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Diabetic nerve pain reduced with enzyme and vitamin combination

Nikki Hancocks

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Daily supplementation with a combination of Superoxide Dismutase, Alpha Lipoic Acid, Acetyl LCarnitine, and Vitamin B12 (B12) can help improve with symptoms of diabetic nerve damage, according to a new study

27/10/2020- Nutraingredients

Daily supplementation with a combination of Superoxide Dismutase, Alpha Lipoic Acid, Acetyl LCarnitine, and Vitamin B12 (B12) can help improve with symptoms of diabetic nerve damage, according to a new 18-month study of 85 diabetic patients.

One of the most common and costly microvascular complications of diabetes mellitus (DM) is diabetic neuropathy (DN). The most common forms of DN are diabetic distal symmetrical sensorimotor polyneuropathy (DPN) and diabetic autonomic neuropathy (DAN).

At least 50% of patients with Diabetes Mellitus Type 2 (DMT2) and up to 59% of DM type 1 develop DPN. Sadly, approximately 30% of patients develop Painful Diabetic Neuropathy (PDN) with neuropathic pain and symptoms like burning, needles, cold, or heat cramps, electric shock, weakness, and allodynia. Long-term strict glycemic control is shown to delay the progression of DN in DMT1 patients, but in DMΤ2 patients the effects are modest and several drugs have been suggested but without high efficacy. 

The mechanisms underlying the development of DN remain unknown but long-standing hyperglycemia is the main key factor because of the metabolic alterations it induces, such as increased polyol flux, which leads to accumulation of advanced glycation end products, oxidative stress, and lipid disorders.

The duration of DM and cardiovascular risk factors (hyperlipidemia, smoking, hypertension, and obesity) play a significant role and alterations of microvessels, similar to those observed in diabetic retinopathy and nephropathy appear to be associated with the pathologic alterations of nerves. 

Superoxide Dismutase (SOD) and A-Lipoic acid (ALA) exert an antioxidant action, SOD by preventing formation of free radicals, and ALA by removing already formed free radicals. N-acetyl-carnitine (ALC) is believed to have a neurotrophic action. In addition, vitamin B12 (B12) levels are often low in DM patients, due to metformin treatment as the first-line agent of diabetes treatment.

In particular, metformin is associated with a low concentration of B12 and a higher risk of B12 deficiency, but the exact mechanism remains elusive.  
Researchers therefore undertook the present study to investigate the efficacy of a new combination of these four elements - SOD 10mg, ALA 570 mg, ALC 300mg, and B12 250mcg - in one daily tablet, in DN in patients with DMT2, and generalised neuropathy who have received metformin for at least four years.

This is the first placebo-controlled randomised, double-blind trial of a tablet containing the combination of ALA, SOD, B12, and ALC as a food supplement that investigated the efficacy of the tablet on all three major forms of chronic generalized DN, i.e., peripheral sensorimotor neuropathy, autonomic neuropathy, and painful neuropathy. 

The team hypothesised that by acting at different metabolic key points these four elements could work synergistically and thereby be more effective in treating DN in patients with DMT2.

A sample of 85 patients with Diabetes Mellitus Type 2 (DMT2) were randomly assigned, either to receive the combination of four elements (active group, n = 43), or placebo (n = 42) for 12 months. 

The Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE) was used to measure the vibration perception threshold (BIO) and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN to check sural nerve conduction velocity (SNCV) and amplitude (SNAP), plus pain (PS) and quality of life (QL) questionnaires were administered.

The resulting data revealed that BIO, MNSIQ, QL, PAIN, and SNCV, SNAP, and B12 levels significantly improved in the active group (p <0.001, p <0.001, p <0.001, p <0.001, p = 0.027, p = 0.031, and p

The authors conclude that the combination of the four elements in one tablet for 12 months improved all indices of peripheral neuropathy, including SNAP and SNCV, pain, and Quality of Life perception, except CARTs and MNSIE.

The authors note the relevance of this study: "Compared to other studies, the patients in our study had relatively good glycemic control at the beginning of the trial and maintained good control during the entire follow-up period, whereas in most other studies glycemic control was poor at the baseline and improved to suboptimal level during the course of the study.

"It follows, that in these studies, the pure efficacy of the investigated drug or substance on DN remained somehow uncertain. Another major limitation of these studies was that they did not examine concurrently in the same patient DPN, DAN, and neuropathic pain, as we did."

Noted limitations of the study include that all patients originated from one diabetes center which does not allow for extrapolation of the results to other populations. The team also only measured sural nerve and not other nerve conduction velocity and amplitude, although the researchers did this because they state is is widely accepted that sural nerve velocity is also representative of other nerves.

They did not measure methylomalonic acid and homocysteine, which are associated with vitamin b12 deficiency. The report explains this was because these are more specific and expensive markers are not always available in every-day clinical practice and are shown to not be necessarily needed for the diagnosis of vitamin B12 deficiency.

Prior studies

Acetyl L-Carnitine is the acetyl ester of L-carnitine which is synthesised in the human brain, liver, and kidney from lysine and methionine, or is taken-up through the diet. It has been proposed for the treatment of DN due to its analgesic action mediated by reducing the concentration of glutamate in synapses.

It has also demonstrated cytoprotective antioxidant and antiapoptotic effects in the nervous system. In a meta-analysis of four RCTs with 523 patients, ALC was shown to significantly reduce neuropathic pain. ALC 500 mg or 1000mg three times per day improved pain estimation and vibration perception threshold after one year, both in DMT1 and DMT2 patients.

The dose of 500 mg was shown to increase fiber numbers and regenerate nerves to a significantly higher extent compared to 1000mg, but without improving velocity and amplitude. In another study, ALC had beneficial action to DPN over 24 weeks, with an equal strong effect as methylocobalamin.

SOD is a metalloenzyme which appears to have a potential antioxidant action through the neutralization of superoxide. Superoxide is thought to be overproduced due to hyperglycemia and leads to oxidative stress, which in turn contributes to the development of DSPN. Experimental data show an association between low levels of SOD and the progression of DN.

SOD3 levels that are produced as a response to inflammatory cytokines are inversely associated with premature sensory and motor nerve conduction changes in patients with DM type 1 and recently diagnosed DM type 2 with DSPN.

ALA is a medium chain fatty acid, naturally derived from plants and animal with potential antioxidant action. The Neurological Assessment of Thioctic Acid in Diabetic Neuropathy trial (NATHAN), the longest and largest multicenter, randomised, double-blind, parallel-group trial in patients with uncontrolled diabetes and DPN, showed a favourable effect of a daily dose of 600 mg ALA orally for four years on neuropathic symptoms but not in conduction velocity. In a meta-analysis, 600 mg ALA either orally or intravenously was shown to reduce significantly neuropathic symptoms.