To understand this new thinking it would be helpful to start at the beginning. There are actually two "functional" circulatory or vascular systems found in the human body: the Macro-circulation and the Micro-circulation. The Macro-circulation consists of the larger "conduit" arteries in the body that conduct blood to and from 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"). The acute treatment of these large conduit "macro" vessels is commonly the focus of the news media, internet web sites and television shows. These treatments are routinely used and "sold" by scientific (more properly called statistical) "evidenced-based" medical practitioners. These are the arteries said to be chronically "plugged up" (arterial plaque build up) from the common "statistical" risk factors promoted by "evidence-based" scientific medicine: cholesterol, "bad" genes, high blood pressure, smoking, etc. Please note that no one that speaks from scientific authority 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 plaque to form.

Plaque occurs in localized, "specific" sites withing Macro-Vessels, but, oddly enough, the statistical risk factors, which occur throughout the entire vascular system, theoretically should affect all arteries in the same way. Yet we commonly see plaque blocking up 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... but isn't just as much cholesterol going down 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 life style changes (weight reduction, exercise, stress control, etc.), and/or prescribing pharamceutical drugs (statin drugs, ACE inhibitors, ARB blockers, ß-blockers, aspirin, Plavix®, etc.), angioplasty and/or surgery. The plan in mild to moderate plaque build up is to reduce or lower weight, blood pressure, inflammation, heart rate and to increase blood thinning... all things that have been "statistically" ("evidence-based") demonstrated to reduce the risk and severity of Macro-Vascular 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 build up over time. Advanced or high grade plaque build up (80-90-100%) is mechanically (surgical, angioplasty) repaired as it is simply defective plumbing, but this mechanical therapy does NOT correct the actual cause! That's about it, "scientifically speaking," for the Macro-Circulation treatment from a scientific, "evidence-based" prospective.

The Micro-circulation is turning out to be radically "different." The Micro-Circulation is also referred to in "evidenced-based" 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, nutrients and removes Carbon Dioxide and other metabolic waste from the vital organs (i.e heart, brain, kidney, liver, etc.). Incredibly, it now appears (from a "evidence-based" scientific medicine perspective) that Micro-Circulatory disease is primarily related to the biological toxicity of Sugar... not fat as in Macro-Circulatory theory. Yes, the "joke" of Mother Nature on modern medical science is that it turns out that substances that are absolutely "essential" to Life (Oxygen, Sugar) also turn out to be extremely Toxic to life. Mother 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 Gluco-Toxicity. By way of simple analogy, Oxygen Toxicity can be thought of in simple terms similar to "rusting" of molecules and the tissues and organs that these molecules make up (Free-Radical pathology). In the same vein, Sugar Toxicity is being discovered to act by causing "glycation" or "caramelization" of essential structural and functional proteins. 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 stiffening or "mummifying" the affected vital organ (i.e. heart, brain, etc.). When this process involves living tissue it occurs with subtle, but devastating physiological consequences over time. The "non-enzymatic" (meaning in the absence of the enzyme Insulin) attaching of a sugar to a protein destroys (Glycates or Caramelizes) the protein forever. Protein Glycation is currently considered by evidence-based scientific medicine as being non-reversible. This "evidence-based" assumption may actually no longer be scientifically correct.^77,78

The most widely scientifically recognized "evidence-based" clinical condition involving abnormal tissue Glycation leading to clinical Micro-Circulatory 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 Micro-vascular disease in the remaining "viable" tissue. Diabetes is a condition that exists in the annals of "evidence-based" scientific medicine by definition. 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 the "average" population (either fasting, 2 hours after eating or by glucose-tolerance testing). The definition includes establishing the "normal" and "abnormal" blood sugar levels during fasting, after eating and/or during a laboratory glucose tolerance testing. The definition of Diabetes is focused on how high the blood sugar goes. It turns out that glycation from gluco-toxicity also occurs from glucose (Sugar) being in prolonged contact with tissue. Thus, the newly described "metabolic syndrome" (also called dys-metabolic syndrome, syndrome X or insulin resistance), which also exists by definition, involves the inability of potentially toxic sugar to exit or, in more technically correct "evidence-based" scientific terminology, be "disposed of" from the blood to the cell as quickly as possible. Thus, Diabetes, by definition, is about how high blood sugar goes and Metabolic Syndrome, by definition, is about how long sugar remains in the blood.

The actual clinical end-effect of Micro-Circulatory protein glycation is a stiffening of the capillaries throughout the affected organ... actually a mummification of the organ involved. This process involves both abnormal biochemistry (protein glycation) and structural circulatory regulation changes (stiffening of Micro-Vascular resistance). The gradual glycation of protein molecules lining the small capillary Micro-Circulation stiffens those Micro vessels so they cannot pulsate with the heart beat. In addition, glycation of the proteins in the red blood cell stiffens their external membranes making it more difficult for the stiffened cells to pass through the also stiffened capillary beds one at a time. The resultant structural problem is the inability of the Micro-Circulation to pulsate open with the kinetic (pumping) force of the heart beat, coupled with the red blood cells inability to bend, twist and deform to slip through theses stiffened capillaries one at a time. This situation results in small "strokes" around the affected Micro-Circulatory vessel directly involving the affected organ or tissue. Over time (probably years to decades) the collective effects of this process appears clinically. Interestingly, the clinical syndrome that appears depends on which organ(s) are affected. So Micro-Circulatory disease mimics Macro-Circulatory disease in that it "skips" around, affecting different areas of the body. Thus, if Micro-Circulatory glycation occurs in the heart there will be a development NOT of clinical "heart attack" (myocardial infarction), but of Congestive Heart Failure (CHF). This process does NOT involve the active process of the heart contracting, but its inability to relax effectively after contraction due to Mico-Vascular stiffening of the involved heart muscle. Thus, the pump fails to fill effectively and clinical congestive heart failure (fluid back up into the lungs, legs, etc.) develops. CHF is the now th most common and least treatable form or heart disease affecting the American population. Similarly, if capillary glycation involves primarily the kidney high blood pressure will develop. Interestingly, both high blood pressure and Sugar toxicity ("metabolic syndrome") are now "epidemic" among Americans, old and young!

The underlying metabolic basis of gluco-toxicity is the inability of the enzyme Insulin to activate Insulin receptors on all cell surfaces ("membranes") that allow the sugar to move quickly from the blood into the tissue 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 potentially toxic sugar can be transported 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 Micro-Vessels and cellular Red corpuscles "stiffen" and lose their ability to pulsate with the heart; 2) the un-disposed of sugar is immediately shunted into fat production, and more specifically centralized body fat. Thus, one of the clinical markers used to define metabolic syndrome is centralized body fat (a large waist line). 3) an additional pathological events related to poor glucose disposal include excess sorbitol production leading to nerve damage (diabetic neuropathy) and cataracts. Other "defining components" of metabolic syndrome that have been "suggested" or adopted are high blood pressure, high cholesterol, high triglycerides, high fasting Insulin levels or 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 a 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 diagnosis of metabolic syndrome they are already manifesting significant and late stage clinical evidence of severe tissue glycation (i.e. high blood pressure, obesity, heart disease, etc.). So much for academic exercise of diagnosing disease by definition.

One major problem faced by clinicians interested in prevention and early intervention is that there is no single test in "evidenced-based" medicine that can "diagnose" metabolic syndrome. Abnormal glycation diseases are diagnosed using several clinical and laboratory findings, NOT by a single laboratory test. However, a simple blood of Hbg A1C test called the Hemoglobin A1C or Glyco-hemoglobin (Hbg A1C) 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 "evidence-based academic medical journals) is to understand that the laboratory statistical "norms" are not related to the individual optimal values. A value for Hbg A1C above 4.6 should be considered "abnormal" (meaning evidence of abnormal cellular membrane glycation).⁸¹ In most commercial laboratories Diabetes is said to be present, by definition, if the value is 6.0 or higher. This is "why" most diabetics demonstrate severe vascular disease before anyone in 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" Hbg A1C. In addition, objectively testing for disturbed Micro-Circulatory function can also demonstrate the effects of abnormal vascular glycation (loss of Micro-Vascular compliance, scientifically speaking).

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 somewhere. In some cases the receptor is located on the cell membrane (i.e. Insulin receptor) or the nuclear membrane (i.e. Thyroid receptor). Thus, in many individual ("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 clinically. This is a very common clinical phenomenon seen with Insulin resistance syndrome. Blood simply acts as a transport medium to get from where the hormone was made to where it will have its actual metabolic effect. As stated earlier, the Insulin receptor it 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 (which have reverted to a more primitive cellular metabolism referred to as anerobic or "without Oxygen" glycolysis, thus having significantly more Insulin receptors on the cell surface than non-cancer cells) and at the low point of the blood sugar very small doses of chemotherapy drugs are given to allow the cancer cell to preferentially take in the drugs as they are in their Sugar "feeding frenzy." A physiolgic "Trojan Horse" approach that significantly minimizes side-effects and yet maximizes therapeutic benefit to the actuallly target the problem cells, thus sparing toxicity to normal cells and tissue. The clinical results can be quite amazing when appropriately employing IPT therapy.

Returning to the discussion of Micro-Vascular glycation related stiffening or lack of pulsatile ability of vascular tissue, if abnormal Micro-Circulatory disease develops in the brain loss of memory and/or cognitive dysfunction and AD/SDAT gradually develops.⁶⁶ Pulsation of the Micro-Circulation turns out to be critical for all major organ health. This is the simple reason that "scientific medicine" cannot develop an effective 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 Micro-Vascular stiffening... 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. It appears from recent scientific evidence that the main "cause" of pathological Micro-Vascular stiffness is gluco-toxicity.^82,83 Clinical counterparts of this "laboratory" phenomenon of increased organ Micro-Circulatory stiffness are commonly encountered, but just as commonly, the causal underlying mechanism (Micro-Vascular stiffening due to protein glycation) is commonly NOT clinically recognized and thus crude, non-curative symptomatic drug or surgical therapy follows. Commonly missed clinical examples of this phenomenon are heart and peripheral arterial vascular stunning and hibernation.^84,85 Integrative Medicine employing Chelation Therapy has demonstrated clinical effectiveness in reversing stunning and hibernation, in both entire organs (heart Micro-Circulation) and extremities (Leg Macro-Circulation).^84,85 The actual cause of the phenomenon of stunning and hibernation is "unknown" in evidence-based medicine, but Gluco-Toxicity of the Micro-Circulation in the corresponding capillary bed (heart = organ; muscle = capillary Micro-Circulation) or Vasa Vasorum (or Micro-Circulation) of the Macro-Vessel arterial wall.

Interestingly, in addition to the toxic Micro-Circulatory effects of glucose and subsequent protein glycation now being described in AD/SDAT⁶⁶, scientific evidence also shows that the abnormal accumulation of a protein (Beta or ß-amyloid), thought to be "specific" for AD/SDAT, actually causes reduced circulation (vaso-constriction) in the brain and ß-amyloid protein also reduces endothelium-dependent brain vaso-dilation.^30,38-40 As if to add insult to injury, any temporary lack of oxygen in the brain can also lead to increased production of ß-amyloid protein.^30,38-40 Thus, it is scientifically becoming increasingly apparent that Micro-Circulatory 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 condition affecting the individual. In addition to and as further proof of this situation, the microscopic changes in brain tissue that are thought to be "specific" for AD/SDAT syndrome have clearly been described in patients with heart vascular disease and no evidence of dementia.⁴⁰ The increase in body fat that is part of "metabolic syndrome" also contributes to the "bad" situation. It turns out that body fat is actually a functioning endocrine organ. Body fat secretes certain pro-inflammatory Hormones (Tumor Necrosis Factor alpha [TNF-a] and Inter-Leukin-6 [IL-6], etc.). Thus, increased body fat leads to increased inflammation!! (see statistical risk factors for Macro-Circulation diseases). Thus, many previously recognized "independent risk factors" are now being connected through the understanding of the biologically toxic properties of Sugar secondary to malfunction of cellular Insulin receptors.

Treatment of the clinical state of Insulin Resistance (metabolic syndrome, gluco-toxicity) is, at best, in its infancy. Currently, there are few drugs and no devices or surgical approaches available, with the possible exception of gastric bypass or banding for the morbidly obese. In these later individuals the metabolic effects of Insulin resistance and excess fat (high blood pressure, diabetes, symptomatic cardio-vascular disease) seemingly disappear as the excessive body fat is eliminated. For those who are NOT morbidly obese the basic treatment consists of Diet, Exercise and possible medication or supplements. A high protein low carbohydrate-sugar diet (to reduce body fat and blood Insulin levels), regular exercise (to lower blood Insulin levels) along with the use of an Insulin Receptor sensitizing agent (Metformin, Dioxinal®, etc.), or possibly a new class of pharmaceutical agents that work by blocking endo-cannaboid-1 receptors in the brain⁸⁶ is currently the recommended "evidence-based" scientific medical approach. In addition to diet, exercise and drugs, there is mounting evidence that low level environmental toxic metal accumulation (Mercury, Lead, Cadmium, etc.) may be contributing to increasing Insulin Receptor resistance among the general population. This porblem can only be treated medically with the process of Chelation Therapy. There is also growing clinical evidence that sub-optimal (Not to be confused with "sub-normal") levels of Vitamin D have been linked to the clinical state of Insulin Receptor resistance and providing Vitamin D3 in amounts that result in blood levels of 25- Hydroxy (OH) Vitamin D above 50 ug/dl ("optimal" levels are being argued among the "experts" to now constitute levels between 50 and 70 ug/dl) may be helpful clinically. Finally, there is no "evidence-based" treatment now available for the resulting Micro-Vascular disease from Gluco-Toxicity, but the use of External Counter Pulsation Therapy (ECP) and Chelation Therapy clinically improves Micro-Vascular disease in the extremities, heart and brain.