Page 1, 2,
in Individuals With MSX – Better Described as Diabetes Type
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
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
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
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
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
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.
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
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
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).
Klevay has shown a positive relationship between a relative copper deficiency
and heart disease. A deficiency of copper relative to zinc (elevated Zn/Cu
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.
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
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.
Page 1, 2,