(This website is made available by Yngve Bersvendsen, Bergen, Norway. Comments can be sent to
bersvendsen@nsd.uib.no).
Last updated: August 2001. Text written in italics is new since last update (september 2000).
The reason for my interest is that I have relatives and friends who have diabetic neuropathy and conventional medicine can’t offer them much help. So I tried to find effective approaches to this disease, using INTERNET as a search tool. In this way I got in contact with neuropathy sufferers in USA who are researching this subject. So, I'm not the originator of this material; Stan Angilley is the author of this study.
The information about diabetic neuropathy which is presented here represents up-to-date research work. By publishing this document on a Website, we hope that others can find information which can be useful in managing this painful disease. If someone personally wants to follow up on some of the suggestions given here, we would appreciate knowing.
The average time it takes medical research findings to enter clinical practice is best measured in decades. But this problem is known and may be rectified, eventually; see (Owen, 1995). Until that time comes around, it is the patient who is the ultimate loser. In the meantime, the best strategy is to arm oneself and/or one's physician with as many pertinent facts as are necessary to make more fully-informed decisions about the management of your neuropathy.
There is a vast amount of medical research extant on sound, valuable remedies that
ultimately end up ignored for lack of promotion (usually due to limited profit potential)
in spite of being, demonstrably, the most effective ones available.
Thus we have found a treatment which emphasizes the judicious use of nutrients
together with the novel use of some prescription drugs.
The result of this broken process is shortage of GLA and its metabolites; prostacyclin and prostaglandins. Diabetic neuropathy is a progressive disease that is most probably caused by the effects of a chronic deficiency of prostacyclin and prostaglandins. This is central to the pathogenesis of diabetic neuropathy.
Prostacyclin (PGI2) is a major vasoprotective molecule with multiple physiological functions. Pivotal to its synthesis is an enzyme called cyclooxygenase (COX). Two isoforms of COX have been identified: COX-1 which produces both prostacyclin and anti-inflammatory prostaglandins, and COX-2, which produces both Thromboxane A2 (TxA2) and some of the prostaglandins which produce inflammation.
The aim of pain-killers is it reduce pain and inflammation by stopping production of the prostaglandins that produce that effect. The "ideal" pain-killer would be one that inhibited COX-2 but left COX-1 intact. Unfortunately, most common pain-killers destroy both COX-1 and COX-2 and thus stop production of much needed prostacyclin as well as the anti-inflammatory prostaglandins. So, by the uncritical use of analgesics it is possible to create an unintentional break in the conversion of GLA to PGI2, which has the effect of removing some pain, but making the underlying neuropathy much worse by exacerbating a prostacyclin deficiency.
But by judicious use of pain-killers it is possible to manage
this situation:
Like aspirin; naproxen, indomethacin, piroxicam and acetaminophen
attempt to block the production of pain-producing prostaglandins
but unfortunately all of them (except aspirin) block everything
produced from COX, including prostacyclin. Of the commonly used
pain-killers, aspirin inhibits prostacyclin production the least
(3-4 hrs); piroxicam the most (3-4 days). But this can be turned
to our advantage: (Drvota, 1990) shows that one aspirin taken every
3 days maximizes prostacyclin production while minimizing production
of the COX-2 prostanoid TxA2, which causes
hypertension and has been implicated in development of vascular disease.
Since TxA2 (an EFA metabolite co-produced with prostacyclin) is
antagonistic to prostacyclin in many of its effects, the criterion
of maximizing PGI2 production (relative to TxA2) is satisfied.
Other than one aspirin every three days, should pain relief be necessary,
it must be sought by the use of either non-cylooxygenase inhibitors,
ie: Tramadol - Ultram (Harati, 1998) for severe pain or ideally COX-2
inhibitors (Kalgutkar,1998) like: nimesulide, vioxx
or celecoxib (Celebrex); also usable: Indobufen (Davi,1993) or Sulindac
(Clinoril). For those seeking an effective but gentler agent, curcumin
(tumeric extract) may well suffice (Ramsewak, 2000). Do not use
paracetamol or acetaminophen (Tynenol).
Because of the very low levels of prostacyclin/prostaglandins among diabetics, the red blood corpuscles of diabetics tend to be brittle and unable to be deformed. The consequence is that the oxygen-carrying corpuscles cannot enter the small capillary vessels. They simply cannot be "squeezed" into them. So, if the micro-blood vessels in the nerves cannot receive oxygen, then nerve cells will die. Physically , this is exactly what happens with neuropathy. The result is endoneural hypoxia, which is the overt cause of diabetic neuropathy. Early symptoms of this process is varying degrees of irritation and pain, especially in the extremities. Symptoms of more advanced disease include gastroparesis and impotence.
So the aim of a nutritional treatment is to:
1. Gamma-linolenic acid/Trental
The key nutrient is gamma-linolenic acid (GLA), and supply this through the diet.
If the EFA metabolism is only broken in one place, then GLA supply can resolve the
prostacyclin/prostaglandin deficiency problem. GLA makes the blood corpuscles more
deformable, regenerate veins/capillaries and in the long run encourage nerve growth.
A study, (Cameron, 1990), showed that endoneural capillary density increased by 22 %
with the use of GLA (Efamol). A good source of GLA is Evening Primrose Oil (EPO).
It takes 8-10 weeks for the EPO to start having an effect.
(Fang, 1997) demonstrates the extreme effectiveness of GLA in this
regard when administered as evening primrose oil (EPO) which not
only provides the arachidonate as raw material for the production
of prostacyclin, but also stimulates COX-1 expression in some tissues.
(Cameron, 1996) showed that a novel essential fatty acid derivative ascorbyl-GLA was 40 times as efficacious as GLA as a treatment for neuropathy. It is not as yet available commercially, but the same study showed that GLA plus ascorbate was over 75% as efficacious as ascorbyl-GLA. Ascorbate (vitamin C) is flushed from the human body every 5 hours, so it is prudent to always take it together with the GLA.
(Cameron, 1998) shows a marked synergy between GLA and racemic alpha-lipoic acid (mixed in a 1:3 to 3:1 ratio) yielding compounds that have at least an order of magnitude increase in efficacy over either one alone in correcting motor nerve conduction velocity and endoneural blood flow defects. A 1.3:1 GLA:alpha-lipoic acid ratio appears to be optimal against experimental diabetic neuropathy. Recent experimental work confirms that GLA-aLA (equimolar) conjugate is so effective that it completely reverses the effects of the broken neurotrophic mechanisms that correlate with diabetic neuropathy (Hounsom, 1998). The insulin-mimetic effects of this unique conjugate are further explored by (Peth, 2000).
If essential fatty acid metabolism is badly broken and the supplementation of GLA will not produce the necessary products in the quantities needed, then also the drug TRENTAL (pentoxifylline) can be used. (TRENTAL is the commercial name, pentoxifylline the scientific name) TRENTAL is usually prescribed for blood circulation problems, including diabetes-induced PVD (Campbell, 1993). In the case of diabetics, it behaves very much like prostacyclin because it causes prostacyclin to be liberated by the body. The problem with GLA produced prostacyclin is that it takes time, it might not work well and the level of prostacyclin might be low or non-existant.
Even though both TRENTAL and EPO can have duplicate functions, the best way is probably to begin using both of them together. TRENTAL have a more immediate effect, EPO is slower, but has a more complete spectrum of effects in managing the fatty acid deficiencies that diabetics suffer from.
EPO and TRENTAL used over a longer time (4 months to 1 year) cause the blood to become
thinner - which is not a bad thing for diabetics - but is a bad thing if it is excessive
which can lead to bruising and slower wound-healing. Getting the correct balance might require
some attention. TRENTAL should be used with care and attention and maybe should be
withdrawn once the GLA starts having the same effect (2-3 months). In the long run it is
probably better to produce prostacyclin "naturally" by taking GLA if that is possible.
But this has to be tried out individually, evaluating the effect of the programme.
Note: Use of steroids is decidedly counterproductive to the formation of prostacyclin under almost all circumstances.
One of the least known and most useful side-effects of pentoxifylline (TRENTAL) is its ability to suppress tumour necrosis factor alpha (TNF-alpha) production (Zabel, 1993), which is a major cause of insulin resistance (Hotamisligil, 1993), (Feinstein, 1993) and (Liu, 1998). Use of pentoxifylline short-circuits one of the circles within vicious circles that afflict diabetics: Obesity -> TNF-a -> insulin resistance -> more insulin -> more obesity -> more TNF-a -> more insulin resistance .....
Do not expect your physician to know about pentoxifylline's usefulness in suppressing TNFa overexpression; the research demonstrating that functionality was done only a few years ago (Zabel, 1993).
Excess levels of TNFa can account for up to 40% of insulin resistance. There is evidence (Yamamoto, 1998) that high TNFa levels causes COX-2 overexpression which may be the cause of the established increase in levels of TxA2 found in NIDDM resulting in hypertension and attendant vascular complications.
Whereas GLA has a broader and more desirable spectrum of effects, both GLA and pentoxifylline ameliorate diabetic neuropathy through promoting the release of prostacyclin. Should either or both of these agents be unavailable, these others have been proven to promote prostacyclin release:
Of those, Ginkgo Biloba (EGb) is preferred as either a substitute or an adjunct to Trental since it is almost as efficacious in its production of prostacyclin and has the added feature of being a powerful antioxidant that is effective in preventing retinopathy and in treating macular degeneration (DeFeudis, 1991).
Given a choice of anti-hypertensive drugs, the ACE-inhibitors mentioned have been shown to achieve part of their blood-pressure reduction activity through prostacyclin release; but they are also prescibed for diabetics by virtue of the prophylaxis they offer against the deveopment of kidney and heart complications.
Since humans have lost the ability to convert sugar into vitamin C, diet is the only source. Given its central role in vascular health, which is so important in diabetes, a substantial intake is recommended. Daily intake should not exceed 4,300mg if you wish to avoid gastrointestinal problems.
Vanadium is an excellent insulin-mimetic than can completely suppress TNFa-induced insulin resistance (Kroder, 1996) and induce sustained prostacyclin release (Shimizu, 1994). However, further study is needed on some of the delivery systems - IMHO (SA).
2. Antioxidants
Diabetics have significantly accelerated levels of oxidative stress (Mohanty, 2000)
and this almost certainly accounts for or contributes massively to most diabetic
complications; neuropathic, cardiovascular, retinal, renal, etc.
(Kahler, 1993) showed that DM is a free radical-associated disease and the
use of adjuvant antioxidants: 600mg thioctic acid, 1200iu vitamin E or
100mcg selenium may all lead to regression of diabetic late complications.
(Ziegler, 1997), in a careful clinical study, shows that 800mg of alpha-lipoic
acid orally per day (200mg qid) for 4 months resulted in a small but significant
improvement in cardiac autonomic neuropathy in NIDDM patients. Experimental work by
(Garrett, 1997) shows that thioctic acid is superior to nerve growth factor in the
induction of neurotrophic support. (Rudich, 1999) shows that cells treated
alpha Lipoic acid are thus protected against oxidative stress-induced
insulin resistance. (Androne, 2000) in a clinical study, concludes that
"..antioxidant therapy with Lipoic Acid improves and may prevent
diabetic neuropathy".
Alpha-lipoic acid (aLA) is a coenzyme essential for energy production, a superb
antioxidant that recycles vitamins C, E and the important enzymatic antioxidant
glutathione, and, is antihyperglycemic too (as is physical exercise); it can
increase glucose disposal up to 50 % when given at 1,200 mg i.v. per day - which
is, incidently, the maximum dose before side-effects appear (Ziegler, 1995). When
starting to take any form of aLA it may be prudent to monitor bg levels and make
adjustments, should they prove necessary. Another potential benefit of aLA use could be
a lowering of the levels of glycosylated hemoglobin through reduced bg levels.
Comprehensive information on aLA is available in the excellent online book and
research database found on MRI's website:
http://www.lipoic.com/cover.htm
One's body has 4 main defences against oxidative stress, one non-enzymatic: Vitamin E; and three enzymatic: Superoxide dismutase (SOD), glutathione peroxidase (GSH) and catalase.
Hyperglycemia significantly diminishes glutathione levels lowering defences against oxidative stress. N-acetyl-cysteine (NAC) is the precursor to GSH and (Sagara,1996) showed that dietary NAC inhibited the development of functional and structural abnormalities of peripheral nerves in experimental diabetes. In a clinical trial (Gilligan, 1995), NAC reduced lipoprotein(a) by a significant 24% in NIDDM patients. (Busse, 1992) showed an increase in intracellular GSH after administration of alpha-lipoic acid - which may recycle GSH.
(Curcio, 1995) showed that SOD and GSH prevents hyperglycemia-induced free radical cell damage and may help reduce the vascular complications of diabetes. Given its established usefulness in treating diabetic retinopathy due to its SOD liberating properties; the nerve regeneration capabilities of one of its fractions (Bruno, 1993); its relatively low toxicity; ubiquity and affordability; catholic use of Ginkgo Biloba extract is indicated.
The ideal maintenance-level antioxidant mixture to provide adequate
levels of enzymatic and non-enzymatic agents would include:
3. Vitamin E
Vitamin E has a synergistic effect with GLA; it protects
prostacyclin and thins the blood. Under conditions of hyperglycemia it may restore
depressed PGI2 production by the vascular wall (Kunisaki, 1992). It widens the blood
vessels, even the smallest capillaries, and therby improves blood circulation and
capillary permeability. It also has the ability to bind oxygen, which
reduces the amount which is needed. Vitamin E acts as an anticoagulant in the veins
by preventing clotting of blood platelets. Can prevent rupture of red blood cells.
It improves wound-healing. The vitamin E should contain mixed tocopherols,
specifically d-gamma-tocopherol in addition to the usual d-alpha-tocopherol,
since it provides protection against electrophiles - extremely reactive radicals
implicated in LDL-cholesterol oxidation and coronary heart disease (Christen, 1997).
(Ceriello, 1991) showed that at a dosage of 600mg/day of vitamin E,
glycosylated protein is reduced by 21.6% vs placebo in ID diabetic
patients; at 1200mg/day the reduction is 31.1% vs placebo group.
Conclusions: "This study demonstrates for the first time that vitamin E
administration in diabetic patients reduces protein glycosylation in vivo.
..... in our patients, mean (...fasting and daily...) plasma glucose remained
unchanged during the study, whereas the indices of protein glycosylation
significantly decreased."
4. Acetyl L Carnitine (ALC)
Carnitine is an amino acid. Research has shown that this amino acid, in the acetyl-L-carnitine
(ALC) form, can be most useful in treating neuropathy and repairing neural damage.
A recent randomized, controlled clinical
trial (Quatraro, 1995) demonstrated "a significant amelioration of symptoms" when patients
took 2 x 500mg ALC (intramuscular injection) per day. (Note: The absorption of ALC
taken orally is unlikely to be equivalent to the absorption of injectable ALC).
There is extensive research literature dealing with the beneficial effects of ALC
treatment for diabetic neuropathy.
Notes: Only the "L-" form of synthetic carnitine should ever be used, D-carnitine is cardiotoxic. ALC should not be taken during pregnancy or lactaction. Injectable ALC is manufactured by Glaxo in Italy and may be obtainable through them with the help of your physician.
5. Chromium
This is the most important micronutrient in helping to stabilize blood sugar level.
Chromium affect cellular absorption and makes a more effective use of the insulin,
but it does not increase the panceas' production of insulin. It has its greatest
effect on type II diabetes. DIABETICS SHOULD MONITOR GLUCOSE carefully after taking
chromium because less insulin may be needed.
6. Biotin
The biotin concentration in diabetes patients is shown to be significantly
lower than in healthy control subjects. Research has indicated that biotin
in high doses could be suggested for diabetic patients for the prevention and management
of peripheral neuropathy.
In an intriguing study (Maebashi, 1993) demonstrated that serum glucose
levels of NIDDM patients given biotin at 9mg/day decreased from
12.9 +/- 2.6 mmol/l to 7.1 +/-1.2 mmol/l (232.2 +/- 46.8mg/dl to 127.8 +/-
21.6 mg/dl) after 1 month's administration. Serum insulin levels remained
unchanged. After cessation of biotin administration, the plasma glucose
level returned to the initial level. In a long-term study, BG levels
dropped to normal within 2 months and remained within the normal range
throughout the > 4 year study. No undesirable side-effects were observed.
7. Niacin
Niacin (vitamin B3) improves blood circulation by restoring electrical
polarity in blood cells, and it expands the capillaries. It participates in
metabolism of glucose. Niacin is important for the function of the nerve system.
The "time-release" form of niacin should be avoided however since it
appears to cause liver problems.
8. Inositol and Taurine
Diabetics over-excrete the vitamin inositol, and they therefore have a
general shortage of this. It plays a role in the fat metabolism, and may
protect nerve fibers from excess glucose.(Stevens, 1993) postulates that the equilibrium
between the amino acid
taurine and inositol gets disturbed by the increasing sorbitol levels
caused by hyperglycemia. Which means that taurine supplementation is
as least as important as inositol supplementation.
(Franconi, 1995) showed that it required 1.5g/day of supplemental taurine
for IDDM subjects to reach the serum taurine levels of non-diabetic control
subjects. Taurine deficiency is also implicated in the development of
diabetic cardiomyopathy. Studies have shown that some animals fed a
taurine deficient diet develop (reversible) cardiomyopathy. Whereas
humans might not be quite that lucky, taurine certainly helps those of
them with it; see (Azuma, 1992).
In animal or clinical studies taurine supplementation; reduces total proteinuria and albuminuria by nearly 50% (Trachtman, 1995); attenuates iabetes-induced hypertrigyceridemia, prevents arrhythmias, stabilizes platelets, lowers elevated blood pressure, retards cholesterol-induced atherogenesis. The beneficial effect of taurine on the diabetic kidney is related to reduced renal oxidant injury with decreased lipid peroxidation and less accumulation of advanced glycosylation end-products (AGEs) within the kidney. Under conditions of oxidative stress (a permanent condition in the body),taurine is converted to taurine chloramide, which has been shown to reduce TNFa overexpression hence increase insulin sensitivity.
The vascular endothelium forms the thin, innermost monolayer in capillaries and other blood vessels. It is a highly active metabolic and endocrine organ producing prostacyclin, thromboxane amongst a host of other essential substances. It is easily damaged; Zinc, taurine and magnesium are protective and critical nutrients for maintenance of endothelial integrity (Connell, 1997), (Wang, 1996), (Jellinek, 2000).
9. Magnesium
A number of studies have shown that a magnesium deficiency, typical in
diabetes - apart from its invisible but devastating effects on the
vascular system - can manifest as neuropathy; this makes a case for
ensuring that the vitamin C complex chosen to enhance the GLA contain
at least some magnesium ascorbate. Based on an RDA of 350mg per day,
in the US there is a typical dietary shortfall of 90 to 178 mg of
elemental magnesium per day (Altura, 1995).
Magnesium orotate or magnesium aspartate will directly increase intracellular magnesium which is depleted in diabetes and is probably the "missing link" in the diabetes-hypertension connection (Paolisso, 1997). Most other forms of magnesium merely increase extracellular magnesium.
The second programme is more comprehensive in dealing with diabetes and diabetic neuropathy.
Note: Niacin (a form of vitamin B3) can cause flushing of the skin of the face and neck if taken on an empty stomach. It is the "prickly heat" type of flushing and whilst discomforting to some, it goes away quickly.
Note: The programmes are designed as paced, dosage guidelines but are not required to be followed absolutely as a rigorous regimen. ALC, GLA + aLA and NAC must be taken between meals on an empty stomach (at least 1 hr before and 2 hrs after eating) and some nutrients must be taken together (ie: GLA + vitamin C; GTF chromium + niacin). The large, therapeutic doses of certain nutrients have been clearly defined; for the others, use whatever dosage recommendations you normally follow. Careful choice of the particular daily multi-vitamin/mineral used can seriously reduce the number of tablets you have to deal with each day. Inform and consult your physician on all aspects of whatever programme you choose to follow.
Note: Excessive magnesium intake can cause renal problems. If on
a program requiring the use of magnesium orotate, do not switch to
magnesium taurate, just reduce the amount of taurine taken after 15 days.
Literature:
