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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.205 Insulin receptor dysfunction from chronic toxic metal burdening is also a factor.206-211 Vitamin insufficiency and/or deficiency and hormone deficiency/insufficiency also contribute to the clinical presentation of metabolic syndrome.212-221 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.222-228 Memory testing can be done using a number of bedside evaluation methods.229-235 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.83,84 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.236-238 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.239,240 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.241 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.142
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.15,64 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.194-197 Only vitamin D3 should be employed. Vitamin D2, which has been reported to cause and aggravate atherosclerosis, should be avoided.180,198,199 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.201-204 Certain herbal supplements can also be helpful, such as Gymnema sylvestre, bitter melon, prickly pear cactus, ginseng, and fenugreek.242,243 Carnosine, a dipeptide of the amino acids beta-alanine and histidine, is an antioxidant and antiglycating agent (reverses the sugar toxic Maillard reactions).56,244
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.245-249 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.250 In addition, if metformin is used for a prolonged period, it could possibly lead to vitamin B12 deficiency.251 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.252 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 1999.253The 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.254,255 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.256 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.257-260 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.261
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.262 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.263-265 Interestingly, the reduction in events in patients treated with EDTA chelation was twice as effective in diabetics then in nondiabetics.266 The "cholesterol experts" are trying to figure out why diabetes responded so well compared with nondiabetics.159-162 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.148,149 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.161,162
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