sludge as fertilizer on most farmland has led to widespread low-level toxic metal burdening. Toxic metals inhibit insulin receptors and competitively inhibit intestinal absorption of essential nutritional minerals. Essential minerals are required for optimum functional of insulin (zinc) and/or insulin receptors (chromium, vanadium). Avoiding gluten is warranted in some patients. A high-protein, low-carbohydrate-sugar diet, moderate in plant based fats, should be recommended. The goal is to reduce body fat, blood sugar and blood insulin levels. Fructose in all forms (e.g., agave), especially high-fructose corn syrup, should be avoided completely. There are several specific diet programs (Paleo, HCG, Sugar Busters, Atkins, etc.) that can serve as a guide to individualizing the diet. Regular exercise (lowers blood sugar and insulin levels), along with other lifestyle changes, such as smoking cessation, moderate use of alcohol, and so on, should be advised. The effect of diet and lifestyle treatments can be monitored using weight, blood pressure, and laboratory parameters such as daily blood sugar and/or HbA1c level every 3 to 4 months and CPR if elevated. It should be kept in mind that the HbA1c test involves both the rise in blood sugar as well and the impaired sugar disposal from blood to cellular metabolism due to insulin receptor resistivity. In addition, it has been shown that AGEs can come from food preparation, depending on how high (>120º) and how long the food is heated. These AGEs add to glycation toxicity.

Currently, there are few drugs and no medical devices or surgical approaches available to treat metabolic syndrome, with the exception of surgical gastric bypass or lap banding for morbid obesity. After such surgery, the metabolic effects of insulin resistance: excess central fat, high blood pressure, diabetes, and cardiovascular disease improve and may be eliminated in many individuals. Interestingly, those with a thin or normal body habitus manifesting other signs of metabolic syndrome/sugar toxicity store their “excessive body fat” in their organs, such as fatty liver (nonalcoholic hepatic steatosis). Fructose (high-fructose corn syrup) has been specifically implicated as a cause of fatty liver. The clinical management of sugar toxicity/insulin resistance consists of diet, lifestyle changes, exercise, supplements, and/or medication. Supplements that benefit insulin resistance include chromium, vanadium, magnesium, cinnamon, alpha-lipoic acid, benfotiamine, pyridoxamine, pyridoxal phosphate, methyl-B12 and methylfolate, and others. There is also growing clinical evidence that suboptimal (not to be confused with “subnormal”) levels of vitamin D have been linked to the clinical state of insulin receptor resistance. Providing vitamin D3 in amounts that result in blood level of 25-hydroxy (OH) vitamin D above 50 ug/dl (“optimal” 50 to 60 ug/dl) is helpful clinically. Only vitamin D3 should be employed. Vitamin D2, which has been reported to cause and aggravate atherosclerosis, should be avoided. Chronic inflammatory conditions as described in the Marshall plan should be considered if 25-hydroxyvitamin D levels are low or suboptimal and 1,25-dihydroxyvitamin D levels are normal or high. Certain herbal supplements can also be helpful, such as Gymnema sylvestre, bitter melon, prickly pear cactus, ginseng, and fenugreek. Carnosine, a dipeptide of the amino acids beta-alanine and histidine, is an antioxidant and antiglycating agent (reverses the sugar toxic Maillard reactions).

Medication treatment of insulin resistance involves using pharmaceutical agents that improve insulin receptor function, reduce liver sugar production, lower blood sugar, increase sugar excretion, and/or inhibit intestinal absorption of sugar. The most effective pharmaceutical agent in common use today is the biguanidine drug metformin. Metformin activates insulin receptors and suppresses endogenous liver production of sugar (gluconeogenesis) to reduce HbA1c levels. Side effects and costs of metformin are minimal. The main side effect is gastrointestinal intolerance (nausea, diarrhea, bloating) and is usually self limited. Current cost for metformin can be as little as $4/month. If side effects persist more than 2 to 3 weeks, a trial of the brand-name product Glucophage should be tried and will commonly eliminate side effects. Another concern with metformin is the rare condition of lactic acidosis, but this effect was found in the now off-market biguanidine phenformin and may not actually occur with metformin. In addition, if metformin is used for a prolonged period, it could possibly lead to vitamin B12 deficiency. Other pharmaceutical agents that may be helpful in treating insulin resistance include thiazolidinedione drug (Actos), SGLT2 inhibitors (Invokana, etc.), alpha-glucosidase inhibitors (Precose), GLP-1 agonists (Byetta, Victoza ), and DPP-4 inhibitors (Onglyza, Januvia,^, etc.). These additional agents are all still under patent, meaning “expensive.” The side effects can be annoying to life threatening: Actos may cause bladder cancer, SGLT2 may cause urinary symptoms and genital yeast infections, Precose can cause excessive gas. Insulin receptor sensitizing therapy has been shown to improve atherothrombotic and inflammatory parameters in insulin resistance/sugar toxicity. Pharmaceutical agents such as insulin in all its forms and/or sulfonylurea drugs (glyburide, glymepiride) should be avoided if possible, since they do not help the resistant receptors and, although they may lower blood sugar and hemoglobin A1c, they do so at the expense of increasing body fat (increased inflammation and insulin resistance).

An older pharmaceutical agent with a unique mode of action is aminoguanidine (Pimagedine). Aminoguanidine acts by reversing the Maillard reaction (glycation) by removing the sugar molecule from the protein moiety. Originally investigated in the 1980s for its ability to reverse diabetic kidney damage, financial, political and regulatory issues resulted in all research on this agent’s being terminated in 1999.The drug is still available from England as an “anti-aging” supplement. Another interesting pharmaceutical is rimonabant. Rimonabant represents a new class of neuropharmaceuticals known as endocannabinoid 1 (CB1) receptor blockers. Developed in Europe as an antiobesity drug, it was withdrawn from the market due to neurotoxicity. Rimonabant was useful for weight loss; smoking cessation; reducing addictive behavior to cocaine, alcohol, cannabis, opiate agents, and sugar; improving short-term memory, and increasing sperm motility. Based on their profile of activity, CB1 receptors appear to be quite widespread in their biologic activity. More importantly, reducing sugar craving is additional evidence that sugar is addictive. Interestingly, the use of cannabis (marijuana) has been shown to reduce blood glucose, insulin levels, and the risk for developing diabetes. Ironically, an herbal medicinal substance in use dating back to the third millennium BC that is banned by modern legislatures, courts, and government bureaucrats turns out to be an effective treatment for the toxicity of a substance (sugar) that is completely unregulated by government and may represent the root cause of almost all chronic degenerative vascular diseases of the modern era.

Beyond the general treatment of metabolic/insulin resistance/sugar toxicity syndrome, specific symptom complexes related to insulin resistance/metabolic syndrome (cardiovascular disease , neurologic disease, etc.) may require specific additional treatment protocols. Hypertension can be controlled using antihypertensive medications. Diabetes is treated with diet, exercise and antidiabetic medication(s). Coronary artery disease (CAD) is treated with diet, exercise, and various “standard” medications (beta blockers, nitroglycerine, ACE inhibitors, ARB blockers, statins, etc., bypass surgery and/or angioplasty-stenting). Diastolic heart failure is treated with various drug cocktails and/or pacemaker-defibrillator devices, enhanced external counterpulsation (EECP), and/or possible heart transplantation in the extreme. All “evidence-based” scientific medical approaches, with the possible exception of EECP, are directed at symptom control and not the actual cause. They do not increase life span and are used to improve quality of life. Additional “clinical anecdotal” approaches that are directed toward the underlying sugar toxicity and microvascular disease have been shown or reported to be beneficial. EDTA chelation therapy has recently been shown to be effective for coronary disease. Interestingly, the reduction in events in patients treated with EDTA chelation was twice as effective in diabetics then in nondiabetics. The “cholesterol experts” are trying to figure out why diabetes responded so well compared to non-diabetics. They are focused on “cholesterol” rather than sugar toxicity. The mechanism(s) of action of EDTA chelation lowers blood sugar (temporarily), synergizes insulin activity, removes toxic metals, and improves microvascular function. The mystery is not in how it worked in the trial, but why the findings have yet to be evaluated with consideration that the cholesterol theory of CVD may be incomplete at best and wrong at worst.

There are several neurological syndromes related to microvascular disease caused by sugar toxicity Included are asymptomatic leukoaraiosis, symptomatic leukoaraiosis, stroke/lacunar infarct syndromes, cognitive decline, Alzheimer’s syndrome, lateral temporal sclerosis and/or autonomic dysfunction. Leukoaraiosis in the absence of “symptoms” is generally considered to be related to aging and of no consequence, but recent science now contradicts this “accepted” thinking. The different symptomatic clinical syndromes are generally treated with “standardized” drug therapy, depending on specific clinical pattern (aspirin, antiplatelet agents, antiseizure drugs, anticoagulants, memory enhancing drugs, sedative-hypnotics, SSRI drugs, etc.). All drugs only treat symptoms and not the cause of the problem. The underlying “cause” in these clinical syndromes is microvascular disease from sugar toxicity. Symptomatic treatment may be necessary, but treating the underlying causative microvascular disease is more logical, clinically astute and critical. Biological Maillard reactions (sugar toxicity) are fundamentally progressive, degenerative, chronic inflammatory, aging/disease processes that glycate, caramelize, and chronically immune activates (“inflame”) specific tissues, organs, and organ systems. The pharmacologic drugs currently used to treat symptoms of Alzheimer’s disease and other labeled “idiopathic” forms of cognitive decline consist of two classes: cholinesterase inhibitors and NMDA receptor blockers. Cholinesterase inhibitors are basically insecticides. Their short-term effectiveness is marginal and only lasts for months on average. Side effects and cost are limiting factors for their use. Additional conventional methods that are helpful include exercise, melatonin, growth hormone, and testosterone. There is mounting evidence that low-level environmental toxic metal accumulation (aluminum, mercury, lead, cadmium, etc.) contribute to cognitive decline/memory loss. This problem can only be treated medically with the process of chelation therapy. Certain vitamins, other nutrients, and herbs have also shown effectiveness anecdotally.

A common problem with understanding the academic, scientific classification of memory loss/cognitive dysfunction syndromes is language. True Alzheimer’s “disease” (cognitive decline and autopsy evidence of amyloid/tau protein with neurofibrillary tangles) as originally described and defined by Alois Alzheimer always occurred, by definition, before 55 years of age. Because of this relatively young age it was also sometimes also referred to as presenile dementia or dementia praecox (psychiatric label). If the patient was 56 years old or older, the problem was called “senile” dementia or chronic organic brain syndrome. The two conditions and terms are now commonly mixed and referred to as Alzheimer’s-like senile dementia (ALSD) or Alzheimer’s syndrome. In addition, there are other “syndromic” variations of memory loss problems (Pick’s disease, Parkinson’s disease, age-related cognitive decline, Huntington’s disease, and others).To add to this taxonomic confusion, microvascular ischemic cognitive dysfunction, the underlying cause of most “Alzheimer’s-like senile dementia (ALSD, Alzheimer’s “syndrome,” leukoaraiosis, or neurological microvascular sugar toxicity) is much more common than true Alzheimer’s “disease” (genetics, abnormal amyloid or tau proteins, and anatomic neurofibrillary tangles). There are many theories about how Alzheimer’s disease develops. Alzheimer’s syndrome and other forms of leukoaraiosis are caused or aggravated by microvascular sugar toxicity. The similarities and overlap between the two conditions (Alzheimer’s disease vs. Alzheimer’s syndrome/vascular dementia) are clinically difficult to discern. Despite the clinical and scientific name differences, they are all conventionally treated with the same pharmaceutical drugs (cholinesterase inhibitors and/or NMDA blockers), either on or off label.

Additional “nonstandard” treatments for cognitive decline related to brain microvascular disease are intravenous EDTA (ethylenediaminetetraacetic acid) chelation therapy, intravenous orthomolecular therapy (glutathione/Myers cocktail), and EECP. Although considered “off-label” (i.e., not FDA approved for this clinical use), there is mounting evidence for effectiveness in reversing cognitive dysfunction. In addition, ongoing research has demonstrated that modifying standard EDTA chelation (a modification called metabolic or metachelation) to reverse microvascular glycation can lead to further clinical improvement in memory loss/cognitive decline. Capillary microvessels are essentially naked, functional endothelium without the additional connective and muscular tissue found in macrovessels. Microvascular capillary endothelial networks perfuse through all tissues and organs, providing the biophysical, biomechanical, and biochemical matrix for normal physiologic function. When capillary microvessels maximally dilate during cardiac systole (“contraction”), they are 10 microns in diameter. During cardiac relaxation (diastole), they collapse to 5 microns. A red blood cell is 8 microns in diameter. Red blood cells must pass through these pulsating capillary networks in single file. Caramelized/glycated capillaries (endothelium) and/or red blood cells (HbA1c) gradually become rigid (loss of compliance/abnormal PORH/PVR), leading to small areas of ischemia (lack of oxygen) or cellular/tissue damage (i.e., heart “infarct,” brain lacunar “stroke,” kidney “nephrosclerosis,” muscle “trigger point,” joint “degenerative arthrosis,” etc.). Standard EDTA chelation therapy acts biochemically to provide therapeutic effects involving free radical toxicity (toxic metals), blood viscosity (anticoagulant), metabolism (lowers blood sugar), tissue decalcification, and other probable unspecified mechanisms. Metachelation incorporates additional intravenous nutrients, minerals and supplements to reverse protein glycation. Orthomolecular therapy acts biochemically to support cell and mitochondrial metabolism. EECP therapy works by biomechanically disrupting (“fracturing”) the sugar stiffened endothelial glycocalyx via increasing diastolic blood pressure (“diastolic augmentation”) and biophysically reentraining physiologic cardiac pulsation in the endothelial microvascular matrix.

In an interesting study, diabetic patients with cognitive decline due to microvascular ischemic brain atrophy treated in a clinical trial with “intensive” glucose control failed to show improved cognitive function. However, patients in the intensive treatment group had significantly greater brain volume at 40 months of treatment. Brain atrophy is common as we age and considered to be “normal aging” in conventional medicine, but it really is not “normal” in healthy aged. The cause is the gradual (years to decades) development of global microvascular ischemic atrophy of the brain. The study demonstrated that while late application of intensive sugar control for a defined period of time did not benefit functional decline, it had a positive and dramatically beneficial effect structurally. Function may be preserved if the process is treated much earlier. By slowing glycation, the preservation of brain volume strongly suggests improved microcirculation function (fluid balance, oxygenation, nutrients, waste removal, end circulation pulsatile waves). This strongly suggests that the earlier clinical evidence of sugar toxicity is detected, the more likely the process can be treated and potentially reversed.

Autonomic dysfunction diagnosed by clinical symptoms (palpitations, anxiety, insomnia, dizziness, etc.) or testing (abnormal PORH, EAV testing, etc.) can be treated and improved or eliminated by improving the underlying metabolic syndrome and/or removing toxic minerals with chelation therapy. In addition, following homeopathic-isopathic concepts, dysautonomia is commonly associated with the homeopathic-isopathic nosodes Coxsackie-/enterovirus. Interestingly, scientific evidence has been documented that enteroviruses, such as Coxsackie and other neurotropic enteroviruses (EV 68-71), cause dysautonomic syndromes by attacking the brainstem and spinal cord. Interestingly, Coxsackievirus has also been implicated as a cause of type 1 diabetes. Additional therapy directed at viral issues include intravenous ozone therapy (major autohemotherapy), intravenous hydrogen peroxide therapy, ultraviolet blood irradiation (UVBI) intestinal antibiofilm therapy, and Coxsackie isopathic nosode therapy.

Conclusion

Free radical chemistry is both necessary for life, but also toxic to life. Sugar interactions with biological molecules are likewise essential for life (glycosylation) but also toxic to life (glycation). The important difference between the two processes is that physiologic glycosylation is regulated and controlled by enzymes while pathological glycation is not. Glycation is hazardous in its deactivation and caramelization of structural and functional proteins. With the clinical realization that sugar-driven microvascular disease is the fundamental pathophysiologic and pathological process underlying most chronic degenerative syndromes and diseases, sugar excess has become the main dietary element that should be identified and avoided before and after symptomatic disease appears. Perhaps modern society should revisit the ancient Greek Delphic oracular admonition of “Nothing in excess (Meden agan).” When one considers the extreme amounts of sucrose, glucose, and fructose now found in the American diet and the underlying pathology caused by such dietary madness, the clinical implications for treatment and, more importantly, prevention become staggering. Treatment to reverse such microvascular and protein glycotoxic pathology is time consuming, expensive and could become almost unnecessary if the process is recognized early and effective preventive measures are adopted by government, politicians, and medical science. Unfortunately, the politics, economics, and rampant scientism currently shaping scientific nutritional and medical thought seem incapable of addressing this problem. One bright glimmer on the horizon, however, is the new science of the “microbiome.” This new science is beginning to relate the microbes that live in and on the human body to overall health and disease patterns, including glycotoxicity syndromes. Perhaps one day treating chronic glycotoxic degenerative diseases may be as simple as fecal transplant or providing an encapsulated freeze-dried sample of healthy fecal microorganisms from those who are to those unfortunate enough to be plagued by these chronic diseases. Until that time, however, practicing physicians will have to make do with the current state of praxis in dealing with sugar toxicity.

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The entire text and notes of “Sugar Toxicity: A Silent Epidemic” are available on TownsendLetter.com.

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