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The naturopathic management of diabetic peripheral neuropathy.

Abstract and Objective

The purpose of this article is to help the reader understand and distinguish between positive and negative symptoms of patients suffering from diabetic peripheral neuropathy. A presentation of the disease description along with modifying versus symptomatic strategies in the management of diabetic peripheral neuropathy will be discussed. A major objective is to facilitate an understanding of the currently utilized diagnostic instrumentation and methods for determining diabetic peripheral neuropathy, including epithelial nerve density biopsy techniques and remittive therapy with oral nutraceuticals. The off-label use of metformin in the treatment of polycystic ovary disease and how it relates to peripheral neuropathy will also be discussed.

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The treatment of diabetic neuropathy brings to bear the principles of naturopathic philosophy: the "healing power of nature," to identify and treat the causes of disease by utilizing methods and medicine substances that minimize the risk of harmful effects, and apply the best intervention necessary to diagnose and restore health; and "do no harm."

When we think of the type 2 diabetic patient, naturopathic physicians see it as a multisystem disease for patients with diabetes. There are nearly 21 million people in the US who have diabetes, according to the Centers for Disease Control and Prevention (CDC). Approximately 6.2 million of these people are not aware that they have the disease. The CDC also estimates that over 40 million people have prediabetes, a condition that increases the risk of developing type 2 diabetes, and over 20% of adults 60 years of age and older have diabetes in the US. "Diabetes is the leading cause of adult blindness, limb amputation, kidney disease, and nerve damage," notes Frank Vinicor, director of the CDC's Diabetes Program. (1)

Type 2 diabetic patients present many challenges when it comes to managing the multisystem effects of diabetes. The diabetic patient population also presents a greater risk of complications due to vascular and neurological pathology directly attributed to diabetes.

There are a multitude of modalities in the armamentarium of the naturopathic physician for the treatment of these multiple organ system pathologies that are a result of the diabetic condition. Naturopathic physicians are familiar with the dietary management of diabetes utilizing the glycemic index and glycemic load of foods, along with appropriate exercise, to help maintain better blood sugar control for the type 2 diabetic (2)

Diabetes Care published a systematic review of the current literature on the efficacy and safety of herbal therapies and vitamin/mineral supplements for glucose control in patients with type 2 diabetes. (3-4) The authors concluded that the herbal extracts from Cocina indica and American ginseng showed good glycemic control results. Positive preliminary results from clinical trials demonstrated that extracts from Gymnema sylvestre, aloe vera, and vanadium were also helpful in reducing hyperglycemia.

A double-blinded, placebo-controlled balanced crossover study in the Swiss journal of Psycho-pharmacology (2005) demonstrated that taking 200 mg of Panax ginseng orally demonstrated a significantly reduced blood sugar levels for type 2 diabetic patients.

So we can see that there are multiple natural substances that have a positive effect on blood sugar. Elevated blood sugars directly correlate to the development of diabetic peripheral neuropathy.

I will discuss several evidence-based studies of innovative diagnostic techniques and therapies that I employ in my practice for the treatment of diabetic peripheral neuropathy.

What Does Conventional Medicine Use in the Treatment of Diabetic Peripheral Neuropathy?

There are many allopathic medical options available, such as Lyrica, Cymbalta, tricyclic antidepressants, and Neurontin, that have been utilized for the treatment of diabetic neuropathy with mixed clinical results. These typically prescribed medications have a plethora of adverse reactions, since the above medications have to be given over a prolonged period to achieve some type of positive clinical response.

Some of the more common side effects of the SSRI group of drugs are nausea, constipation, fatigue, somnolence, and the danger of the antidepressant activity, which may cause clinical worsening of depression, suicidality, and unusual changes in behavior, especially during the first few months of the course of the therapy for peripheral neuropathy. Often the side effects prevent continuation of the medication by the patient, thus causing a return of the painful symptoms of diabetic peripheral neuropathy. (5)

What is Diabetic Peripheral Neuropathy?

A consensus definition is the following: "The presence of symptoms and or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes." Diabetic neuropathy may occur in 50 to 90% of patients depending upon the criteria used for diagnosis.

For many years, the focus of our understanding of diabetic neuropathy was its relationship to hyperglycemia. We now know that with tight glycemic control there is a reduction in the incidence of neuropathy in type 1 diabetics. This is due in part to the fact that glucose is metabolized by the polyol pathway, which includes aldose reductase, an enzyme that converts it to a nonmetabolized sugar, sorbitol. Persistent hyperglycemia leads to an accumulation of sorbitol in the nerve, which alters nerve conduction. Another component contributing to peripheral neuropathy is nerve ischemia from the microvascular disease that is also present in diabetes types 1 and 2. This leads to increased oxidative stress in the nerve, with loss of neurotrophic support, immune stimulation, and altered protein synthesis. Sorbitol within the nerve also depletes myoinositol from the nerve membrane, leading to nerve injury and abnormal conduction. With the onset of hyperglycemia, the microvascular and nerve complications began both in the retinal vessels of the eye and the kidneys, resulting in retinopathy and nephropathy that we see with diabetes type 2. However, in macrovascular complications, including neuropathy, the process starts well before the onset of recognizable diabetes as a state characterized by insulin resistance and lipid abnormalities, along with hypertension, inflammation, and endothelial dysfunction: what we call metabolic syndrome or syndrome X. (10)

There is a significant clinical and financial impact on the health care system as a result of diabetic peripheral neuropathy. Approximately 60% to 70% of foot ulcers that are preceded by this condition. Eighty-five percent of diabetes-related lower-limb amputations are preceded by a foot ulcer. Three out of 10 patients who undergo limb amputation will lose another leg within three years, and over half of them will die within the first five years of the first amputation. (6)

As naturopathic physicians who specialize in the diagnosis and management of disease to prevent complications, these statistics should give us cause for concern and a renewed impetus when we take histories and perform physical examinations on patients with diabetes.

Signs and Symptoms of Diabetic Peripheral Neuropathy

Distal symmetrical sensorimotor neuropathy is the most common form of diabetic peripheral neuropathy. Signs and symptoms may progress from distal to proximal overtime.

Signs are diminished vibratory perception, decreased knee and ankle deep-tendon reflexes, reduced protective sensation such as pressure, decreased hot and cold perception, and pain. Protective sensation is usually measured by Semmes-Weinstein, 5.07, 10 gram wire. There is diminished ability to sense position of toes and feet.

Symptoms are numbness, loss of feeling, trickling and tingling sensations, usually to the toes and feet. Aching, burning, or lancinating pain are seen. Unusual sensitivity or tenderness called allodynia is experienced when the feet are examined. (7)

Diabetic peripheral neuropathy produces positive and negative symptoms. Positive symptoms can be spontaneous pain, dysesthesias involving the C-fibers, and paresthesias involving the A-fibers. Negative symptoms are loss and/or impairment of sensory quality, numbness, dry skin, erectile dysfunction, incontinence, and gait instability with fall risk. (8)

These positive and negative symptoms have an impact on the patient's functioning and quality of life. The latter is a unique and individual experience. It involves how people perceive and react to their health status. Patients with diabetic peripheral neuropathy can have psychosocial morbidity including depression, anxiety, anger, and loss of self-esteem. As a result, there can be social consequences such as isolation, strained relationships, and effects upon intimacy/sexual activity. (9)

Diagnostic Tests for Diabetic Peripheral Neuropathy

1. Nerve Conduction Studies/ Electromyography. This test measures the speed in amplitude of sensory and motor conduction. It is objective and parametric, and noninvasive; however, it is insensitive in acute and small fiber neuropathy. There is a greater than 50% false negative result for tarsal tunnel syndrome.

2. Quantitative Sensory Test. This test detects sensory thresholds for migration, heat, and pain. It is useful in tracking the progression of neuropathy in large cohorts of patients and the efficacy of treatment in points in multicenter clinical trials.

3. Skin Biopsy, IENFD (intraepidermal nerve fiber density). This biopsy test measures the density of intraepidermal nerve fibers at various sites in the leg. Loss of nerve fibers is associated with increased neuropathic pain. Although the test is invasive, it requires a 3 mm skin biopsy specimen and enables a direct study of small nerve fibers and therapy results after recognition of decreased nerve fiber density. (10)

4. Utilization of a 5.07 Semmes-Weinstein monofilament wire to determine presence or absence of protective sensation.

5. Biosthesionmeter.

6. Calibrated Tuning Fork.

7. Disk-Criminator, for two point spacing.

8. Neurometer CPT.

9. PSSD (earliest detection of pathology of A-Beta skin surface/touch fibers.

10. Neuropad (correlates with IENFD P = 0 .04)

11. Serum homocysteine levels when elevated have been demonstrated to be present in those patients with diabetes affected by neuropathy. Homocysteine elevation may result in direct and indirect neuropathic processes resulting in the evolution of both positive and negative symptoms. The direct adverse effects of elevated serum homocysteine levels result from the endothelial toxicity of homocysteine, which causes endothelial thrombosis with a loss of vascular peripheral ischemia neuropathy with resultant symptomatology.

Homocysteine interferes with the synthesis of nitric oxide, a gaseous free radical required for normal nerve and vascular function. Nitric oxide is a smooth muscle relaxant that increases neural blood flow, in part due to relaxation of the tunica media of the blood vessels. Nitric oxide is required for normal neural function. (11)

Nutritional management to increase in the oxide synthesis offers the potential advantage of improving blood flow to the peripheral nerves. A medical food complex called Metanx regenerates BH4, a cofactor for eNOS to convert arginine into nitric oxide. The nitric oxide is diffused into the smooth muscle cells, and smooth muscle cells dilate and blood flow is improved to the peripheral nerves, reducing some of the neuropathy symptoms experienced by diabetic patients. (11)

Small fiber neuropathy is a major cause of painful burning, numbness, and tingling in the feet and hands of diabetic patients. Small fiber neuropathy often precedes the diagnosis of diabetes and is also known as impaired glucose tolerance neuropathy. Utilizing the epidermal nerve fiber density measurements by a simple biopsy of intraepidermal nerve fibers at various sites on the neuropathic patient's leg provides a diagnostic reference point of approximately 80%, and evaluating peripheral neuropathy. Routine nerve conduction studies and electromyographic studies are typically normal because they involve only the large fibers, which are not affected until later into the disease. From the naturopathic standpoint, the management of small fiber neuropathy should involve controlling the symptoms and aggressively treating the underlying cause. (18)

As previously mentioned, there is a wide range of treatment modalities available for diabetic neuropathic pain patients, which suggests that there is no one approach that addresses all the disease factors. Despite this broad spectrum of drugs available with different modes of action, patients still remain inadequately treated in several aspects of the disease. It should be noted that the vast majority of drug therapies and natural therapies are to provide symptomatic relief. However, there are specific nutrient therapies that have actually been shown to increase the number of intraepidermal nerve fibers, which have been shown clinically to help reduce symptoms of diabetic peripheral neuropathy.

Skin punch biopsies of the calf in the above photos (Figure 2) demonstrate the results of remittive therapy with increased epidermal nerve fiber density with patients treated by Metanx, a combination of L-methylfolate 2.8 mg, pyridoxal 5'-phosphate 25 mg, and methylcobalamin 2 mg per dose, given twice a day.

[FIGURE 2 OMITTED]

Metformin Therapy for Neuropathy and Polycystic Ovary Syndrome

Metformin (trade name Gluco-phage) is a drug that has been used to help control blood glucose levels in people with type 2 diabetes. Although Glucophage has been used in Europe for over 25 years, it was not approved or available in the US until 1995. The FDA has approved metformin only for the treatment of type 2 diabetes. Consequently, some physicians don't have much clinical experience with Glucophage, or are reluctant to use it unless the patient has diabetes. Metformin helps control diabetes by decreasing the absorption of dietary carbohydrates through the intestines. Secondly, it reduces the production of glucose by the liver. The liver uses the raw material in food to create a reserve supply of blood sugar. When the body experiences stress, the liver releases the reserve glucose to supply the brain and muscles with an immediate source of energy to cope with the stress. Metformin depresses the production of this reserve fuel.

Metformin's third and perhaps most important mechanism of action is to increase the sensitivity of muscle cells to insulin. Insulin is a hormone that delivers glucose into the cells to be burned as fuel, or stored.

Women with polycystic ovary syndrome (PCOS) frequently have insulin resistance. Metformin assists the transport of glucose with relatively less insulin, thus lowering insulin levels. A chronically high level of either glucose or insulin in the bloodstream contributes to obesity, heart disease, infertility, and certain cancers, as well as the development of diabetes.

[FIGURE 1 OMITTED]

A number of studies indicate that metformin reduces insulin, testosterone, and blood glucose levels, which reduce acne, hirsutism, abdominal obesity, amenorrhea, and other symptoms. In one study conducted at the Virginia Commonwealth University, 24 obese women with PCOS were given metformin or a placebo. The 11 women who received the metformin experienced a reduction in insulin levels, which slow the activity of an enzyme in the ovaries that stimulates the production of excess testosterone. As a result of taking metformin, serum testosterone levels are lowered.

Metformin appears to have the same result as above for nonobese women with PCOS, according to a study from the University of Medical Sciences in Poznan, Poland. Other studies have shown that metformin can prevent or delay the onset of diabetes; it restores normal menstrual cycles, improves the chance of pregnancy, reduces the risk of miscarriage, reduces the risk of gestational diabetes, and has been used for weight loss in some diabetics.

Metformin also has severe adverse reactions, which include malaise (15%-25%), Gl disturbances (30%), vitamin B12 malabsorption (10%-30%), elevated homocysteine levels, and elevated homocysteine, which may cause pregnancy complications such as preeclampsia. It can cause anemia, liver, or kidney problems; hair loss; and lactic acidosis. It can aggravate diabetic peripheral neuropathy by increasing homocysteine levels and decreasing B12 levels. An important natural alternative to metformin is d-chiro-inositol. A form of niacin, d-chiro-inositol increases the action of insulin in women with PCOS. It improves ovulatory function and decreases male hormones, triglycerides, and blood pressure. (20-26)

Remittive therapy implies the restoration of nerve function. Remittive therapy suggests the possibility of relieving anesthesia present in some patients with advanced diabetic neuropathy, by restoring or improving motor nerve and autonomic nerve function. Remittive therapy involves the manipulation of underlying metabolic paths of the physiology and relief of oxidative stress. The regeneration of peripheral nerves in diabetic laboratory specimens has been demonstrated by the utilization of pharmacological therapy, as well a surgical decompression. (12-14) The physiological effects of certain supplements on remittive therapy for diabetic peripheral neuropathy will be discussed from a therapeutic and biochemical point of view.

Thiamin (vitamin B1) is the active form of thiamine pyrophosphate, which functions as a cocarboxylase. It is required for the oxidative carboxylase of pyruvate to form active acetate and acetyl coenzyme A. It is also required for the oxidative carboxylase of the other alpha-keto acidssuch as alpha-ketoglutaric acid, going to keto-carboxylase derived from the amino acids methionine, threonine, leucine, isoleucine, and valine. Allicin, a substance found in onions and garlic, combines with thiamine and renders it more absorbable. Thiamine pyrophosphate is involved in the oxidation pathway and may be responsible for the energy required for nerve conduction.

Diabetics who have a high intake of carbohydrates need increased thiamine in their diet, since they have a higher urinary excretion of thiamine. The recommended daily allowance (RDA) is 1.0 to 2.4 mg. The therapeutic values of thiamin for patients with diabetes should be in the range of 60 mg per day in divided doses. Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and are therefore more suitable for the therapeutic purposes of treating diabetic neuropathy. Benfotiamine, an aliphatic thiamine derivative, prevents the progression of diabetic complications, probably by increasing tissue levels of thiamin diphosphate and so enhancing trans-ketolase activity. One of the postulated mechanisms of action of Benfotiamine is that it blocks three major pathways (the hexosamine pathway, the advanced glycation end product formation pathway, and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) by probable removal of glyceryl aldehyde 3-phosphate and fructose 6-phosphate through the activation of the pentos phosphate enzyme transketolase. (15)

Riboflavin is essential in the activation of vitamin B6 and is involved in the conversion of tryptophan to niacin. Riboflavin is essential for the production of corticosteroids and in regulation of gluconeogenesis and thyroid enzymes. Vitamin B2 is the component of two major energy enzymes: flavin mononucleotide and flavin adenine dinucleotide. B6 is also important in glucose metabolism, which uses glucose stores and can dramatically alter levels of the vitamin's active coenzyme form. The recommended daily allowance (RDA) for vitamin B2 is 1.2 to 1.6 mg, 1.5-12.7 mg per day during pregnancy/lactation. Therapeutic levels of vitamin B2 should be in the range of 60 mg per day. No toxicity due to riboflavin has been found.

Vitamin B6 in its active form is involved in the transamination of ammonia groups to other amino acids. It is also involved in the deamination or removal of amino acids. It can also be useful as an energy source and in decarboxylation process for the removal of carboxyl (COOH) groups from certain amino acids to form another compound. It is required in the synthesis of neurotransmitters such as serotonin, norepinephrine, and histamine from tryptophan and tyrosine. The RDA for vitamin B6 is 2 to 2.2 mg, 5 to 6 mg per day during pregnancy/lactation. The therapeutic level of vitamin B6 is at least 60 mg per day.

Toxicity with vitamin B6 has been reported in one case in which a dosage of 200 mg 4/per day was administered and resulted in peripheral neuropathy. Normally it would take a dosage of 225 mg per day for a few months to cause toxic symptoms consisting of numbness and tingling in the extremities. The symptoms usually disappear once the patient discontinues the B6, but may linger for a few months if severe. If the patient is on L-dopa for Parkinson's disease and takes B6, the vitamin will convert the L-dopa into dopamine outside the blood-brain barrier, rendering the L-dopa ineffective because dopamine cannot pass the blood-brain barrier.

If the patient is on Sinemet (a combination of L-dopa and carbidopa), B6 may actually have a synergistic effect. Carbidopa stops conversion of L-dopa outside the blood-brain barrier. Vitamin B6 would then cross the blood-brain barrier along with the unchanged L-dopa. Once past the blood-brain barrier, the B6 would then convert the L-dopa into dopamine and the brain could then effectively use it. (19)

Several research articles have appeared on the use of alpha-lipoic acid for treating peripheral neuropathy. Lipoic acid is approved in Germany for preventing and treating diabetic neuropathy. The effect may result from the medication's antioxidant activity. Researchers have shown that lipoic acid replenishes vitamin C and glutathione, and helps recycle vitamin E. Lipoic acid may also be helpful in reducing blood glucose and the damaging glycosylation of proteins. Nagamatsu et al. demonstrated that lipoic acid improves nerve blood flow, reduces oxygen stress, and improves distal nerve conduction in diabetic neuropathy. (16)

Combining acetyl-L-carnitine and lipoic acid has an added benefit in the treatment of peripheral diabetic neuropathy. I have utilized this combination in my practice over the years and have found significant clinical improvement in patients with diabetic neuropathy and also short-term memory loss. A recent randomized, double blind placebo-controlled trial with 330 patients examined the use of acetyl-L-carnitine at 1000 mg per day intramuscularly for 10 days, followed by oral acetyl-L-carnitine in 2000 mg or day for one year. Nerve conduction velocities dramatically decreased by several fold in the acetyl-L-carnitine group compared with the placebo treatment. Acetyl-L-carnitine treatment also significantly decreased painful neuropathies by 39% from baseline scores. The authors of this study stated that acetyl-L-carnitine was a promising treatment for diabetic neuropathy. (17)

A well-studied oral remittive therapy for the treatment of diabetic peripheral neuropathy has been Metanx. This medical food complex addresses the distinct nutritional requirements of diabetic patients with specific diagnose diseases or conditions such as low plasma/RBC folate, hyperhomocysteinemia,and endothelial dysfunction. This combination is orally administered for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy.

The safety profile of Metanx when administered according to instructions has not demonstrated allergic sensitization to the L-methylfolate. Paresthesias, somnolence, nausea, and headaches have been reported with pyridoxal-5' phosphate. Mild transient diarrhea, polycythemia, itching, transitory exanthema, and the feeling of swelling the entire body have been associated with cobalamin.

These side effects and or distinct discontinuation rates are similar to placebo. A prescription product, Metanx is generally regarded as safe by the FDA.

There have been 13 well parameter studies on 741 patients showing the efficacy of this combination for improvement and vibratory detection, improvement with short-term paresthesias, pain, temperature, and numbness. However, the most significant clinical finding has been the increase in intraepidermal nerve fiber density after beginning oral therapy with this medical food. Baseline and six-month biopsy specimens have shown a dramatic increase in nerve fiber density. (27)

A statistically significant majority of patients with type 2 diabetes demonstrate some form of peripheral neuropathy. Ten percent to 20% of these patients demonstrate positive symptoms of diabetic neuropathy, while an overwhelming majority of these patients have undetected negative symptomatology including anesthesia, motor neuropathy, and autonomic neuropathy. Patients with clinically positive symptoms associated with diabetic neuropathy can be managed effectively with proper glycemic control, antinociceptive therapy, and remittive therapy.

Conclusion

It is interesting to note that a small percentage (10%-20%) of diabetic patients have clinically positive neuropathology. This leaves approximately 80% to 90% of patients who have negative clinical symptoms of diabetic neuropathy. Interestingly, however, the number of patients with negative symptomatology, including anesthesia, motor neuropathy, and autonomic neuropathy, develop the most significant morbidity and mortality, because they just can't feel the pathological changes resulting from their disease.

Remittive therapy, even if initiated early in the disease process after appropriate laboratory testing, can offer the potential to interdict or even lessen future manifestations of clinically negative diabetic peripheral neuropathy. This early interdiction turned the tide of extremity amputations that are currently being experienced here in the US. (28-30)

by John Hahn, DPM, ND

Dr. John Hahn received his doctor of podiatric medicine degree from the California College of Podiatric Medicine and completed his surgical residency at the California Podiatry Hospital, both in San Francisco, California. He received his degree as a doctor of naturopathic medicine from the National College of Naturopathic Medicine in Portland, Oregon. He is board certified in foot surgery. Dr. Hahn is an active staff member of the Gresham Station Surgical Center in Gresham, Oregon, and Legacy Good Samaritan Hospital in Portland, Oregon. He has served in the United States Army IRR, Medical Service Corps. He has published several scientific articles in numerous journals. Dr. Hahn is currently a professional consultant for Cryosurgical Concepts Inc. and Heel Inc., and is a member of the Medical Advisory Board for GVI. He maintains a private part-time practice in Portland, Oregon

[ILLUSTRATION OMITTED]

Notes

(1.) Centers for Disease Control and Prevention. National diabetes fact sheet. 2005.

(2.) Jenkins TJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981;24:362-366.

(3.) Khan A, Safdar M, Khan MMA, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003;26(4):32015-3218.

(4.) Garrison RH, Somer E. Nutrition Desk Reference. 2nd ed. New Canaan, CT: Keats Publishing; 1985:93.

(5.) Physicians' Desk Reference. Thomson Healthcare, 2008.

(6.) Gordois C et al. The health care costs of diabetic nephropathy in the United States. Diabetes Care. 2003;26:1790-1795.

(7.) Boulton AJ et al. Diabetes Care. 2006 April. 28(4):956-962.

(8.) Baron R. Clin J Pain. 2000;16(2 5 suppl):512-520; Argroff CE et al. Mayo Clin Proc. 2006;81(4 suppl):55-81; Boulton et al.

(9.) Argoff et al:53-511

(10.) Pathways: Prescriptive in Modern Neurology and Pain Management. July 2007;3:6.

(11.) Cohen JA, Jeffers BW, Stabler S, et al. Increasing homocysteine levels in diabetic autonomic neuropathy. Auton Neurosci. 2001;87:268-273; Ambrosch A, Dierkes J, Lohmann R, et al. Relation between homocysteinaemia and diabetic neuropathy in patients with type 2 diabetes mellitus. Diabet Med. 2001;18(3):185-192.

(12.) Ebenezer GJ, Hauer PE, Gibbons C, et al. Assessment of epidermal nerve fibers: a new diagnostic and predictive tool for peripheral neuropathy, J Neuropathol Exp Neurol. 2007;66:1059-1073.

(13.) Polydefkis M, Hauer, P, Seth S, et al. The time course of epidermal nerve fiber regeneration: studies in the normal controls and in people with diabetes-with and without neuropathy. Brain. 2004:127:1606-1615.

(14.) Hsieh CH, Jeng SF, Lu TH, et al. Loss of small fiber entrapment neuropathy and their regeneration after surgical decompression in a rat model. J Neurotrauma. 2007;24:1058-1066.

(15.) Volvert M-L, Sayer S, et al. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivative. BNC Pharmacol. Nov. 19, 2008.

(16.) Nagamatsu M, Nickander KK, Schmelzer. et al. Lipoic acid improves nerve blood flow, reduces oxygen stress and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995;18:1160-1167.

(17.) DeGrandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy: a long-term, randomized, double-blind, placebo-controlled study. Drugs R D, 2002;3(4):223-231.

(18.) Quattrini C, Tavakoli M, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;50(6):2140-2154; De Sosa EH, Hays AP, et al. Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibers on skin biopsy. J Neurol Neurosurg Psychiatry. 2006;70(7):983-985.

(19.) Solomon LR, Cohen K. Erythrocyte 02 transport and the metabolism and effects of vitamin B6 therapy in type 2 diabetes mellitus. Diabetes. 1989;38(7):881-886.

(20.) Adams JS et al. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanidine therapy. Diabetologica. 1983;24(1):16-18.

(21.) DeSouza C et al. Drugs effecting homocysteine metabolism: impact on cardiovascular risks. Drugs. 2002;62(4):605-616.

(22.) Virbikova J et al. Homocysteine and steroid levels in Metformin treated women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2002;110(2):74-76.

(23.) Sorensen TK et al. Elevated second trimester serum homocysteine levels and subsequent risk of preeclampsia. Gynecol Obstet. Invest. 1999;40(2):98-103.

(24.) Miller WC et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or Metformin. N Engl J Med. 2002;346(6):393-403.

(25.) Gluek CJ et al. Metformin to restore normal menses in oligo-amenorrheaic teenage girls with polycystic ovary syndrome. J Adolesc Health. 2001;229(3): 160-169.

(26.) Gerli S et al. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Eur Rev Med Pharmacol Sci. 2003 November-December;7(6):15l-159; Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med. 1999;340(17):1314-1320.

(27.) Ang CD, Alviar MJM, Dans AL, et al. Vitamin for treating peripheral neuropathy. Cochrane Database Sys Rev. 2008;3.

(28.) Chen H, Lamer TJ, Rho RH, et al. Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc. 2004;17:1533-1545.

(29.) Diabetes. 2005;23:9-15.

(30.) Boulton AJ, Malik RA, Arezz JC, et al. Diabetic somatic neuropathies. Diabetes Care. 2004;27:1458-1486.

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