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From the Townsend Letter
May 2007


Metabolic Syndrome X – As Defined Through Hair Tissue Mineral Analysis (HTMA) Patterns
by Dr. David L. Watts

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Diabetes in Individuals With MSX – Better Described as Diabetes Type 3
Since diabetes occurs in both metabolic types, the mechanisms and progression of diabetes must be different as well. Insulin resistance and insulin antagonism or deficiency occur along a very fine metabolic line and therefore use of the term diabetes type 2 may not be appropriate. I suggest that a better term would be a new classification of diabetes to include diabetes type 3, based on insulin antagonism or insulin deficiency rather than
insulin resistance or reduced insulin sensitivity. Mechanisms for this hypothesis are discussed below, based upon HTMA analysis.

Insulin Antagonism Due To Endocrine Abnormalities in Diabetes Type 3
Obesity is known to be related to endocrine abnormalities involving increased adrenal cortical activity (Cushing's syndrome), insulinoma, polycystic ovarian syndrome (PCOS), hypothyroidism, testosterone, and growth hormone deficiency. Treatment of the underlying endocrine abnormalities can lead to a reversal of obesity (Kokkoris P et al. 2003). By the same token, since diabetes is associated with co-existing endocrine abnormalities involving the hypothalamus, pituitary, adrenal, thyroid, parathyroid, gonads, and adipose endocrine function (Alrefaih et al. 2002), it is reasonable to assume that treatment of the endocrine abnormalities can lead to control and even amelioration of diabetes.

Diabetes type 3 is associated with insulin antagonism rather than insulin resistance. Insulin antagonism can be caused by any one or combination of endocrine abnormalities listed above. Individuals with Cushing's syndrome, Grave's disease, and acromegaly usually have impaired glucose tolerance and high levels of circulating insulin. Hyperthyroidism can antagonize the effect of insulin in hepatic and extrahepatic tissues. Excessive adrenal glucocorticoids also have an insulin antagonism effect (Iitaka M et al. 2000) and respond to a reduction in adrenal activity (Ogura M et al. 2003).

Excessive Free Fatty Acids and Insulin Antagonism
Increased adrenal and thyroid activity contribute to an increase in lipolysis, thus also contributing to increased circulating levels of free fatty acids (FFA). An increase in GC provides a ready supply of cortisol to the adrenal medullas and enhances the rate of norepinephrine to epinephrine conversion (Hormones [2nd ed] 1997). Hormones from the adrenal medulla and cortex activate fat cell lipase, which in turn causes hydrolysis of tryglycerides, releasing large quantities of FFA and glycerol into circulation (Guyton and Hall, Physiology 1996) and enhancing gluconeogenesis.

The thyroid has a synergistic relationship to the adrenal hormones. Typically, when the adrenals are dominant, the thyroid is also dominant. An increase in thyroid secretion also enhances the secretion of other endocrine glands. In its relationship with the adrenals, thyroid hormone increases the rate of GC inactivation by the liver. This causes a feedback mechanism of increasing adrenocorticotropic hormone production by the anterior pituitary that increases the rate of glucocorticoid production by the adrenals (Hormones [2nd ed.] 1997). This vicious circle results in their combined effects of increasing central adipose deposition, antagonizing insulin, and further contributing to lipolysis and excessive FFA in circulation. Normal metabolic levels of FFA do not adversely affect insulin, but high levels may antagonize insulin, and contribute to lipotoxicity (Bergman 2000, Feldstein et al. 2004, Reaven 1988, Koutsari 2006). Excessive FFA produces ectopic redistribution of fat into the liver, musculature, and even the pancreas. This process is associated with carbohydrate sparing effect, increased glucose production, and decreased glucose uptake through changes in the activity and ratios between leptin, resistin, tumor necrosis factor-alpha, and adiponectin (Harris et al. 2004).

Inflammation and Insulin Antagonism
Inflammation has also been associated with diabetes and cardiovascular disease risk. Inflammation apparently produces a defect in insulin-stimulated muscle glucose transport involving activation of the serine kinase cascade. This can lead to an increase in intramuscular cellular lipid content similar to defects in mitochondrial fatty acid oxidation
(Perseghin et al. 2003). Elevated sympathetic activity leads to increased cortisol, which increases levels of interleukin-6 and C-reactive protein that is an indicator of inflammation (Hjemdahl 2002).

Elevated Homocysteine and Insulin Antagonism
Hyperhomocysteinemia is a contributor to increased vascular risks. Animal models have shown that elevated homocysteine levels were associated with a significant increase in triglycerides and blood pressure (Oron-Herman et al. 2003). The sympathetic dominant mineral pattern, particularly the elevated Na and K and low Na/K ratio, indicates an increased need for Co and B12. B12 requirements may also be increased when the K/Co ratio is elevated above 450.

Neurohumoral Response to Stress and Insulin Antagonism
The release of corticotrophin, epinephrine, norepinephrine, and glucocorticoids are increased during periods of stress and are mediated by sympathetic stimulation (Guyton 1996). Excessive stress – or, more importantly, when adaptation to stress is lacking the ensuing endocrine and metabolic cascade discussed previously – will become prolonged and contribute to type 3 diabetes because of exacerbation of insulin antagonism (Hjemdahl 2002, Bjorntorp 1999). Stress or maladaptation has a major influence on disease progression, particularly in cardiovascular disease and diabetes. Perceived stressors initiate the hypothalamicpituitary- adrenocortical axis, thereby enhancing glucocorticoid release. Faulty glucocorticoid receptors (GR) lead not only to insulin antagonism but also to altered Na-K ATPase activity (Hjemdahl, 2002, Bjorntorp 1999, Kurup 2003). Another neuronal pathway exists between the liver and adipose tissues via the afferent vagus nerve from the liver to the hypothalamus and, eventually, the sympathetic neurological effects upon adipose tissues. Normally, as excess energy builds up within the liver, information is sent to the hypothalamus via the afferent vagus nerve, which then activates the sympathetic response to increase energy expenditure and lipolysis (Uno, K et al. 2006). When this homeostatic control mechanism is disrupted, another vicious cycle develops. Increased lipolysis results in an increase in FFAs, further contributing to liver lipotoxicity, which activates the afferent vagus-hypothalamic-sympathetic response increasing lipolysis and further release of excessive FFAs.

Nutritional Imbalances and MSX
The Fast Metabolic type has nutritional imbalances that can contribute further to and/or exacerbate MSX, diabetes, and the associated cardiovascular predisposition, progression, and complications. HTMA studies can readily reveal these imbalances and provide a specific targeted approach to therapy.

Calcium and Vitamin D Deficit
An increase in the need for calcium and calcium cofactors (vitamin D) are usually present in the Fast Metabolic Type. This is related to the neuroendocrine factors such as increased adrenal and thyroid activity as well as a reduction in PTH expression. As mentioned previously, PTHrP enhances beta cell function in the pancreas and inhibits beta cell death (Sawads et al. 2001, Cerbian et al. 2002). This neuroendocrine pattern leads to diminished absorption and an increase in the loss of calcium from the body. This would result in a decrease in normal insulin release from the pancreas, since insulin requires adequate amounts of extra cellular calcium concentration for its release (Nordin 1988).

Since insulin release is calcium-dependent, low calcium/phosphorus calcium/sodium, and calcium/potassium ratios would indicate reduced insulin release and /or insulin antagonism and is associated with a reduction in PTH. This neuroendocrine pattern also results in the retention of the minerals phosphorus, sodium, and potassium, which are also antagonistic to calcium and calcium cofactors. Increased retention of these elements would further reduce insulin release.

A lack of magnesium or an increase in the requirement for magnesium exaggerates the stress response. As stated by Seelig, "When magnesium deficiency exists, stress paradoxically increases risk of cardiovascular damage including hypertension, cerebrovascular, and coronary constriction and occlusion, arrythmias, and sudden cardiac death" (Seelig 1994). The adrenergic stimulation of lipolysis is intensified with magnesium deficiency, and magnesium deficiency enhances adrenergic stimulation, increasing the release of catecholamines by the adrenals. This can be brought on by physical or psychological stress. Low intracellular magnesium is implicated as a significant component of MSX (Seelig 2002) and diabetes type 2 (Huerta 2005, Hasebe 2005, Mitka 2004, Lal et al. 2003, Rodriguez-Moran et al. 2003). Experimental magnesium deficiency has been shown to be related to an inflammatory syndrome and excessive free radical production (Mazure et al. 2006).

Increased sodium retention antagonizes magnesium retention and, of course, a reduction in magnesium enhances sodium retention. This interrelationship leads to an elevation in blood pressure. This condition of excess sodium retention and increased magnesium loss are both associated with the inflammatory response.

Magnesium deficiency has also been associated with metabolic disturbances due to a mitochondrial defect. A mutation in a mitochondrial gene has been found to be associated with hypertension and hypercholesterolemia, in conjunction with lowered levels of magnesium (Marx J 2004).

It is interesting to note that Watson suggested that individuals who he classified as having a "Fast Oxidation" rate were experiencing a rapid glycolytic activity within the cell (Watson 1972). The first step of glucose metabolism in the glycolysis cycle involves the enzyme hexokinase, which is magnesium-dependent. Watson's description of the "Fast Oxidizer" tends to resemble our description of Fast Metabolic Types recognized through HTMA mineral patterns. Even though magnesium is deficient in the Fast Metabolic HTMA pattern, a rapid rate of cellular glycolytic activity may still exist due to increased levels of glucose-6-phosphatate (G-6-P), an enzyme that can inhibit hexokinase and can be hydrolyzed directly by glucose-6-phosphatase (G-6-Pase). G-6-Pase is present in the liver, kidneys ,and intestine and yields free glucose. Liver G-6-Pase activity requires and is enhanced by the presence of lipids (Bondy et al. 1980). Increased activity of this enzyme may account for the elevated glucose in patients with MSX.

Copper is essential in collagen synthesis and antioxidant enzyme systems and, therefore, vascular integrity as well. A deficiency of copper is known to result in glucose intolerance and decreased insulin response. Copper deficiency is also associated with hypercholesterolemia, abnormal HDL/LDL ratios, and enhanced glycation. Copper deficiency is known to be related to diabetes and cardiomyopathy (Saari et al.1999, Prohaska 1990, Medeiros et al.1993, Schuschke 1997).

Copper / Iron Ratio
Since copper is necessary for the binding of iron to hemoglobin, a deficiency of copper can result in an increase in hepatic and pancreatic iron accumulation. Excess iron relative to copper enhances lipid peroxide formation, adversely affecting insulin release and liver function (Bureau et al. 1998, Watts 1988,1989).

Zinc/Copper Ratio
Klevay has shown a positive relationship between a relative copper deficiency and heart disease. A deficiency of copper relative to zinc (elevated Zn/Cu ratio >14) is associated with a decrease in HDL and an increase in LDL (Klevay 1975).

An elevated hair zinc/copper ratio has been found in individuals who were hospitalized for myocardial infarction (MI). The similar hair mineral imbalance was also found in the descendants of MI patients. This suggests that an elevated Zn/Cu ratio may be predictive in younger individuals to the susceptibility of MI (Taneja et al. 2000).

Statistical studies conducted at Trace Elements revealed that the HTMA Zn/Cu ratio was elevated in over 75% of a patient population who had suffered a stroke.

Nutritional Indications and Contraindications in MSX
Diet as well as dietary supplementation can play a significant role in the prevention or progression of syndromes related to MSX. High carbohydrate diets and trans fatty acids, for example, have been shown to adversely affect and even accentuate the metabolic abnormalities of MSX such as weight gain, atherosclerosis, and insulin abnormalities (Reaven 1997, Odegaard et al. 2006, Mozaffarian et al. 2004).

Excess fructose intake has also been related to increase blood pressure in animal studies. Fructose is known to antagonize copper (Fields M et al. 1984, O'Dell 1990) and thus can exacerbate the imbalance between zinc-copper and iron-copper ratios (Watts 1989). These imbalances lead to increased free radical production and tissue damage.

Other factors, such as excess intake of vitamin C, vitamin A, niacin, zinc, molybdenum, and iron also are antagonistic to the mineral copper and can contribute to insulin abnormalities and cardiovascular disease as well as other components of MSX. It can be noted that these factors are unrelated to fat intake (Bogden et al. 2000). Copper is an essential element in reversing the tissue damage caused by free radical damage, particularly those caused by excess of other elements, such as iron.

Vitamin A in small concentrations aids in the stimulation of insulin release from the pancreas, but high concentrations can inhibit insulin release (Mooradian et al. 1987). A recent study found elevated levels of retinol-binding protein 4 (RBP4) in patients with central obesity and in patients with diabetes, compared to individuals who did not exhibit obesity or diabetes. RBP4 is, of course, the principle transport protein for vitamin A or retinol and is secreted by adipocytes (Graham et al. 2006). This would be expected since vitamin A is antagonistic to vitamin D and calcium (Watts 1991, 1990).

Any dietary or other factors that would inhibit calcium could potentially worsen any of the syndromes associated with MSX. The Mediterranean-style diet is known to reduce the prevalence of MSX and associated risk factors. However, an increase in hypertension has been found in individuals who add cereal intake in conjunction with the diet (Meydani 2005). Cereals and grains contain phytates that inhibit calcium absorption and may reduce retention and increase excretion of calcium, as well as other critical elements from the body.

The avoidance of refined carbohydrates, grains, cereals, and fructose is extremely important for reducing the progression of MSX and related syndromes. Adequate protein intake is important for building lean muscle mass and weight loss.

Magnesium has been proven to be important in individuals with MSX as well as in anyone with cardiovascular disease, diabetes, and related disorders. Magnesium, along with calcium and vitamin D, helps prevent progression of MSX complications by aiding in the reduction of the stress reaction as well as helping reduce blood pressure and maintain glucose control. Chromium supplementation is found helpful in all types of diabetes and may play a significant role in preventing progression of cardiovascular disease.

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