Diabetic Neuropathy.Diabetic neuropathy, a common complication of diabetes, that is associated with many uncomfortable sensations, such as pain. There are a number of ways that diabetes damages the nerves, and they all seem related to blood glucose being too high for a long period of time. Diabetes-related nerve damage can be painful, but in most cases, it isn’t severe. Approximately twenty million Americans have diabetes mellitus. Eighty percent of all diabetics will die from cardiovascular complications. Sixty to seventy percent of patients with diabetes have complications that include one or more of the following: Neuropathy (nerves) Retinopathy (eyes) and/or Nephropathy (kidneys). Among the most serious complication is the Peripheral and Autonomic Neuropathy: Cardiac autonomic neuropathy is an independent risk factor for cardiovascular disease. Peripheral Neuropathy is the leading cause of limb amputation in the United States. Other consequences of Neuropathy include among others:
WHAT INSPIRED TO CREATE DHVWe wish our story was more like the famous Sir Alexander Fleming that discovered the antibiotic substance penicillin (from the fungus Penicillium notatum in 1928, due to an accident with a culture of Staphylococcus contaminated with the famous mold). But, this is not our case. Our story dates back to 1996 when we became aware of the struggles that all Doctors were having trying to alleviate the pain, discomfort, infections, and, amputations of patients with diabetic neuropathy. Being a son and brother to diabetic patients suffering from severe neuropathy, a Board Certified Endocrinologist studied in depth the causes of neuropathy, which are categorized in three hypotheses.
With the vascular hypothesis the most important issue is the ischemic disease of arterioles. In the axonal hypothesis you see structural degeneration (Myelin). So why do you obviously have these problems? It stands to reason then, that it must be all the metabolic effects of the diabetes. The first conclusion to come to his mind was the Myo-inositol content of nerves, but further studies revealed no decrease of myo-inositol in the sural nerves in diabetic patients. Then, it was found that the Sorbitol content of nerves is inversely related to the number of myelinated fibers. There were several studies conducted with aldose reductase inhibitors to inhibit polyol accumulation in tissues (Epalrestat, Sorbiniyl). This however, didn’t work. Another mechanism is the oxidative stress, enhanced oxidative stress resulting from an imbalance between production and neutralization of reactive oxygen species (ROS) and is a well-recognized mechanism in the pathogenesis of diabetic neuropathy. The role for ROS in diabetes-associated nerve blood flow and conduction deficits has been demonstrated in studies with alpha lipoic acid which is known to combine free radical and metal–chelating properties with the ability to regenerate levels of other antioxidants like gluthatione (GSH). Finally, the vascular mechanism where there is a role for the nerve blood flow thru the destruction of the vasa nervorum. This was found in the study using Hydroxyethyl stach-deferoxamine (HESD) which is confined to vascular space when administered intravenously. HESD reversed NBF and nerve conduction deficits. Therefore, with this finding, he looked for a substance that increased micro-vascularization which is prostaglandin E. The source of prostaglandin is Gamma linolenic acid. Combining these two substances, alpha lipoic acid and gamma linolenic acid, is the core for the current life-changing invention (Patent Pending in Washington). As a secondary benefit, he included Chromiun, B12 and Folic Acid to enhance the insulin receptor with Chromium to enhance the insulin receptor, but in no way to replace the diabetic medications. The Study.Use of Alphalipoic acid and Gammalinolenic acid in diabetic neuropathy, October 9, 2007.There are approximately 20 million people with Diabetes Mellitus in the United States and according to the world health organization is estimated that there is a prevalence of 189 million sufferer’s world-wide. The incidence of diabetic Neuropathy is present in approximately 40% to 60 % of the entire diabetic population with 60% of this number symptomatic. (2) The pathogenesis of the neuropathy is a microscopic vasculitis and subsequent ischemia or infarction of the nerve. Focal ischemia results in segmental Demyelination followed by remyelination. In diabetic patients, remyelination is defective and delays the repair of focal deficits. Delayed remyelination may be a consequence of diabetes-induced Schwann cell dysfunction. (1) In the case of the Distal Symmetrical polyneuropathy (DSPN) there are several hypotheses. The prevailing theory is that persistent hyperglycemia is the primary factor. The gluco-toxicity may cause a metabolic defect that includes alteration of the polyol or sorbitol pathway, lipid metabolism, deficiencies of dihomogammalinolenic acid (GLA) and carnitine glycation or AGE formation. It increases oxidative stress and growth factor defects. Histopathologic studies show the presence of different degrees of endoneuria and epineuria microvasculopathy, mainly vessel basement membrane thickening and obstruction of vasa nervorum. One of the complications of diabetes neuropathy is neuropathic foot ulceration, 83% of the 120,000 non-traumatic lower extremity amputations performed each year in the United States, involve persons with diabetes(2). Post amputation mortality rates associated with diabetes are worse than cancer, ranging from 13 to 40% after 1 year and 35 to 65% after 3 years (3). There is no treatment per se for neuropathy except for partial improvement of painful neuropathy. Among these treatments include triclyclic antidepressants, anticonvulsant, and just recently the FDA has approved the use of SSRI. Obviously this medication may cause mild and serious adverse reactions that are well published. Alpha lipoic acid (Thioctic acid), a derivative of cotanoic acid, is present in food and is also synthesized in the liver, and is a natural cofactor in the pyruvate dehydrogenase. It has proved effective in ameliorating the somatic and autonomic neuropathies in Diabetes Mellitus. Gamma-Linolenic Acid is an essential fatty acid that is metabolized to GLA, which serves as an important constituent of neuronal membrane phospholipids and also as a substrate for prostaglandin formation, seemingly important for preservation of nerve blood flow. In diabetic patients, conversion of gamma-linoleic acid to gamma-linolenic acid and subsequent metabolite is impaired, this substance has demonstrated significant improvements in both clinical and electrophysiological tests. The present study tests the use of alpha-lipoic acid and gamma-linolenic acid for the improvement of the neuropathy with symptoms. Methods Used.20 patients were studied during the period of January 2004 through March 2005. For 4 weeks, 10 patients were assigned in open label a placebo and 10 to alphalipoic 500 mg and Borage Oil 500mg equal to 200mg of gamma linolenic acid (GLA). This combination is marketed as (DHV). Neuropathic symptoms (4) were scored at baseline and day 28 as total diabetes neuropathy symptom score (DNS) and measurements with biothesiometer. The placebo patient also received a combination of Folic Acid with Vitamin B6 and B12. Statistics.Results were analyzed using the Chi Square with one degree of freedom. Study Results.All the demographics at the entrance were similar. The total DNS at baseline for the Placebo patients was 83 and the score for patients assigned DHV was 86. At the re-assessment in 4 weeks the total score for Placebo and DHV was 90 and 41 respectively, this is a 55% decrease in symptoms with a P: <0.01. The average Diabetic Neuropathic score was 8.3 in the placebo and the DHV assigned group 8.6 at baseline screening. Four weeks later the average in the placebo patients was 9.0 whereas in the DHV patient, it was 4.1 points. See picture # 1: 
In the Biothesiometer measurement there was a total patient–score at baseline of 401 in the patients allocated a placebo and 414 in the patients allocated to DHV. Four weeks later, the patient-score allocated to a placebo and DHV was 405 and 343 respectively, this significant 15% improvement in the threshold for vibratory sensation with a P: <0.05. The average measurement in biothesiometer was in the placebo patients 40.1 and in the DHV assigned patient it was 40.4 but after 4 weeks the average measurement in the placebo patient was 40.5 whereas in the DHV assigned it was 34.3 See picture # 2:  Study Conclusions.The study of 20 patients showed statistical significance in the improvement of the symptoms and neurophatic deficits measured by the biothesiometer. Other studies like the SIDNEY (5), ALADIN III (6), and DEKAN (7) have shown to be beneficial in the improvement of the symptoms of neuropathy. This study has also shown a significant statistical improvement in the nerve conduction that was measured by biothesiometer measurements. The combination of Alphalipoic acid and Gammalinolenic acid are beneficial for the diabetic Neuropathy. Study References.1.William’s textbook of endocrinology tenth edition 1542-1543. 2.Moaz Mojaddidi; Current diabetes report Vol. 5 number 6; 423-427. 3.Reiver GE; epidemiology of foot ulcers and amputation in the diabetic foot. The diabetic foot Mosby; 2001; 13-32. 4.Meijer JWG, Diabic Neuropathic Score; Diabetes Medicine, 19:962-5. 5.Ametov A; the SYDNEY Study. The sensory symptoms of diabetic polyneuropathy are improved with alphalipoic acid. Diabetes Care 2003; 26; 770-776. 6.Ziegler D treatment of symptomatic diabetic polyneuropathy with the antioxidant (ALADIN III). Diabetes Care 22; 1999; 1296-1301. 7.Ziegler (Deutche Kardiale Autonome Neuropathy). Diabetes Care 20; 369-373, 1997. Benefits of DHVDHV - Neuropathy Care combines:
The benefits of DHV are:
Other references:1. ALADIN I (ALPHA-LIPOIC ACID IN DIABETIC NEUROPATHY) IV infusion of Thioctic Acid (TA) (Alpha lipoic acid) IV infusion of TA in 382 Type II Diabetic patients. Total symptoms Score in the feet decreased from baseline to day 19 by -4.5(48%) points in the group receiving TA 1200mg). -5.0(63.5%) points in the group receiving TA600mg) and -3.3(43%)in the group receiving TA 100mg whereas the group receiving placebo had a -2.2(38.4%) the pain score was significantly reduced. 2. ALADIN III STUDY Dan Ziegler Diabetes Care, Volume 22, Number 8, August 1999. Multicenter randomized double-blind 509 patients were enrolled. One group received Intravenous Alpha lipoic acid 600mg a day for three weeks, followed by 600mg three times a day for 6 months (167 patients). The second group received alpha-lipoic acid 600mg intravenously a day followed by a placebo PO three times a day for six months (174). And the last group took a placebo IV for three weeks and then a placebo orally three times a day for 6 months (168). Total symptom Score decreased by 3.7 points in the group that received IV and -3.0 in the placebo. After 7 months the three groups were equal due to symptom scoring assessing variability. 3. DEKAN (Deutsche Kardiale Autonome Neuropathie) STUDY - Dan Ziegler Cardiac autonomic dysfunction has a 2 to 5 increase in the risk or mortality including sudden death. 800mg/day (39 patients) (34 patient- placebo) of Alpha lipoic acid showed favorable effect on TA. 4. OPRIL Study Hermann et al.,1996 24 patient received either 600mg three times a day or a placebo for 3 weeks decreased -3.7 in the TA group and -1.94 in the placebo group. 5. Sydney Study Diabetes Care 29; 2365-2370 Dan Ziegler 181 Diabetic patient in Russia and Israel received once-daily oral doses of 600mg (=45) 1,200mg (n=47) 1800mg (n=46) Placebo (n=43). The study was conducted for 5 days and it showed an average decrease of 4.9 points (51%) ,4.9in group that received 1200 and 4.7 in the 1800 whereas there was a 2.9 pints decrease in the placebo group the dose of 600mg a day appeared optimum. Go to the Sydney Study Diabetes Care website 6. The γ linolenic acid multicenter trial group Diabetes Care Vol. 16 8-15 1993 Harry Keen et al. Randomized double-blind, placebo-controlled study 111 diabetic patient with mild diabetic neuropathy from seven center were enrolled. Received 480 mg/day. Isometric muscle strength was assessed together with thermal threshold tester, and sensation of vibration with a pinprick touch and tuning fork in the index finger and the lower extremities. The result was statistically beneficial in favor of γ linolenic acid. Go to the Gamma-Linolenic Acid Multicenter Trial Group website |
