Hairs to Health, Inc. wanted the ME/CFS diagnosed people that submitted hair charts to see the following information. All the charts reviewed indicte a very low level of hair manganese with a very low ability for gluconeogenesis (Ca/Mg ratio). Considering that Yale and Harvard University used hair manganese readings to determine body manganese status, (as previously posted) these hair tests would appear to indicate manganese deficiency. In addition, the liver biopsies preformed on dogs with hair tests indicating low hair manganese, all showed deficient liver stores of manganese. Since manganese is vital for the Krebs energy cycle, this may be one piece in the puzzle of low energy production (see below).
Handbook of Behavior, Food and Nutrition, Volume 1
By Victor R. Preedy, Ronald Ross Watson, Colin R. Martin
Springer, June 29, 2011
As a critical component of dozens of proteins and enzymes, manganese is present in all mammalian tissues and is active in maintaining normal immune function, regulation of blood sugar, and cellular energy, reproduction, digestion, bone growth, defense against free radicals and blood clotting in concert with vitamin K (Aschner et al 2005).
Key brain functions of Manganese:
Cofactor essential for production of ATP via gluconeogenesis
Antioxidant functions through the action of Mn-SOD
Regulates brain ammonia levels as a component of glutamine synthetase
Manganese Metalloenzyme Function Consequence of Loss
Glutamine synthetase Regulation of ammonia levels Severe brain modification
Phosphoenolpyruvate carboxykinase (PEPCK)*
Manganese-SOD Antioxidant defense Oxidative damage
http://en.wikipedia.org/wiki/Phosphoenolpyruvate_carboxykinase
Phosphoenolpyruvate carboxykinase (PEPCK)*
As PEPCK acts at the junction between glycolysis and the Krebs energy cycle, it causes decarboxylation of a C4 molecule, creating a C3 molecule. As the first committed step in gluconeogenesis, PEPCK decarboxylates, and phosphorylates oxaloacetate (OAA) for its conversion to PEP, when GTP is present. As a phosphate is transferred, the reaction results in a GDP molecule.[11]
Humans
PEPCK is enhanced, both in terms of its production and activation, by many factors. Transcription of the PEPCK gene is stimulated by glucagon, glucocorticoids, retinoic acid, and adenosine 3,5-monophosphate (cAMP), while it is inhibited by insulin.[15] Of these factors, insulin, a hormone that is deficient in the case of diabetes, is considered dominant, as it inhibits the transcription of many of the stimulatory elements.[15] PEPCK activity is also inhibited by hydrazine sulfate, and the inhibition therefore decreases the rate of gluconeogenesis.[16]
In prolonged acidosis, PEPCK is upregulated in renal proximal tubule brush border cells, in order to secrete more NH3 and thus to produce more HCO3-.[17]
The GTP-specific activity of PEPCK is highest when Manganese (Mn2)+ and Magnesium (Mg2+) are available.[7] In addition, hyper-reactive cysteine (C307) is involved in the binding of Manganese (Mn2)+ to the active site.[11]
Whereas most reactions of gluconeogenesis can use the glycolysis enzymes in the opposite direction, the pyruvate kinase enzyme is irreversible. The enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase provide an alternate path to effectively reverse the actions of pyruvate kinase.
Function in Gluconeogenesis
It has been shown that PEPCK catalyzes the rate-controlling step of gluconeogenesis, the process whereby glucose is synthesized. The enzyme has therefore been thought to be essential in glucose homeostasis, as evidenced by laboratory mice that contracted diabetes mellitus type 2 as a result of the over expression of PEPCK.[8]
A recent study suggests that the role that PEPCK plays in gluconeogenesis may be mediated by the citric acid cycle, the activity of which was found to be directly related to PEPCK abundance.[9]
Animals
In animals, this is a rate-controlling step of gluconeogenesis, the process by which cells synthesize glucose from metabolic precursors. The blood glucose level is maintained within well-defined limits in part due to precise regulation of PEPCK gene expression. To emphasize the importance of PEPCK in glucose homeostasis, over expression of this enzyme in mice results in symptoms of type II diabetes mellitus, by far the most common form of diabetes in humans. Due to the importance of blood glucose homeostasis, a number of hormones regulate a set of genes (including PEPCK) in the liver that modulate the rate of glucose synthesis.
PEPCK is controlled by two different hormonal mechanisms. PEPCK activity is increased upon the secretion of both cortisol from the adrenal cortex and glucagon from the alpha cells of the pancreas. Glucagon indirectly elevates the expression of PEPCK by increasing the levels of cAMP (via activation of adenylyl cyclase) in the liver which consequently phosphorylates the S133 on a beta sheet in the CREB protein. CREB then binds upstream of the PEPCK gene at CRE (cAMP response element) and induces PEPCK transcription. Cortisol on the other hand, when released by the adrenal cortex, passes through the lipid membrane of liver cells (due to its hydrophobic nature it can pass directly through cell membranes) and then binds to a Glucocorticoid Receptor (GR). This receptor dimerizes and the cortisol/GR complex passes into the nucleus where it then binds to the Glucocorticoid Response Element (GRE) region in a similar manner to CREB and produces similar results (synthesis of more PEPCK).
Together, Cortisol and Glucagon can have huge synergistic results. Activating the PEPCK gene to levels that neither cortisol or glucagon could reach on their own. It is most abundant in the liver, kidney, and adipose tissue.[2]
Researchers at Case Western Reserve University have discovered that over expression of cytosolic PEPCK in skeletal muscle of mice causes them to be more active, more aggressive, and have longer lives than normal mice; see metabolic supermice.
Metabolic supermice are mice which as a result of genetic modification have up to 100 times the concentration of the PEPCK-C enzyme in their muscles, compared to ordinary mice.
They were created by a team of American scientists led by Richard Hanson, professor of biochemistry at Case Western Reserve University at Cleveland, Ohio,[1][2] to gain a greater understanding of the PEPCK-C enzyme, which is present mainly in the liver and kidneys.
Professor Hanson noted that the supermice "are metabolically similar to Lance Armstrong biking up the Pyrenees. They utilize mainly fatty acids for energy and produce very little lactic acid. They are not eating or drinking and yet they can run for four or five hours. They are 10 times more active than ordinary mice in their home cage. They also live longer up to three years of age and are reproductively active for almost three years. In short, they are remarkable animals." However, "they eat twice as much as control mice, but they are half the weight, and are very aggressive. Why this is the case, we are not really sure."
