Hi
A new website - www.diabetescommunity.org.uk has just been launched
for those in Cambridgeshire seeking advice, news on new drugs and
trials, recipes for healthy diabetic diet, dedicated diabetic book
shop, forum and the start of a new support group in Cambridgeshire.

A news release for those that are diabetic with damage to their
nerves is as follows. I personally have Peripheral Neuropathy and am
trying the Alpha Lipoic Acid and have bought it from Natures Best
which is the most competitive online shop.

Diabetic Peripheral Neuropathy
Neuropathy is disease of the nerves. In a diabetic, it takes two
forms: Autonomic Neuropathy and Peripheral Neuropathy.

Autonomic Neuropathy
The autonomic nervous system is the one that operates in the
background, controlling things like breathing, heartbeat, stomach
emptying, etc.

The most common diabetes-related autonomic neuropathy is
gastroparesis, or delayed/irregular stomach emptying. Many longtime
Type-1s can tell you how this can make insulin bolus dosing a
nightmare. Other symptoms are aberrations in sweating, postural
hypotension, bladder control, abnormal febrile responses, impotence,
diarrhea, nausea, and on and on.

You can do a simple test for autonomic neuropathy simply by taking
your pulse. This is called the R-R Interval. Take your pulse and note
the (hopefully) regular beat when inhaling. Your pulse will normally
slow when exhaling. If it doesn't, it may be an indication of
autonomic neuropathy which should be checked with your doc.

Peripheral Neuropathy
One of the first complications noted by many diabetics is a tingling,
pain, or loss of sensation in the toes and feet. This is often a
symptom of Diabetic Peripheral Neuropathy or DPN.

Not every ache, pain, or numb feeling is DPN. It should not be
confused with numbness on one side only, as it most often presents
bilaterally (on both sides of the body) and tends to start in areas
farthest from the heart, i.e., in the toes, feet and fingers. If you
have one-sided symptoms, it is more likely a pinched nerve, sprained
or strained muscle, tendon or ligament, carpal tunnel or something
else completely unassociated with diabetes. It could also be a
symptom of a blocked blood vessel, which is a potentially life
threatening condition. Only your doctor can diagnose the cause, so it
is wise to seek medical attention as soon as possible. You might have
to visit a neurologist for specialized tests described below.

Causes of DPN
The current theory seems to be that there are two potential causes
DPN. They are Advanced Glycation Endproducts [AGE] and what is being
called "Oxidative Stress."

Glycation is the attachment of glucose. AGEs are the result of the
glycation of proteins, a particular problem in diabetics due to our
hyperglycemia. Like the glycation of hemoglobin (measured as HbA1c)
or the glycation of albumin (measured as fructosamine), other
proteins can become glycated. One course of study centers around the
glycation of lipoproteins, like HDL, LDL, and triglycerides. It is
thought that this glycation makes the proteins sticky, causing
aggregation in the blood vessels, and hence the formation of plaque
in the arteries, and the subsequent increased cardiac risk. Since it
is believed that a major contributor to this process is free
radicals, the use of antioxidants is being studied to scavenge the
free radicals.

Oxidative Stress is thought to be part of the process related to
diabetic neuropathy and retinopathy. Again, the free radicals
apparently cause damage to the vessels and nerves. There is still
much research to be done, and we do not have all the answers yet, but
even the most pessimistic should agree that this line of research has
potential.

Symptoms of DPN

Most diabetics who are experiencing DPN have shooting pains, burning
pains, hyper-sensitivity, or numbness in their toes and feet.
Untreated, this can eventually spread up the legs and also cause
similar symptoms in the fingers and hands. Some report that they feel
like they are wearing socks when they aren't, or that they feel a non-
existent fold or crease in the socks they are wearing.

Testing for DPN

Common tests for DPN can be carried out in your doctor's office using
two simple tools: monofilament, and a tuning fork. Monofilament is a
short piece of common fishing line. By using a specific length of a
specific diameter of monofilament, your doctor will touch the skin of
your toes and feet and ask you when you feel the touch. Similarly,
the doctor will strike the tuning fork to start it vibrating and hold
it to your foot, asking you to report when you can no longer feel the
vibration. Depending on your doctor's interpretation of these tests,
you may be referred to a neurologist for additional testing.

A neurologist will probably want to do two somewhat more complex
tests, called NCV and EMG. Nerve conduction velocity (NCV) tests the
speed of conduction of impulses through a nerve. The nerve is
stimulated, usually with patch-like electrodes on the skin (similar
to those used for ECG) over the nerves at various locations. One
electrode stimulates the nerve with a very mild electrical impulse.
The resulting electrical activity is recorded by the other
electrodes. The distance between electrodes and the time it takes for
electrical impulses to travel between electrodes are used to
calculate the nerve conduction velocity.

The second test is called Electromyography (EMG). For an EMG, a
needle electrode is inserted through the skin into the muscle. The
electrical activity detected by this electrode is displayed on an
oscilloscope, and may be heard through a speaker.

After placement of the electrodes, you may be asked to contract the
muscle (for example, by flexing your foot). The presence, size, and
shape of the wave form produced on the oscilloscope provide
information about the ability of the muscle to respond when the
nerves are stimulated.

Treatment of DPN

The first, best, and most important step in treating DPN is to
reestablish normal blood sugars.
In addition, your doctor has pharmaceutical tools, such as small
doses of tri-cyclic antidepressants like amitriptyline, or the more
potent anti-seizure meds like Tegetrol (carbamazepine), Dilantin
(phenytoin), and Neurontin (gabapentin). These will mask the
symptoms, but do nothing to address the underlying pathology.

Another approach attempts to treat the underlying causes of DPN,
i.e., Advanced Glycation Endproducts and Oxidative Stress through the
use of antioxidants, specifically Alpha Lipoic Acid, which is also
known as Thioctic Acid, and Gamma Linolenic Acid. Probably the most
leading-edge work is being done in Germany, and has been reported in
the DEKAN Study (see footnote below).

The DPN Cocktail

The following is a recommendation for treatment of DPN by use of anti-
oxidants, and is based on the research of Stan Angilley. It has been
used successfully by many diabetics to reduce or even eliminate DPN.
Before starting on this regimen, you should discuss it with your
doctor, as you may have other medical issues which would
contraindicate its use. It is likely that your doctor will have heard
little or nothing about this approach, so we have provided citations
to applicable literature below.

The DPN cocktail has three components: Alpha Lipoic Acid (ALA), Gamma
Linolenic Acid (GLA) as contained in Evening Primrose Oil (EPO), and
Vitamin C. These components are available from many sources,
including pharmacies, health food stores, and over the internet. The
ALA component is somewhat expensive, so we will provide some internet
sources that many have used successfully. We have no profit motive
here, and suggest that you research sources to find your best buy.
The unique properties of the components make this cocktail
synergistic, in other words, the parts work together to reinforce and
replenish each other.

Alpha Lipoic Acid (ALA), also known as thioctic acid, has a short
plasma half-life of about 30 minutes. It is also both water and fat
soluble, which assists in its transport in the body. It also isn't
cheap, so to get the maximum benefit use only Extended Release
versions. This used to limit you to formulations from the Lipoic
Foundation and Jarrow. Nowadays, it is made by a couple of others.
ALA is a sulfur based compound, so expect your urine to have a sulfur
smell. ALA is also known to assist in the reduction of blood
glucose, likely by decreasing peripheral insulin resistance. You
should carefully monitor its effect on your BG to avoid potential
hypos.

Gamma-linolenic acid (GLA) is an n-6 (omega-6) polyunsaturated fatty
acid commonly contained in Evening Primrose Oil (EPO) and Borage Oil
(BO). EPO typically contains more GLA than BO. Depending on the
method of extraction from the plants, EPO can contain varying amounts
of GLA. Buy a brand of EPO that contains at least 10% GLA. For
example, choose a 1300mg EPO tablet that contains at least 130mg of
GLA.

The last component is Vitamin C. There is nothing special required in
selecting a specific form of Vitamin C, so you can choose generic,
Rosehips, or Ester C.

The components of the cocktail are:

300mg Slow Release Alpha Lipoic Acid
1300mg Evening Primrose Oil
500mg Vitamin C
Starting off, take one cocktail morning and night. After you get
relief from the neuropathy feelings, you should be able to reduce
this to a maintenance dose of once a day. Most report improvements in
DPN after about 3 months of use. Some report stomach upset from the
cocktail, so taking it with a meal may help. No other serious adverse
reactions have been reported.

Again, we have no vested interest in where you get the components.
Here are several internet sources should you have difficulty in
obtaining them from your local pharmacy or health food store. Prices
change, so research your best buy.

iHerb
Vitamin Shoppe
Puritan's Pride
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Citations to Literature for Your Skeptical Doctor
http://www.medscape.com/viewarticle/547879

Alpha-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy

Diabetes Care 2006;29:2365-2370.

Alpha-lipoic acid (ALA) given orally improves symptoms in patients
with diabetic polyneuropathy, according to a report in the November
issue of Diabetes Care.

A recent meta-analysis showed that daily intravenous treatment with
ALA could reduce pain, paresthesia, and numbness in diabetic
patients, the authors explain, but little work has been done to
investigate the use of oral ALA.

Dr. Dan Ziegler from Heinrich Heine University, Duesseldorf, Germany
and colleagues compared three doses of oral ALA to placebo in 166
patients with symptomatic diabetic polyneuropathy.

Mean total symptom scores and stabbing/lancinating and burning pain
subscores were significantly reduced after 5 weeks in all active
treatment arms compared with the placebo arm, the authors report.

ALA treatment had no measurable effect on paresthesia and numbness,
the results indicate.

Symptoms improved significantly as early as 1 week with the highest
ALA dose (1800 mg daily) and within 2 weeks with the other doses (600
mg and 1200 mg daily), the researchers note, and there were no
significant differences among the three ALA groups for changes in
mean total symptom score at any time point.

The findings were similar when Neurology Symptoms and Change Score
was used instead of mean total symptom score, the report indicates.

Nausea, vomiting, and vertigo were more common with ALA treatment
than with placebo treatment, the investigators say.

"Whether the observed favorable short-term effect of ALA on
neuropathic symptoms and deficits can be translated into slowing the
progression of diabetic polyneuropathy in the long term is unknown,"
the authors write. "However, our finding that neuropathic deficits
such as impaired sensory function were improved is encouraging,
because these are major risk factors in the development of
neuropathic foot ulcers."

"In the absence of a dose response and because the higher doses
resulted in increased rates of gastrointestinal side effects, 600 mg
once daily seems to be the most appropriate oral dose," the
researchers add.


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http://tinyurl.com/ofqag

Effects of treatment with the antioxidant alpha-lipoic acid on
cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized
controlled multicenter trial (DEKAN Study). Deutsche Kardiale
Autonome Neuropathie.

Ziegler D., Schatz H, Conrad F., Gries FA, Ulrich H, Reichel G
Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat,
Dusseldorf, Germany.

OBJECTIVE: To evaluate the efficacy and safety of oral treatment with
the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with
cardiac autonomic neuropathy (CAN), assessed by heart rate
variability (HRV). RESEARCH DESIGN AND METHODS: In a randomized,
double-blind placebo-controlled multicenter trial (Deutsche Kardiale
Autonome Neuropathie [DEKAN] Study), NIDDM patients with reduced HRV
were randomly assigned to treatment with daily oral dose of 800 mg
ALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at
rest included the coefficient of variation (CV), root mean square
successive difference (RMSSD), and spectral power in the low-
frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.15-0.5 Hz)
bands. In addition, cardiovascular autonomic symptoms were assessed.
RESULTS: Seventeen patients dropped out of the study (ALA n = 10;
placebo n = 7). Mean blood pressure and HbA1 levels did not differ
between the groups at baseline and during the study, but heart rate
at baseline was higher in the group treated with ALA (P < 0.05).
RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1)
[median (minimum-maximum)] in the group given ALA and decreased by -
0.1 ms (-19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs.
placebo). Power spectrum in the LF band increased by 0.06 bpm2 (-0.
09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (-0.48 to 1.86)
in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a
trend toward a favorable effect of ALA versus placebo for the CV and
HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo).
The changes in cardiovascular autonomic symptoms did not differ
significantly between the groups during the period studied. No
differences between the groups were noted regarding the rates of
adverse events. CONCLUSIONS: These findings suggest that treatment
with ALA using a well-tolerated oral dose of 800 mg/day for 4 months
may slightly improve CAN in NIDDM patients.




http://www.mayoclinic.org/news2003-rst/1733.html

Mayo Clinic in Rochester

Monday, April 07, 2003

Antioxidant Alpha Lipoic Acid (ALA) Significantly Improves Symptoms
of Diabetic Neuropathy

ROCHESTER, Minn. -- A collaborative study between Mayo Clinic and a
medical center in Russia found that alpha lipoic acid (ALA)
significantly and rapidly reduces the frequency and severity of
symptoms of the most common kind of diabetic neuropathy. Symptoms
decreased include burning and sharply cutting pain, prickling
sensations and numbness.

The findings appear in the March 2003 issue of Diabetes Care,
http://care.diabetesjournals.org/.



Diabetes 1997 Sep;46 Suppl 2:S62-6
Alpha-lipoic acid in the treatment of diabetic peripheral and
cardiac autonomic neuropathy.

Ziegler D, Gries FA Diabetes Research Institute at the Heinrich
Heine University,
Dusseldorf, Germany.


Antioxidant treatment has been shown to prevent nerve dysfunction in
experimental diabetes, providing a rationale for a potential
therapeutic
value in diabetic patients. The effects of the antioxidant alpha-
lipoic
acid (thioctic acid) were studied in two multicenter, randomized,
double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in
Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic
peripheral neuropathy were randomly assigned to treatment with
intravenous infusion of alpha-lipoic acid using three doses (ALA
1,200
mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom
score (TSS) (pain, burning, paresthesia, and numbness) in the feet
decreased significantly from baseline to day 19 in ALA 1,200 and ALA
600
vs. PLAC. Each of the four individual symptom scores was
significantly
lower in ALA 600 than in PLAC after 19 days (all P < 0.05). The total
scale of the Hamburg Pain Adjective List (HPAL) was significantly
reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days
(both
P < 0.05). In the Deutsche Kardiale Autonome
Neuropathie Studie, patients with NIDDM and cardiac autonomic
neuropathy diagnosed by reduced heart rate variability were randomly
assigned to treatment with a daily oral dose of 800 mg alpha-lipoic
acid
(ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four
parameters of heart rate variability at rest were significantly
improved
in ALA compared with placebo. A trend toward a favorable effect of
ALA
was noted for the remaining two indexes. In both studies, no
significant
adverse events were observed. In conclusion, intravenous treatment
with
alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in
reducing symptoms of diabetic peripheral neuropathy, and oral
treatment
with 800 mg/day for 4 months may improve cardiac autonomic
dysfunction
in NIDDM.
PMID: 9285502, UI: 97429864




J Neural Transm 1998;105(8-9):1005-15
Cytotoxicity of advanced glycation endproducts is mediated by
oxidative stress.


Loske C, Neumann A, Cunningham AM, Nichol K, Schinzel R, Riederer P,
Munch G
Physiological Chemistry I, Biocenter, Wurzburg, Federal Republic of
Germany.
Non-enzymatic glycation of proteins with reducing sugars and
subsequent
transition metal catalysed oxidations leads to the formation of
protein
bound "advanced glycation endproducts" (AGEs). They accumulate on
long-lived proteins and are for example structural components of the
beta-amyloid plaques in Alzheimer's disease. Since the oxidation of
glycated proteins as well as the interaction of AGEs with cell
surface
receptors produces superoxide radicals, it was tested in BHK 21
hamster
fibroblast cells and SH-SY5Y human neuroblastoma cells if AGEs can
exert
cytotoxic effects on cells. Cell viability was assessed with three
independent tests: MTT-assay (activity of the mitochondrial
respiratory
chain), lactate dehydrogenase assay (release of cytoplasmatic
enzymes,
membrane integrity) and Neutral Red assay (active uptake of a
hydrophilic dye). Two model AGEs, chicken egg albumin-AGE and BSA-
AGE,
both caused significant cell death in a dose-dependent manner. The
cytotoxic effects of AGEs could be attenuated by alpha-ketoglutarate
and
pyruvate, by antioxidants such as thioctic acid and N-acetylcysteine,
and by aminoguanidine, an inhibitor of nitric oxide synthase. This
suggests that reactive oxygen species as well as reactive nitrogen
species contribute to AGE mediated cytotoxicity. Since AGEs
accumulate
on beta-amyloid plaques in AD over time, they may additionally
contribute to oxidative stress, cell damage, functional loss and even
neuronal cell death in the Alzheimer's disease brain.
PMID: 9869332, UI: 99084677




http://www.medscape.com/viewprogram/705


Oxidative stress, caused by enhanced free radical synthesis, may play
an important role in contributing to the pathogenesis of diabetic
neuropathy.[19,20,30]
Alpha-lipoic acid (ALA) is a potent lipophilic free-radical scavenger
that has demonstrated effectiveness in preventing neuropathic
abnormalities in animal models of diabetes.[87-89]

In the limited clinical trials published so far, ALA administration
has yielded small but significant improvements
in neuropathic pain and heart rate variability.[90,91]


87.Nagamatsu M, Nickander KK, Schmelzer JD, et al:
Lipoic acid improves nerve blood flow, reduces
oxidative stress, and improves distal nerve conduction
in experimental diabetic neuropathy. Diabetes Care
18:1160-1167, 1995.
88.Garrett NE, Malcangio M, Dewhurst M, et al:
Alpha-lipoic acid corrects neuropeptide deficits in
diabetic rats via induction of trophic support. Neurosci
Lett 222:191-194, 1997.
89.Hounsom L, Horrobin DF, Tritschler H, et al: A lipoic
acid-gamma linolenic acid conjugate is effective
against multiple indices of experimental diabetic
neuropathy. Diabetologia 41:839-843, 1998.
90.Ziegler D, Schatz H, Conrad F, et al: Effects of
treatment with the antioxidant alpha-lipoic acid on
cardiac autonomic neuropathy in NIDDM patients.
Diabetes Care 20:369-373, 1997.
91.Ziegler D, Gries FA: Alpha-lipoic acid in the treatment
of diabetic peripheral and cardiac autonomic
neuropathy. Diabetes 46(Suppl. 2):S62-S66, 1997.




http://www.medscape.com/medscape/CNO/1999/EASD/EASD-08.html
The Role of Oxidative Stress in Diabetes-Related Tissue Injury


Experimental research is focusing more and more on oxidative
stress
as an important pathogenetic factor in diabetes-related tissue
injury.
However, the methods to detect increased oxidative stress in
specific sites of diabetic complications, such as the eye, have
yielded
conflicting results. Dr. Obrosova from the University of Michigan,
Ann
Arbor, used a new quantitative method specific for malondialdehyde
and
4-hydroxyalkenals (4-HA) to evaluate the level of oxidative stress in
retinae from diabetic rats.[4] This study also included measurements
of
several oxidative defense systems such as reduced and oxidized
glutathione, superoxide dismutase (SOD), and others.


Early in the disease, the main unsaturated lipid aldehydes
accumulating
in diabetic retinae were 4-HA. In addition, SOD was depleted. Of
significance, these changes were prevented by the antioxidant
DL-alpha-lipoic acid, presumably by free-radical scavenging and
upregulation of SOD. These data show that specific lipid peroxidation
products are early markers of oxidative stress in the diabetic retina
and point to the early involvement of specific antioxidant defense
systems as a possible new therapeutic approach.


4.Fathallah L, et al. Accumulation of 4-Hydroxyalkenals is an early
marker of oxidative stress in the diabetic retina. Program and
abstracts
of the 35th Annual Meeting of the European Association for the Study
of
Diabetes; September 28-October 2, 1999; Brussels, Belgium. Abstract
37.




Modulation of cellular reducing equivalent homeostasis by alpha-
lipoic acid. Mechanisms and implications for diabetes and ischemic
injury. (Roy S; Biochem Pharmacol, 1997 Feb 7)


The effect of alpha-lipoic acid on the neurovascular reflex arc in
patients with diabetic neuropathy assessed by capillary microscopy.
(Haak ES; Microvasc Res, 1999 Jul)




Alpha-lipoic acid: antioxidant potency against lipid peroxidation of
neural tissues in vitro and implications for diabetic neuropathy.
(Nickander KK; Free Radic Biol Med, 1996)




Effects of alpha-lipoic acid on neurovascular function in diabetic
rats: interaction with essential fatty acids. (Cameron NE;
Diabetologia, 1998 Apr)




Stimulation by alpha-lipoic acid of glucose transport activity in
skeletal muscle of lean and obese Zucker rats. (Henriksen EJ; Life
Sci,
1997)




Differential effects of lipoic acid stereoisomers on glucose
metabolism
in insulin-resistant skeletal muscle. (Streeper RS; Am J Physiol,
1997
Jul)




alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B
signal transduction and protects against oxidative injury. (Packer L;
Drug Metab Rev, 1998 May)




Diabetes-induced changes in lens antioxidant status, glucose
utilization
and energy metabolism: effect of
DL-alpha-lipoic acid. (Obrosova I; Diabetologia, 1998 Dec)




Alpha-lipoic acid reduces expression of vascular cell adhesion
molecule-1 and endothelial adhesion of human monocytes after
stimulation
with advanced glycation end products. (Kunt T; Clin Sci (Colch), 1999
Jan)




Advanced glycation end product-induced activation of NF-kappaB is
suppressed by alpha-lipoic acid in cultured endothelial cells.
(Bierhaus
A; Diabetes, 1997 Sep)




Effects of diabetes and treatment with the antioxidant alpha-lipoic
acid
on endothelial and neurogenic responses of corpus cavernosum in rats.
(Keegan A; Diabetologia, 1999 Mar)

Alpha-lipoic acid: effect on glucose uptake, sorbitol pathway, and
energy metabolism in experimental diabetic neuropathy. (Kishi Y;
Diabetes, 1999 Oct)

alpha-Lipoic acid decreases oxidative stress even in diabetic
patients
with poor glycemic control and albuminuria. (Borcea V; Free Radic
Biol
Med, 1999 Jun)

Derek
www.diabetescommunity.org.uk