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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.1 Cardiac performance has been shown to be impaired by switching from a low-carbohydrate diet including fiber to a high-carbohydrate diet.2 Switching from saturated fatty acids to carbohydrates with high glycemic index values shows a statistically significant increase in the risk of myocardial infarction.3 Other studies have shown that 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.4 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.5 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.6-26 In addition, a connection between Alzheimer's disease and fructose has been suggested, but remains the subject of debate.27,28 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.29
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.30-32 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–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 and 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.33 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.34,35 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.36
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.37 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.38 These changes can be distinguished from large artery (macrocirculation) stiffness and obstruction by the use of pulse volume recording (PVR).
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. Themacrocirculation 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 lifestyle 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." Microcirculationis 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.38-48 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.48-57
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 howhigh 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).58-64
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