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As Dr. Lee stated, adequate protein digestion is essential for the function of hormones that control calcium metabolism (called parathyroid hormones), so we would expect to find evidence of abnormal calcium metabolism in patients with MS. In the following study the researchers evaluated parathyroid hormone levels in patients with MS and concluded that the "endocrine circuitry" regulating serum calcium may be altered in MS.



J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):152-7. Epub 2007 Jun 19.
A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis.

METHODS: We measured 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), calcium, phosphate, magnesium, chloride, alkaline phosphatase, albumin and thyroid stimulating hormone in serum every 3 months and at the time of relapse over 1 year in 23 patients with MS and in 23 healthy controls. MRI burden of disease and T2 activity were assessed every 6 months.

RESULTS: Vitamin D deficiency (S-25(OH)D < or = 37 nmol/l) was common, affecting half of the patients and controls at some time in the year. Seasonal variation of 25(OH)D was similar in patients and controls, but 25(OH)D serum levels were lower and intact PTH (iPTH) serum levels were higher during MS relapses than in remission. All 21 relapses during the study occurred at serum iPTH levels > 20 ng/l (2.2 pmol/l), whereas 38% of patients in remission had iPTH levels < or = 20 ng/l. Patients with MS had a relative hypocalcaemia and a blunted PTH response in the winter. There was no correlation between serum 25(OH)D and MRI parameters.

CONCLUSIONS: The endocrine circuitry regulating serum calcium may be altered in MS..."





In the following study the researchers found that patients with MS had significantly lower levels of calcium in white matter, but significantly higher levels elsewhere in the central nervous system.

Biological Trace Element Research
March 1993, Volume 36, Issue 3, pp 251-255
Calcium concentration in brains from multiple sclerosis patients.

“The Ca concentration was determined by neutron activation analysis in autopsy samples taken from the 26 subanatomical regions of CNS tissues…In the 26 subanatomical regions of the CNS (whole CNS), the average Ca concentration was significantly higher in MS patients…compared to controls…Although the mean Ca concentration in the 26 CNS regions combined was higher in the four MS patients than in the controls, the content of white matter was lower. Whether or not this significantly lower Ca concentration found in the white matter of MS patients plays an important role in the demyelinating process remains unclear, although that lower concentration seems not be age dependent, but MS specific…”

Vitamin B12 and Myelin

Vitamin B12 is involved in remylination due to its regulation of epidermal growth factor. Research has found that the loss of epidermal growth factor regulation by vitamin B12 (cobalamin) in MS may be one factor impeding CNS remyelination. Here is the study again that I posted earlier.


Brain Res. 2010 May 28;1333:64-71. doi: 10.1016/j.brainres.2010.03.073. Epub 2010 Mar 27.
Loss of epidermal growth factor regulation by cobalamin in multiple sclerosis.
Scalabrino G, Galimberti D, Mutti E, Scalabrini D, Veber D, De Riz M, Bamonti F, Capello E, Mancardi GL, Scarpini E.

“…Our results indicate that: (a) the positive Cbl-mediated regulation of myelino- and oligodendrocyte-trophic EGF is lost in the CSF of RR- or SP-MS patients; (b) the decrease in EGF levels in the CSF may be one factor impeding CNS remyelination in MS…”




Vitamin B12 is also necessary for the formation of myelin.


As the following study published in The Journal of Biological Chemistry confirms, vitamin B12 helps maintain the myelin sheath by playing a crucial role in the metabolism of fatty acids essential for the maintenance of the myelin. Vitamin B12 is a coenzyme that coverts methylmalonyl coenzyme A into succinyl coenzyme A. Failure of this reaction to occur results in elevated levels of methylmalonic acid. Excessive methylmalonic acid will prevent normal fatty acid synthesis, or it will be incorporated into fatty acid itself rather than normal malonic acid. If this abnormal fatty acid subsequently is incorporated into myelin or if the methylation of the myelin sheath phospholipids fails to occur, the resulting myelin will be too fragile, and demyelination will occur.




August 10, 1970 The Journal of Biological Chemistry, 245, 3771-3775.

Effect of methylmalonyl coenzyme A, a metabolite which accumulates in vitamin B12 deficiency, on fatty acid synthesis.

“We have proposed that the accumulation of methylmalonyl-CoA, which occurs when a deficiency of B12 coenzyme exists, may lead to its incorporation into fatty acids in place of malonyl-CoA. This leads to the production of fatty acids, which are not usually produced and which may be physiologically undesirable…It was shown that methylmalonyl-CoA inhibits fatty acid synthesis and is incorporated into fatty acids.”






Researchers in the following study found that in MS patients there was a loss of polyunsaturated fatty acids and replacement by nonessential fatty acids, which lowered the mean chain length and raised mean melting point significantly.


Proc Natl Acad Sci U S A. 1989 June; 86(12): 4720–4724.

Deficiencies of polyunsaturated fatty acids and replacement by nonessential fatty acids in plasma lipids in multiple sclerosis.
R T Holman, S B Johnson, and E Kokmen

“all subsequent omega 6 acids were subnormal…indicating impairment of chain elongation. All omega 3 acids were subnormal. The paucity of polyunsaturated fatty acids was compensated mass-wise by an increase in saturated acids. Disproportionate increases in short-chain, saturated, and monounsaturated acids, decreases in long-chain homologs, and increases of branched and odd-chain acids were observed. Loss of polyunsaturated fatty acids and replacement by nonessential acids lowered mean chain length and raised mean melting point significantly, suggesting that lowered membrane fluidity was only partially compensated by endogenous synthesis of lower-melting, nonessential acids…”





In the next study published in Journal of the Neurological Sciences the researchers stated: "Vitamin B12 deficiency leads to defective formation of the myelin sheath, due to incorporation into neuronal lipids of non-physiologic fatty acids as well as to defective methylation of myelin basic protein, a major component of CNS myelin." In addition, the researchers discussed the neurological manifestations of a vitamin B12 deficiency, which are all consistent with pathological findings and symptoms of MS. These manifestations include demyelination, axonal degeneration and death, spinal cord degeneration, and such common MS symptoms as Lhermitte’s sign, optic neuropathy, paresthesias (abnormal sensations), and white matter lesions.



J Neurol Sci. 2005 Jun 15;233(1-2):93-7.
Vitamin B12, demyelination, remyelination and repair in multiple sclerosis.
Miller A, Korem M, Almog R, Galboiz Y.

“low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders…Vitamin B12 deficiency leads to defective formation of the myelin sheath, due to incorporation into neuronal lipids of non-physiologic fatty acids as well as to defective methylation of myelin basic protein, a major component of CNS myelin…The neurologic manifestations of vitamin B12 deficiency begin pathologically with demyelination, followed by axonal degeneration and eventual irreversible damage due to axonal death. The spinal cord, brain, optic nerves, and peripheral nerves may all be affected by cobalamin deficiency. The spinal cord is usually affected first…The patient first notices general weakness and paresthesias. As the illness progresses the gait becomes unsteady and stiffness and weakness of the limbs develop, as well as ataxic paraplegia. The Lhermitte phenomenon is not an uncommon finding. Mental signs are frequent and range from irritability, apathy, somnolence and emotional instability to marked confusional or depressive states. Visual impairment due to optic neuropathy may occasionally be the earliest or sole manifestation…In a study evaluating the neuro-physiological and magnetic resonance imaging (MRI) changes in patients presenting with vitamin B12 deficiency and neurological syndromes, the evoked potentials and MRI changes were found to be consistent with focal demyelination of white matter in the spinal cord and optic nerve. MRI imaging of the brain and spinal cord demonstrates, in some cases of vitamin B12 deficiency, a typical pattern of white matter degeneration commonly seen in MS, such as extensive areas of T2 high-intensity signal in the periventricular white matter…”

SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD

As the previous study stated, a lack of vitamin B12 can lead to spinal cord degeneration. Spinal cord degeneration, due to a vitamin B12 deficiency, is called subacute combined degeneration of the spinal cord. The following study published in the Journal of General Internal Medicine confirms the association to vitamin B12 deficiency and serious neurologic complications such as optic neuropathy, bilateral cerebral dysfunction, peripheral neuropathy, and subacute combined degeneration of the spinal cord. The study authors stated, “Subacute combined degeneration is a rapidly progressive myelopathy that can be associated with profound neurologic deficits including progressive sensory abnormalities, ascending paresthesias, weakness, ataxia, loss of sphincter control, and gait impairment…”




J Gen Intern Med. 2006 October; 21(10): 1063–1068.
Potential outcome factors in subacute combined degeneration.

Olavo M Vasconcelos, MD,1 Erika H Poehm, MD,1 Robert J McCarter, ScD,2 William W Campbell, MD,1 and Zenaide M N Quezado, MD

“Vitamin B12 deficiency can lead to serious neurologic complications including peripheral neuropathy, bilateral cerebral dysfunction, optic neuropathy, memory loss, personality changes, impaired recall, and subacute combined degeneration of the spinal cord. Subacute combined degeneration is a rapidly progressive myelopathy that can be associated with profound neurologic deficits including progressive sensory abnormalities, ascending paresthesias, weakness, ataxia, loss of sphincter control, and gait impairment…”




The following information on the cause and symptom manifestations of subacute combined degeneration of the spinal cord is from the National Institutes of Health.

Subacute Combined Degeneration

National Institutes of Health, 25 June 2009

Subacute combined degeneration of the spinal cord is a disorder that involves weakness, abnormal sensations, mental problems, and vision difficulties.

Causes: Subacute combined degeneration of the spinal cord is caused by a vitamin B12 deficiency.

Subacute combined degeneration primarily affects the spinal cord, but it can also damage the brain, the nerves of the eye, and the peripheral (body) nerves. At first, the disease damages the covering of the nerves (the myelin sheath). It later affects the entire nerve cell.

Symptoms: These symptoms slowly get worse and are usually felt on both sides of the body. Abnormal sensations (tingling and numbness), weakness of the legs, arms, middle of the body, or other areas.

Other symptoms include:
• Clumsiness, stiff, or awkward movements
• Unsteady gait and loss of balance
• Change in mental state such as memory problems, irritability, apathy, confusion, or dementia
• Decreased vision
• Depression
• Sleepiness
• Speech impairment (possible)





In subacute combined degeneration of the spinal cord, the posterior columns and corticospinal tracts are specifically damaged, along with the early development of coexistent peripheral nerve damage.

The corticospinal tract is a large tract of nerve cells in the brain that carry movement (motor) signals down to the spinal cord. Damage to the corticospinal tract can result in muscle weakness, spasticity and excessively brisk reflexes.

Babinski's reflex or extensor plantar reflex is a test for dysfunction of the corticospinal tract. The test involves stroking the outside sole from heel to toe with a pointed object. The normal response is a bunching downward (flexor) movement of all the toes. In infants under 2 years of age and people with dysfunction in the corticospinal tract, this causes an upward (extensor) movement of the big toe. Babinski's reflex can occur unilaterally (in just one foot) or bilaterally (in both feet). A positive Babinski's reflex is consistent with several neurological conditions, including multiple sclerosis.

A commonly performed test to evaluate the integrity of dorsal columns of the spinal cord is the Romberg test. A positive Romberg sign reflects blockade of deep sensory impulses from lower extremities and severe compromise of heavily myelinated sensory axons along the posterior columns.

The test is named after the 19th century German ear specialist, Moritz Heinrich von Romberg. The test consists of standing with your feet together and your eyes closed. A positive Romberg sign is excessive swaying or even falling over. This simple test offers an important clue to the presence of pathology in the proprioceptive pathway. Proprioception is the sense of one's body in relation to itself and the world. The slowing down of transmission signals that regulate proprioception will often affect an MS patient’s sense of balance and result in a positive Romberg test.




Many symptoms found in MS, such as trigeminal neuralgia, burning mouth syndrome, optic neuritis, nystagmus, Lhermitte’s sign, and paresthesias can all be attributed to subacute combined degeneration of the spinal cord, due to a lack of vitamin B12. For instance, as the following study confirms, a common early symptom of subacute combined degeneration of the spinal cord, and often considered a classic symptom of MS, is Lhermitte’s sign. Lhermitte’s sign is the term used to describe electric shock-like sensations that radiate down the spine when the neck is flexed forward. This indicates nerve damage which is manifested when the neck is flexed and the nerve stretched.



Lhermitte’s sign in subacute combined degeneration of the cord.
Gautier-Smith, P.C. 1973. J Neurol Neurosurg Psychiatry 36:861-863.

“…Lhermitte’s sign is a common early symptom of subacute combined degeneration of the cord…It is concluded that, in these cases, Lhermitte’s sign is due to stretching of demyelinated fibres in the posterior columns in the cervical cord, produced by neck flexion…”

AUTONOMIC NERVOUS SYSTEM DYSFUNCTION


In the following study the researchers found that ninety percent of the MS patients tested had symptoms related to autonomic dysfunction. In addition, the researchers stated that both parasympathetic and sympathetic functions were impaired.


Autonomic dysfunction in multiple sclerosis: correlation with disease-related parameters.
Gunal DI, Afsar N, Tanridag T, Aktan S. 2002. Eur Neurol. 48(1):1-5.

“…Ninety percent of the patients had symptoms related with autonomic dysfunction…Both parasympathetic and sympathetic functions were impaired…”





Researchers in the following study stated that autonomic dysfunction causes significant disability in patients with MS and that autonomic symptoms such as abnormalities of bladder, bowel, and sexual function have been well documented in previous studies.


Autonomic nervous system function in multiple sclerosis.
McDougall AJ, McLeod JG. 2003. J Neurol Sci. 215(1-2):79-85

“Autonomic dysfunction causes significant disability in patients with multiple sclerosis (MS)…Abnormalities of bladder, bowel and sexual function have been well documented in previous studies…Autonomic symptoms were common in MS patients…which were associated with increased MS severity…”




The following information on the autonomic nervous system and dysautonomia (autonomic dysfunction) is from the Merck Manual.

“The autonomic nervous system is the part of the nervous system that supplies the internal organs, including the blood vessels, stomach, intestine, liver, kidneys, bladder, genitals, lungs, pupils, and muscles of the eye, heart, and sweat, salivary, and digestive glands. The autonomic nervous system controls blood pressure, heart and breathing rates, body temperature, digestion, metabolism (thus affecting body weight), the balance of water and electrolytes (such as sodium and calcium), the production of body fluids (saliva, sweat, and tears), urination, defecation, sexual response, and other processes.

A dysfunction in the autonomic nervous system (dysautonomia) can cause dizziness or light-headedness due to excessive decrease in blood pressure when a person stands (orthostatic hypotension). People may sweat less or not at all and thus become intolerant of heat. The eyes and mouth may become dry. After eating, a person with dysautonomia may feel prematurely full or even vomit because the stomach empties very slowly (gastroparesis).

Some people pass urine involuntarily (urinary incontinence), often because the bladder is overactive. Other people have difficulty emptying the bladder urine retention) because the bladder is underactive. Constipation may occur, or control of bowel movements may be lost. The pupils may not dilate and narrow (constrict) as light changes.”






Symptoms commonly found in MS such as constipation, dry eyes and mouth, nausea, bloating, vomiting, difficulty breathing, and intolerance to heat can all be attributed, at least in part, to autonomic dysfunction. Symptoms can be more common in the morning after arising from sleep and are worsened by any condition that enhances peripheral venous pooling, such as heat or fatigue.



POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS)

Postural orthostatic tachycardia syndrome (POTS) is a symptom of autonomic dysfunction. Postural orthostatic tachycardia syndrome is characterized by the body’s inability to make the neces¬sary adjustments to counteract gravity upon standing. Upon standing, blood pools in the abdomen and legs. Normally, the autonomic nervous system will compensate by constricting blood vessels and pushing blood to the brain. When autonomic nervous system dysfunction is occurring these reflexes, termed baroreflexes, do not function adequately. Presenting symptoms include lightheadedness, palpitations, fatigue, blurred vision, dizziness, exercise intolerance, chest discomfort, and cognitive impairment.




In the following study the researchers concluded that POTS is associated with MS.


Postural orthostatic tachycardia syndrome associated with multiple sclerosis.
Adamec I, Lovrić M, et al. 2013. Auton Neurosci. 73(1-2):65-8. doi: 10.1016/j.autneu.2012.11.009. Epub 2012 Dec 14.

“…The results of this study suggest that POTS is associated with MS.”





OVERACTIVE BLADDER

Overactive bladder is also a symptom of autonomic dysfunction. The next study confirms the association between MS and overactive bladder. The study authors stated that hyperactive bladder is one of the most common symptoms of MS.



The overactive bladder in multiple sclerosis.
Fingerman JS, Finkelstein LH. 2000. J Am Osteopath Assoc. 100(3 Suppl):S9-12.


“Multiple sclerosis is a common neurologic disorder that often affects the genitourinary system. One of the most common symptoms of multiple sclerosis is the hyperactive bladder. These patients will have symptoms that may affect their lifestyle, such as urinary incontinence, urgency, and frequency. They may also suffer from debilitating urinary tract symptoms, such as frequent or recurrent urinary tract infections and also on occasion, damage to the upper urinary tract...”




URINARY TRACT INFECTIONS

Autonomic nervous system dysfunction could also cause the nerves of the bladder to not respond normally to pressure as the bladder fills with urine. This would result in urine staying in the bladder and leading to an increased risk of urinary tract infections. Researchers in the following study stated that MS patients with bladder dysfunction are prone to asymptomatic urinary tract infections.



Multiple sclerosis and asymptomatic urinary tract infection.
Edlich RF, Westwater JJ, Lombardi SA, Watson LR, Howards SS. 1990. J Emerg Med. 1990 8(1):25-8.


“Multiple sclerosis patients with bladder dysfunction are prone to have an asymptomatic urinary tract infection. Because bladder function abnormalities occur at some time in 70% to 90% of multiple sclerosis patients, a quantitative estimate of the bacterial concentration in the urine as well as a culture is mandatory…”

I've read that there is not one MS symptom that cannot also be explained by a B12 deficiency!

PN

Hi PointsNorth~

Vitamin B12 is necessary for every cell in the body, so a deficiency will have far reaching effects for sure.

Protease are not only necessary for the proper metabolism of vitamin B12 though, they digest dietary proteins and release essential amino acids, metabolize iron, etc. The autonomic nervous system dysfunction, for instance, is due not only to a lack of vitamin B12, but also a missing essential amino acid. I'll be posting on this tomorrow once everyone has a chance to read the first post on the ANS dysfunction in MS.



Research has found that patients with MS are deficient in nearly all of the essential amino acids. These missing essential amino acids would explain many of the other symptoms and scientific findings in MS.

In the following study the study authors found that patients with MS had diminished levels of the essential amino acids tryptophan, leucine, isoleucine, valine, and phenylalanine. Leucine, isoleucine, and valine are the three branched chain amino acids (BCAAs). The term “branched chain” refers to their molecular structure. The BCAAs are used by the muscles for energy and in the regulation of protein synthesis. The patients also lacked the amino acid tyrosine. Tyrosine is an amino acid the body makes from the essential amino acid phenylalanine.

J Neurol Neurosurg Psychiatry. 1979 July; 42(7): 640–641.
Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases.
F Monaco, S Fumero, A Mondino, and R Mutani

“…Tryptophan and competing neutral amino acid levels were found to be diminished in the plasma of patients with multiple sclerosis and degenerative diseases…Tryptophan, leucine, isoleucine, valine, tyrosine, and phenylalanine were all diminished in the plasma of patients with multiple sclerosis…”




In the next study the researchers discovered that patients with MS had lower levels of the essential amino acids methionine (Met), valine (Val), phenylalanine (Phe), and lysine (Lys).

J Chromatogr. 1988 Dec 28;459:237-44.
Quantitation of free amino acids in biological samples by high-performance liquid chromatography. Application of the method in evaluating amino acid levels in cerebrospinal fluid and plasma of patients with multiple sclerosis.
Qureshi GA, Baig MS.

“lower levels of Met, Val, Phe and Lys in plasma of MS patients.”



These missing essential amino acids would explain many of the other symptoms and scientific findings in MS. For instance, the essential amino acid tryptophan is needed to produce serotonin (tryptophan>serotonin).


In the following study published in the International Journal of Neuroscience the researchers stated that MS patients are serotonergically depleted and that this depletion correlates with the degree of motor disability and a chronic progressive course.



Int J Neurosci. 1998 Jul;95(1-2):133-40.
Serotonergic neuronal atrophy with synaptic inactivation, not axonal degeneration, are the main hallmarks of multiple sclerosis.
Sandyk R.

“…Biochemical studies have shown that MS patients are serotonergically depleted with the extent of cerebral depletion correlating with the degree of motor disability and a chronic progressive course…”



In the next study the researchers discovered cerebrospinal fluid levels of 5-HIAA were significantly lower in MS patients. 5-Hydroxyindoleacetic acid (5-HIAA) is the main metabolite of serotonin in the human body. In analysis of cerebrospinal fluid, 5-HIAA is used to determine serotonin levels in the body.


J Neurol Neurosurg Psychiatry. 1977 August; 40(8): 741–745.
Monoamine metabolites in cerebrospinal fluid in multiple sclerosis.
D Davidson, I A Pullar, C Mawdsley, N Kinloch, and C M Yates

“…In patients suffering from MS the CSF 5-HIAA concentrations were significantly lower than in comparable controls…”




The lack of serotonin would then account for some of the symptoms found in MS.

SYMPTOMS OF LOW SEROTONIN

• Inability to fall and stay asleep
• Excessive worrying
• Cognitive impairment (inability to focus, poor memory, lack of mental clarity)
• Anxiety in typically low stress situations
• Fatigue in spite of adequate rest
• Mood swings
• Irritability
• Moderate to overwhelming sadness


LOW MELATONIN

Tryptophan and serotonin are both needed to produce the hormone melatonin (tryptophan>serotonin>melatonin). Melatonin is an important factor in a good night’s rest. The following study found that MS patients had significantly decreased levels of melatonin (6-SMT).


J Neurol Sci. 2012 Mar 15;314(1-2):37-40. doi: 10.1016/j.jns.2011.11.003. Epub 2011 Dec 1.
Melatonin dysregulation, sleep disturbances and fatigue in multiple sclerosis.
Melamud L, Golan D, Luboshitzky R, Lavi I, Miller A.

“Sleep disruption and fatigue are common in Multiple Sclerosis (MS). Melatonin is one of the major regulators of sleep-wake cycle…MS patients demonstrated significantly decreased levels of 6-SMT… Sleep efficiency was significantly lower in the MS group compared to controls.”



SYMPTOMS OF LOW MELATONIN

• Insomnia
• Difficulty getting to sleep
• Difficulty falling back to sleep when awakened during the night
• Light sleeper/easy waking during the night
• Early morning awakening
• Un-refreshing sleep
• Lack of dreaming

The lack of vitamin B12 and the essential amino acid phenylalanine found in MS patients would explain the dysfunction of the autonomic nervous system.



There are two parts to the autonomic nervous system, which are referred to as branches. The branches of the autonomic nervous system are:

The Sympathetic System: The sympathetic system activates what is often termed the flight-or-fight response.

The Parasympathetic System: The parasympathetic system is responsible for activities that occur when the body is at rest, including salivation, lacrimation (tears), urination, digestion, and defecation.


The action of the two branches of the autonomic nervous system is mediated by two neurotransmitters. They are adrenaline and acetylcholine. Adrenaline is the predominant sympathetic neurotransmitter, whereas acetylcholine acts in the parasympathetic periphery.


Adrenaline is derived from dopamine and dopamine is derived from the essential amino acid phenylalanine and the amino acid tyrosine (Phenylalanine>Tyrosine>Dopamine>Adrenaline and Noradrenaline). Protease digest dietary proteins and release essential amino acids. The previous studies I posted found that patients with MS lacked the essential amino acid phenylalanine and the amino acid tyrosine.


The parasympathetic neurotransmitter is acetylcholine. Acetylcholine is derived from choline. Vitamin B12 and folate are required for the synthesis of choline before becoming acetylcholine.




LOW ADRENALINE AND ACETYLCHOLINE


In the following study the researchers found that MS patients had lower acetylcholine (ACh) levels in their cerebrospinal fluid and serum (blood) than normal controls. Acetylcholine is the autonomic nervous system parasympathetic neurotransmitter. In an additional study the researchers found there was literally “no acetylcholine” in the cerebrospinal fluid of the MS patients tested (Sahar, 1966).



Relation between pro-inflammatory cytokines and acetylcholine levels in relapsing-remitting multiple sclerosis patients.
Reale M, De Angelis F, et al. 2012. Int J Mol Sci. 2012; 13(10): 12656–12664.

“…ACh levels were lower in CSF and serum of RR-MS patients compared to levels of control subjects…”



In the following study on autonomic dysfunction and MS the researchers discovered that catecholamine levels were significantly lower in active MS patients than in those with stable disease. In the human body the most abundant catecholamines are adrenaline, noradrenaline, and dopamine; all of which are produced from phenylalanine and tyrosine. Adrenaline is the autonomic nervous system sympathetic neurotransmitter.


In addition, the researchers concluded that parasympathetic dysfuncton was "closely related" to the progression of disabilty in patients with MS and that sympathetic dysfunction was associated to the "clinical activity" of MS.The parasympathetic neurotransmitter is acetylcholine, which requires vitamin 12. A lack of vitamin B12, which is needed to produce and regenerate myelin and control homocysteine, would explain why parasympathetic dysfunction is closely related to the progression of disability in patients with MS. The sympathetic neurotransmitter is adrenaline. We will be discussing why the inability to produce adrenaline would be associated with the clinical activity of MS.


Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability.
Flachenecker P, Reiners K, Krauser M, Wolf A, Toyka KV. 2001. Mult Scler. 7(5):327-34.

“Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS)…Median catecholamine levels were significantly lower in active MS patients than in those with stable disease…Parasympathetic dysfunction was closely related to the progression of disability in patients with MS. In contrast, sympathetic dysfunction was associated to the clinical activity of MS. This is in line with previous observations suggesting that the autonomic nervous system may be intimately linked with the disordered immune regulation in MS.





If the autonomic dysfunction found in MS is due to the inability to properly metabolize proteins, which results in missing essential amino acids and an inability to properly metabolize vitamin B12, then we should also find autonomic dysfunction in the other diseases we have been discussing that are associated with missing protease.


As we discussed, a vitamin B12 deficiency, due to a lack of protease, has also been implicated in Alzheimer's disease. Here is the information again.

In the following study the researchers stated that there is increasing evidence for an association between Alzheimer’s disease and “nutritionally independent” cobalamin (vitamin B12) deficiency. The researchers believe this may be due to a protease inhibition, a common factor in Alzheimer’s disease. The lack of protease results in protein-bound cobalamin malabsorption and disrupted cobalamin metabolism.


Trypsin inhibition: a potential cause of cobalamin deficiency common to the pathogenesis of Alzheimer-type dementia and AIDS dementia complex?
McCaddon, A., B. Regland, C.F. Fear. 1995. Med Hypotheses. 45(2):200-4.

“There is increasing evidence for an association between Alzheimer-type dementia (AD) and nutritionally independent cobalamin deficiency. Furthermore, low serum cobalamin values occur in a kindred with familial Alzheimer’s disease (FAD) and histopathological confirmation of AD neuropathology…This paper presents the hypothesis that protease inhibition is a common factor in AD and ADC resulting in protein-bound cobalamin malabsorption and disrupted cobalamin metabolism.”




So, we would expect to find that Alzheimer's disease is also associated with a lack of acetylcholine and autonomic nervous system dysfunction. Here is a link to some information on the lack of acetylcholine in Alzheimer's disease and a quote from the site.

http://www.alzheimer-europe.org/Dementi ... -s-disease

"Research has shown that the amount of a chemical called acetylcholine is diminishing in the brains of people with Alzheimer's disease."



Following is a study on Alzheimer's disease and autonomic dysfunction.

Acta Neurol Scand. 1995 Jan;91(1):14-8.
Autonomic dysfunction in Alzheimer's disease.
Algotsson A, Viitanen M, Winblad B, Solders G.
SourceDepartment of Geriatrics, Huddinge University Hospital, Sweden.


Twenty-nine patients fitting the NINCDS-ADRDA criteria of Alzheimer's disease participated in a study of autonomic functions. A number of tests on parasympathetic and sympathetic functions were made. Eighteen of the patients were tested a second time one year later. Fifteen healthy subjects with no family history of dementia disorders served as controls. Compared to the controls, the patients showed signs suggesting autonomic dysfunction affecting parasympathetic, as well as vasomotor sympathetic, functions.




Autonomic dysfunction is also found in lupus and rheumatoid arthritis. In the following study the researchers concluded that lupus and rheumatoid arthritis are associated with severe autonomic dysfunction.


Cardiac autonomic dysfunction in patients with systemic lupus, rheumatoid arthritis and
sudden death risk.

Milovanovi, B., L. Stojanovi, N. Milievik, K. Vasi, B. Bjelakovi, M. Krotin.
2010. Srp Arh Celok Lek. 138(1-2):26-32.

“Sudden cardiac death due to fatal arrhythmias is frequent in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)… SLE and RA are associated with severe autonomic dysfunction and the presence of significant risk predictors related to the onset of sudden cardiac death.”

ACETYLCHOLINE AND DEFECTIVE NEUROMUSCULAR TRANSMISSION

A lack of acetylcholine can also affect muscle function. Nerve endings release acetylcholine that attaches to receptors on muscles. This signal tells the muscle to contract.


Decreased acetylcholine synthesis has been implicated in the neuromuscular disease myasthenia gravis. A lack of acetylcholine in myasthenia gravis leads to the muscles under the person’s voluntary control becoming weak and easily fatigued. The symptoms of myasthenia gravis include: droopy eyelids, blurred or double vision, difficulty swallowing, chewing, and talking, shortness of breath, and increasing weakness of a particular muscle group during continuous use of those muscles, such as shoulder fatigue and heaviness when washing the hair or thigh muscle fatigue when climbing a flight of stairs.


In the following study the researchers concluded that patients with MS have the same kind of easy fatigability as seen in patients with myasthenia gravis and that some patients with MS have deficient production of acetylcholine, just like patients with myasthenia gravis.



Multiple sclerosis associated with defects in neuromuscular transmission.
Patten BM, Hart A, Lovelace R. 1972. J Neurol Neurosurg Psychiatry. 35(3):385-94.


“patients with multiple sclerosis also had the kind of easy fatigability seen in myasthenia gravis…some patients with multiple sclerosis have deficient production of acetylcholine, just like patients with myasthenia gravis…”





Acetylcholine is the autonomic nervous system "parasympathetic" neurotransmitter, so we would expect to find autonomic nervous system dysfunction in patients with myasthenia gravis. In the following study the researchers stated their results showed mainly parasympathetic cardiac impairment in patients with myasthenia gravis.



Cardiac autonomic control in patients with myasthenia gravis and thymoma.
Peric, S., V. Rakocevic-Stojanovic, T. Nisic, S. Pavlovic, I. Basta, S. Popovic, S. Damjanovic, D. Lavrnic. 2011. J Neurol Sci. 307(1-2):30-3. doi: 10.1016/j.jns.2011.05.028. Epub 2011 Jun 11.

“…Overall autonomic score according to Ewing was significantly increased in patients with MG… Our results showed mainly parasympathetic cardiac impairment in patients with myasthenia gravis…Since autonomic dysfunction may lead to cardiac conduction abnormalities and sudden death, the investigation of autonomic nervous system function in these patients may be significant in everyday clinical practice.”





The association between decreased acetylcholine synthesis and MG was first made by researchers in the 1940’s. In the following study, published in the Archives of Internal Medicine in 1947, the researchers stated that much of the symptomatology in patients with MG can be explained by decreased acetylcholine synthesis. In addition, the researchers discovered that amino acids and proteins were found to increase acetylcholine synthesis in vitro. An in vitro test is a medical test, experiment, or procedure that is done outside of the body, such as in a test tube or laboratory dish.


Effect of amino acids on the function of the muscles of patients with myasthenia gravis.
Torda, C., H.G. Wolff. 1947. Arch Intern Med (Chic). 1947;80(1):68-73. doi:10.1001/archinte.1947.00220130076006. Vol 80, No. 1.


“much of the symptomatology in patients with myasthenia gravis can be explained by a decreased acetylcholine synthesis. Amino acids and proteins were found to increase the acetylcholine synthesis in vitro…”





Patients with MG may also have damaged acetylcholine receptors. Acetylcholine receptors can be damaged by free radicals. Researchers in the following study discovered that both MG and multiple sclerosis patients had “significantly lower” levels of the powerful antioxidant, uric acid. As we have discussed, uric acid is the final break-down product of dietary DNA. The pancreatic enzyme DNase I is responsible for the break-down of dietary DNA. Therefore, a lack of DNase I would lead to low levels of uric acid.



Antioxidant status of bilirubin and uric acid in patients with myasthenia gravis.
Fuhua, P., D. Xuhui, Z. Zhiyang, J. Ying, Y. Yu, T. Feng, L. Jia, G. Lijia, H. Xueqiang. 2012. Neuroimmunomodulation. 19(1):43-9.


“Oxidative stress and changes in antioxidant status have been implicated in the pathogenesis of inflammatory and autoimmune diseases, and free radicals can cause considerable damage to the acetylcholine receptors. 388 individuals, including 97 patients with myasthenia gravis (MG), 135 patients with multiple sclerosis (MS) and 156 healthy controls, were assessed for serum levels of bilirubin and uric acid (UA), in order to determine the levels of these natural antioxidants in the serum. We found that serum UA levels in patients with MG were significantly lower…compared with those of the healthy control group…However, there was no significant difference of serum UA levels between patients with MG and those with MS…”

ACETYLCHOLINE AND SLEEP APNEA

Low acetylcholine can also lead to sleep apnea. Sleep apnea is defined as the cessation of breathing during sleep. Acetylcholine-producing neurons are connected to the part of the brain that controls muscles of the upper airway and tongue, which are involved in sleep apnea. A study published in the journal Neurology found that patients with the lowest acetylcholine levels had the most interruptions in their breathing during sleep (Gilman, 2003).



As the following study confirms, patients with MS have a predisposition for sleep apnea.

Sleep-disordered breathing in multiple sclerosis.
Braley TJ, Segal BM, Chervin RD. 2012. Neurology.


“…These data suggest a predisposition for obstructive sleep apnea and accompanying central apneas among patients with MS…”




NORADRENALINE

The essential amino acid phenylalanine is also needed to produce noradrenaline; Phenylalanine>Tyrosine>Dopamine>Adrenaline (Autonomic Nervous System Sympathetic Neurotransmitter)>Noradrenaline.


Noradrenaline is the neurotransmitter most responsible for concentration and memory. Noradrenaline also exerts anti-inflammatory and neuroprotective effects.


In the following study entitled “Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis” the researchers concluded that MS patients have a reduction in brain noradrenaline levels.

In regards to the study’s findings, the study’s first author, Paul Polak, a research specialist at the University of Chicago, stated, “There is evidence of damage to the Locus Coerulius (LC) in Alzheimer's and Parkinson's disease, but this is the first time it has been demonstrated that there is stress involved to the neurons of the LC of MS patients, and that there is a reduction in brain noradrenaline levels.”


Brain. 2011 Mar;134(Pt 3):665-77. doi: 10.1093/brain/awq362. Epub 2011 Feb 4.
Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis.
Polak PE, Kalinin S, Feinstein DL.

“The endogenous neurotransmitter noradrenaline exerts anti-inflammatory and neuroprotective effects in vitro and in vivo. Several studies report that noradrenaline levels are altered in the central nervous system of patients with multiple sclerosis and rodents with experimental autoimmune encephalomyelitis, which could contribute to pathology…Analysis of the locus coeruleus of multiple sclerosis and control brains showed a significant increase in astrocyte activation, a reduction in noradrenaline levels, and neuronal stress…”

FYI After supplementing vitamin D for over a year (6000iu/day) I found out I was low. Many of us may be low in many vitamins/minerals because we cannot process/absorb them. Serum levels become meaningless.

PN

I agree PN, plus, taking supplements of nutrients you cannot properly metabolize could prove harmful.



ACETYLCHOLINE AND TYPE 1 DIABETES

A lack acetylcholine would also lead to an increased risk of developing type 1 diabetes, a chronic condition in which the pancreas produces little or no insulin. Acetylcholine is “crucial” for pancreatic beta cell (beta cells produce and secrete insulin) function, as the following study confirms.



Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming human beta cell function.
Rodriguez-Diaz R, Dando R, et al. 2011. Nat Med. 17(7): 888–892. doi: 10.1038/nm.2371

“Acetylcholine is a neurotransmitter that plays a major role in the function of the insulin secreting pancreatic beta cell…Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine…Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration…Acetylcholine is crucial for pancreatic beta cell function…”




This is the study I posted earlier on MS and type 1 diabetes, but I think it is worth repeating. The researchers concluded that patients with type 1 diabetes are at an enormously increased risk of multiple sclerosis. The researchers found a 20-fold increase in the prevalence of MS in type 1 diabetic women. There must be some pretty strong common links between these two diseases.


Type 1 diabetes and multiple sclerosis: together at last.
Dorman JS, Steenkiste AR, Burke JP, Songini M. 2003. Diabetes Care 10.2337/diacare.26.11.3192 vol. 26 no. 11 3192-3193

“examination of data collected for our Familial Autoimmune and Diabetes (FAD) Study revealed, for the first time, a highly significantly increased prevalence of multiple sclerosis in adults with type 1 diabetes and their first-degree relatives…Thus, we observed a 20-fold increase in the prevalence of multiple sclerosis in our type 1 diabetic women…We therefore conclude that adult women with type 1 diabetes are at an enormously increased risk of multiple sclerosis, and that the answer to questions about the clustering of these disorders is that they are together at last.”




Acetylcholine would be one factor joining these two diseases together and our old friend "homocysteine" would be another. Researchers in the following study stated that "as homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion." The researchers concluded, "These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors."


J Endocrinol. 2006 May;189(2):301-10.
Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion.
Patterson S, Flatt PR, Brennan L, Newsholme P, McClenaghan NH.



Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.



Research has also found that patients with diabetes have impaired exocrine pancreatic function. The exocrine pancreas is where DNase1 and protease originate.


In the following study the researchers link the peripheral neuropathy found in patients with diabetes with impaired exocrine pancreatic function. The researchers stated that compared to normal controls, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli.


Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy.El Newihi, H., C.P. Dooley, C. Saad, J. Staples, A. Zeidler, J.E. Valenzuela. 1998. Dig Dis Sci. 33(6):705-10.


“…Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol…We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion…”






In the next study the researchers stated their results show that exocrine pancreatic function is impaired in a high percentage of both type 1 and type 2 diabetics. The researchers concluded that diabetes secondary to pancreatic exocrine disease could be much more frequent than believed so far.

Pancreatic exocrine function in patients with type 1 and type 2 diabetes mellitus.
Hardt, P.D., A. Krauss, L. Bretz, M. Porsch-Özcürümez, H. Schnell-Kretschmer, E. Mäser, R.G. Bretzel, T. Zekorn, L. Bretz, H.U. Klör. 2000. Acta Diabetologica Volume 37, Issue 3, pp 105-110.


“Reduced exocrine pancreatic function has been observed in a high percentage of patients with type 1 diabetes in the past…In this study we investigated exocrine pancreatic function in 105 controls and 114 with type 1 or type 2 diabetes mellitus by means of an indirect test (faecal elastase-1 concentration). This test has good sensitivity and specificity for moderate and severe pancreatic insufficiency as compared to the gold standard. Reduced faecal elastase-1 concentrations were found in 56.7% of type 1 patients, 35% of type 2 patients and 18.1% of the controls…The data found for type 1 patients correspond to those reported in earlier studies. The results for type 2 diabetics show that exocrine pancreatic function is also impaired in a high percentage in this group of patients…Observations from autopsies and the data of the controls in this study suggest that chronic pancreatitis might be a common problem. In consequence, diabetes secondary to exocrine disease could be much more frequent than believed so far.”

Annesse wrote:...

This is the study I posted earlier on MS and type 1 diabetes, but I think it is worth repeating. The researchers concluded that patients with type 1 diabetes are at an enormously increased risk of multiple sclerosis. The researchers found a 20-fold increase in the prevalence of MS in type 1 diabetic women. There must be some pretty strong common links between these two diseases.


Type 1 diabetes and multiple sclerosis: together at last.
Dorman JS, Steenkiste AR, Burke JP, Songini M. 2003. Diabetes Care 10.2337/diacare.26.11.3192 vol. 26 no. 11 3192-3193

“examination of data collected for our Familial Autoimmune and Diabetes (FAD) Study revealed, for the first time, a highly significantly increased prevalence of multiple sclerosis in adults with type 1 diabetes and their first-degree relatives…Thus, we observed a 20-fold increase in the prevalence of multiple sclerosis in our type 1 diabetic women…We therefore conclude that adult women with type 1 diabetes are at an enormously increased risk of multiple sclerosis, and that the answer to questions about the clustering of these disorders is that they are together at last.”




Acetylcholine would be one factor joining these two diseases together and our old friend "homocysteine" would be another. Researchers in the following study stated that "as homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion." ...

J Endocrinol. 2006 May;189(2):301-10.
Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion.
Patterson S, Flatt PR, Brennan L, Newsholme P, McClenaghan NH.



Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.



...


In the following study the researchers link the peripheral neuropathy found in patients with diabetes with impaired exocrine pancreatic function. The researchers stated that compared to normal controls, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli.


Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy.El Newihi, H., C.P. Dooley, C. Saad, J. Staples, A. Zeidler, J.E. Valenzuela. 1998. Dig Dis Sci. 33(6):705-10.


“…Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol…We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion…”






In the next study the researchers stated their results show that exocrine pancreatic function is impaired in a high percentage of both type 1 and type 2 diabetics. The researchers concluded that diabetes secondary to pancreatic exocrine disease could be much more frequent than believed so far.

Pancreatic exocrine function in patients with type 1 and type 2 diabetes mellitus.
Hardt, P.D., A. Krauss, L. Bretz, M. Porsch-Özcürümez, H. Schnell-Kretschmer, E. Mäser, R.G. Bretzel, T. Zekorn, L. Bretz, H.U. Klör. 2000. Acta Diabetologica Volume 37, Issue 3, pp 105-110.


“Reduced exocrine pancreatic function has been observed in a high percentage of patients with type 1 diabetes in the past…In this study we investigated exocrine pancreatic function in 105 controls and 114 with type 1 or type 2 diabetes mellitus by means of an indirect test (faecal elastase-1 concentration). This test has good sensitivity and specificity for moderate and severe pancreatic insufficiency as compared to the gold standard. Reduced faecal elastase-1 concentrations were found in 56.7% of type 1 patients, 35% of type 2 patients and 18.1% of the controls…The data found for type 1 patients correspond to those reported in earlier studies. The results for type 2 diabetics show that exocrine pancreatic function is also impaired in a high percentage in this group of patients…Observations from autopsies and the data of the controls in this study suggest that chronic pancreatitis might be a common problem. In consequence, diabetes secondary to exocrine disease could be much more frequent than believed so far.”

Annesse, please let me submit an idea for your consideration and comment:

Type I diabetes (i.e., no effective insulin or no insulin at all to manage the glucose level) was historically called "juvenile diabetes" and, I believe, was thought to have a viral/bacterial cause for the end of beta cell production of insulin. Today it is known that hyperinsulinemia, a.k.a. type II diabetes, (due to diet, disease, etc.) can simply exhaust the pancreas as well, resulting in type I diabetes also.

Did the article you cited above give any details about the history of the "adult women with type I diabetes"? I think it is important to know if their type I diabetes came about as the result of type II diabetes (hyperinsulinemia). Do you think that, in addition to acetylcholine and homocysteine, hyperinsulinemia (overworking the poor little pancreas to exhaustion) could be yet another factor in joining together type I diabetes and multiple sclerosis? By the way, I recall that papers linking type II diabetes and MS have also been posted here at ThisIsMS in the past.

As the May 2006 Journal of Endocrinology article states, the elevated homocysteine was in individuals with metabolic syndrome including vascular disease and insulin resistance (a.k.a. hyperinsulinemia). I submit that this excess insulin alone might have exerted the detrimental effect on the endothelial cells. Are you aware of any investigation of insulin alone as this mechanism?

And, for the record, I believe "the researchers link the peripheral neuropathy found in patients with diabetes" is caused by excess insulin (causally in type I diabetes or currently in type II diabetes).

The statement in the last paragraph is VERY important: "Observations from autopsies and the data of the controls in the study suggests that chronic pancreatitis might be a common problem."

Hi Linda~

I might have to take your thoughts one at a time.

You stated: "And, for the record, I believe "the researchers link the peripheral neuropathy found in patients with diabetes" is caused by excess insulin (causally in type I diabetes or currently in type II diabetes)."




Here is why I believe the peripheral neuropathy found in diabetes is associated with exocrine pancreatic insufficiency and not excess insulin.


A lack of the exocrine enzymes, DNase 1 and protease, would lead to an inability to digest proteins, DNA, essential amino acids and vitamin B12.

In the following study the researchers found that patients with type 1 diabetes showed strongly impaired DNase 1 activity.

Exp Clin Endocrinol Diabetes 2004; 112 - P192
Impaired DNase activity in patients with endocrine autoimmunity and their healthy relatives
M Dittmar 1, S Tietz 1, R Poppe 2, G Fredenhagen 2, M Weber 1, GJ Kahaly 1

The enzyme Deoxyribonuclease (DNase) is involved in degrading DNA during apoptosis. Impaired DNase activity has been reported to increase susceptibility to systemic lupus erythematodus. We therefore analyzed whether serum DNase activity is impaired in 112 patients with endocrine autoimmunity, their 113 relatives, and in 41 healthy controls. Patients had either pluriglandular (involvement of at least two glands, PGA, n=60) or monoglandular autoimmunity (MGA, n=70). Most frequent endocrinopathies were thyropathies (n=119), type 1 diabetes (n=44), and Addison's disease (n=14)... Pathological findings were characterized by a marked activity reduction of serum DNase (AR; cut-off: 25% AR). Compared to controls, both patients and healthy relatives showed strongly impaired DNase activities (chi-square=21.4, df=3, p<0.001). Range (median) AR in patients with PGA, MGA, healthy relatives, and controls were 2.0-57.8% (10%), 3.4-70.4% (19%), 3.6-72.5% (9%), and 4.3-16.8% (7.5%), respectively. Pathological AR in DNase was found in 23%, 30%, 10% and 0% of patients with PGA, MGA, healthy relatives, and controls, respectively. In MGA patients with Graves' disease, Hashimoto thyroiditis, and type 1 diabetes, AR was 4.0-70.4% (median 15%), 3.4-66.9% (17%), and 8.5-57.2% (29%), respectively, whereas pathological AR was noted in 14%, 35%, and 62%, respectively...Since healthy relatives also exhibit seropositive findings without clinically manifest organ failure, the determination of DNase activity may predict future autoimmune endocrine diseases.





A lack of the exocrine pancreatic enzyme-protease-would lead to an inability to properly metabolize vitamin B12. Here is something from my book on the association between vitamin B12, diabetes, and peripheral neuropathy.


"In patients with diabetes, the vitamin B12 connection has been established by researchers at the prestigious Warwick Medical School, University of Warwick. The University of Warwick researchers, led by Professor Paul Thornalley, have shown conclusively that diabetic patients are thiamine (B1) deficient in blood plasma. In the research paper entitled “High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease”, published in Diabetologia, the team found that thiamine concentration in blood plasma was decreased 76% in type 1 diabetic patients and 75% in type 2 diabetic patients (Thornalley, 2007).

The researchers stated that the decreased plasma thiamine concentration in clinical diabetes was not due to a deficiency of dietary input of thiamine. Rather, it was due to a profound increased rate of removal of thiamine from the blood into the urine. Diabetic patients were found to expel thiamine from their bodies at 15 times the normal rate.

No other B vitamin is more dependent on its fellow B vitamins than B1. If you are deficient in B12, you will not be able to absorb B1. It will be excreted in the urine.


As the title to the study stated, the researchers believe the lack of thiamine (not excess insulin) is linked to the vascular complications in diabetes, which the researchers concluded is likely due to problems in endothelial cells.



One of the most common and troublesome complications of diabetes is diabetic autonomic neuropathy. According to the American Diabetes Association: “Autonomic neuropathy affects the autonomic nerves which control the bladder, intestinal tract, and the genitals, among other organs. Paralysis of the bladder is a common symptom. The nerves of the bladder no longer respond normally to pressure as the bladder fills with urine. As a result, urine stays in the bladder, which leads to urinary tract infections.


Autonomic neuropathy can also cause erectile dysfunction when it affects the nerves that control erection. Diarrhea can occur when the nerves that control the small intestine are damaged. Constipation is another common result of damage to nerves in the intestines. Sometimes, the stomach is affected. It loses the ability to move food through the digestive system, causing vomiting and bloating” (American Diabetes Association, 2011).


Autonomic neuropathy is a form of peripheral neuropathy. It involves damage to the nerves that run through a part of the peripheral nervous system. According to the Center for Peripheral Neuropathy at The University of Chicago a clear link has been established between a lack of vitamin B12 and peripheral neuropathy.


In the following study the researchers concluded that vitamin B12 deficiency causes autonomic dysfunction with similar hemodynamic consequences and patterns of autonomic failure as seen in diabetic autonomic neuropathy.


Autonomic dysfunction and hemodynamics in vitamin B12 deficiency.
Beitzke, M., P. Pfister, J. Fortin, F. Skrabal. 2002. Auton Neurosci. 97(1):45-54.

“…The results suggest that vitamin B12 deficiency causes autonomic dysfunction with similar hemodynamic consequences and patterns of autonomic failure as seen in diabetic autonomic neuropathy…”




Low vitamin B12 will lead to elevated levels of homocysteine.



"In the following study of 65 patients with type 2 diabetes, elevated levels of homocysteine were found to be independently associated with the prevalence of peripheral neuropathy. The authors suggested that this association could be explained either by direct cytotoxic effects on nerve function, or by small vessel occlusions caused by endothelial damage. This results in a loss of blood supply to nerve fibers, a pathogenetic mechanism of peripheral neuropathy.


Relation between homocysteinaemia and diabetic neuropathy in patients with type 2
diabetes mellitus.


Ambrosch, A., J. Dierkes, R. Lobmann, W. Kühne, W. König, C. Luley, H. Lehnert. 2001. Diabet Med. 18(3):185-92.

“…Since homocysteine exhibits toxic effects on vascular endothelial cells, the association between homocysteine and the prevalence of neuropathy in type 2 diabetes mellitus was investigated… homocysteine levels…and the frequency of hyperhomocysteinemia were significantly increased in neuropathic patients…The data indicate that homocysteine is independently associated with the prevalence of diabetic neuropathy in a collective of type 2 diabetic patients.”




In the following study published in the Annals of Internal Medicine the researchers concluded that homocysteine was also a strong and independent risk factor for coronary heart disease (CHD) events in patients with type 2 diabetes. Approximately 80% of people with diabetes die of cardiovascular disease.

Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus.
Soinio, M., J. Marniemi, M. Laakso, S. Lehto, T. Rönnemaa. 2004. Ann Intern Med. 140(2):94-100.

“…In this large cohort of patients with type 2 diabetes, plasma homocysteine level was a strong and independent risk factor for CHD events.”



Homocysteine is also associated with ulceration in type 2 diabetes. The study entitled “Plasma homocysteine levels are associated with ulceration of the foot in patients with type 2 diabetes” concluded that for each micromol increase in plasma homocysteine levels there was a 10% increase in the risk of diabetic foot ulceration (González, 2010).


I do agree that excess insulin is involved in the pathogenesis of MS, but I think it happens as a consequence of the missing enzymes DNase 1 and protease.

I have found two factors (both due to a lack of DNase 1 and protease) that would clearly explain the excess insulin found in patients with MS. I will make a new post on this since this one is getting quite long.

One of the factors that would explain the insulin resistance found in patients with MS is elevated tumor necrosis factor. Here are a few studies confirming this.


Tumor necrosis factor alpha inhibits signaling from the insulin receptor.
G S Hotamisligil, D L Murray, L N Choy, and B M Spiegelman


"Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus...These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin."



Exp Clin Endocrinol Diabetes. 1999;107(2):119-25.
Mechanisms of TNF-alpha-induced insulin resistance.
Hotamisligil GS.
SourceHarvard School of Public Health, Department of Nutrition, Boston, MA 02115, USA.


"There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems."



Here are a few studies on MS and elevated tumor necrosis factor (TNF). I will be discussing the reasons for this soon on the thread.


In the following study published in the New England Journal of Medicine the researchers concluded that the level of TNF in cerebrospinal fluid correlated with the severity and progression of MS.


N Engl J Med. 1991 Aug 15;325(7):467-72.
Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis.
Sharief MK, Hentges R.

“Tumor necrosis factor-alpha (TNF-alpha), is a principal mediator of the inflammatory response…These data provide evidence…of TNF-alpha in multiple sclerosis and suggest that the level of TNF-alpha in cerebrospinal fluid correlates with the severity and progression of the disease…”



Researchers in the next study discovered TNF in MS lesions and concluded that the presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.

J Exp Med. 1989 Aug 1;170(2):607-12.
Tumor necrosis factor identified in multiple sclerosis brain.
Hofman FM, Hinton DR, Johnson K, Merrill JE.

“Frozen brain specimens from patients with multiple sclerosis (MS) and other neurologic diseases were analyzed using immunocytochemical techniques for the presence of TNF…TNF+ cells were demonstrated. At the lesion site in MS, TNF+ staining is associated with both astrocytes and macrophages…The presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.”

HYPOTHYROIDISM AND MS

Hypothyroidism is a condition in which the thyroid gland doesn’t produce enough thyroid hormone. The essential amino acid phenylalanine is not only needed for the synthesis of dopamine and both of the adrenal hormones (adrenaline and noradrenaline), it is also required for the synthesis of both of the thyroid hormones. Phenylalanine is converted into tyrosine and tyrosine is then used for the synthesis of the thyroid hormones--thyroxine and triiodothyronine (phenylalanine>tyrosine>thyroxine and triiodothyronine]

The lack of phenylalanine and tyrosine found in patients with MS would explain the association MS has with hypothyroidism. In the following study published in Neurology researchers found that thyroid disorders, which were accounted for mainly by the prevalence of hypothyroidism, were at least “three times” more common in women with MS.

Neurology. 1999 Sep 11;53(4):883-5.
Association of MS with thyroid disorders.
Karni A, Abramsky O.

“…We found that thyroid disorders were at least three times more common in women with MS than in female controls. This was accounted for mainly by the prevalence of hypothyroidism among the female MS patients.”



Just as we would expect, researchers in the following study found low levels of tyrosine in patients with hypothyroidism.

The serum tyrosine level as an index of thyroid function.
Malamos, B., C.J. Miras, J.N. Karli-Samouilidou, D.A. Koutras. 1966. J Endocrinol July 1, 35 223-228 doi: 10.1677/joe.0.0350223.

“Serum tyrosine was measured in 22 normal subjects…10 patients with hypothyroidism…Low values were obtained in hypothyroidism…”



LOW DOPAMINE

Since dopamine is also derived from the essential amino acid phenylalanine (phenylalanine>tyrosine>dopamine>adrenaline and noradrenaline), we would expect to find that patients with MS lack dopamine.

In the following study the researchers found reduced levels of dopamine in MS patients and concluded their results suggest the involvement of dopamine in the pathogenesis of depression in MS.

Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(2 Pt 2):34-40.
The role of dopamine in the regulation of the interaction between nervous and immune systems in multiple sclerosis.
Orlova EV, Pashchenkov MV, Davydovskaia MV, Klimova SV, Khozova AA, Mugutdinova BT, Boĭko AN

“…The results suggest the involvement of dopamine in the pathogenesis of depression in MS as assessed by dopamine and its metabolites levels.”

SYMPTOMS OF LOW DOPAMINE
• Stiff, rigid, achy muscles
• Cognitive impairment
• Impaired motor skills
• Tremors
• Inability to focus attention
• Poor balance and coordination
• Strange walking pattern (gait), frequently with small steps


Low dopamine and a lack of bioavailable iron (we will be discussing the inability to properly metabolize iron in MS) would lead to a condition commonly found in MS—restless legs syndrome. In the following study from Johns Hopkins entitled “Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)” the researchers stated, “It is concluded that there may be an iron-dopamine connection central to the pathophysiology of RLS for at least some if not most patients with this disorder.”

Dopamine and iron in the pathophysiology of restless legs syndrome (RLS).
Allen, R. 2004. Sleep Med. 5(4):385-91.

“It is concluded that there may be an iron-dopamine connection central to the pathophysiology of RLS for at least some if not most patients with this disorder.”




In the following study the researchers concluded that restless legs syndrome (RLS) is a very common finding in MS patients.

Eur J Neurol. 2007 May;14(5):534-9.
High prevalence of restless legs syndrome in multiple sclerosis.
Manconi M, Fabbrini M, Bonanni E, Filippi M, Rocca M, Murri L, Ferini-Strambi L.

“… RLS is a very common finding in MS patients…RLS is also associated with higher disability.”