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.

Citations to Literature for Your Skeptical Doctor


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.


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.


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
 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
 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


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.

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,

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

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

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)

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)



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