Diabetes / Metabolic Syndrome

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

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Diagnosis of diabetic peripheral neuropathy

While the standard test for assessing neuropathy is the EMG (electromyogram), sometimes called a nerve velocity conductance test, these tests focus on the large nerve fibers, whereas the small nerve fibers are most often damaged in diabetic peripheral neuropathy. Assessment of the small fiber neuropathy utilizes QST (quantitative sensory testing), which includes thermal threshold assessment and VPT (vibration perception thresholds), although these tests are somewhat subjective and need specialized physicians and testing facilities to obtain reliable data. For this reason, the gold standard in testing for small fiber neuropathy is the sural nerve biopsy with electron microscopy, and skin-punch biopsy. These tests are not routinely provided, and hence the physicians and technicians needed to properly read these tests are often unavailable. Unfortunately, the diagnosis of diabetic peripheral neuropathy usually relies on the assumption of the treating doctor that this is the type of neuropathy the patient is experiencing. Correct diagnosis is the key to correct treatment protocols.

Peripheral Neuropathy in Diabetes

Serious lower extremity pathologies, such as peripheral neuropathy, peripheral arterial disease, and inflammation/ulcers in the diabetic population are less frequently noted in hospital records in the last 20 years in the United States, but continue to affect patients under age 75 at about 20 per 1000 in the diabetic population, according to the U.S. CDC, and at a much higher number in patients older than 75. Of course, less serious lower extremity pathologies are more common with diabetes, and may be multifactorial in origin. Studies in Europe in 2007 (Diabetologia; 50:18-25; Prompers et al) noted that diabetic patients with foot ulcers showed that nearly half had a comorbid condition of peripheral arterial disease (PAD), and that 1 in 7 patients with diabetes was expected to suffer from a foot ulcer during their lifetime, showing that these conditions were very underreported.

Such pathology is largely ignored because most of the serious cases occur in old age, and standard medicine has no effective treatment strategy to reverse the disease progression. The most prescribed drug to treat diabetic peripheral neuropathy, pregbalin, or Lyrica, works by blocking calcium channels and release of neurotransmitters, offering mild symptom relief only, and with a high incidence of adverse effects, such as somnolence, weight gain, dizziness and peripheral edema. Obviously, a more comprehensive treatment protocol is needed to reverse the pathology and restore peripheral nerve health. To address these common adverse health effects of Lyrica, guidelines call for a large range of dosage to minimize these adverse effects, but with lower dosage, the need for complementary medicine increases. A large cohort study involving 14 medical centers, entitled Eurodiale (The European Study Group on Diabetes and the Lower Extremity), comprised of medical doctors of various related specialties, reviewed medical records of 1229 diabetic patients admitted consecutively at these medical centers with a new foot ulcer in 2003-2004, and found that not only half had peripheral arterial disease, but that diabetic neuropathy was diagnosed in 86 percent of these patients, and serious comorbidities in 60 percent. Patients with diabetic neuropathy should be aware that they need to treat this problem before such serious outcomes occur, as these are potentially debilitating conditions, and may be life-threatening in the case of peripheral arterial disease and skin ulcers. These conditions are very difficult to treat directly, though, and emphasis has been on improving the underlying condition. A more holistic approach both addresses the hyperglycemia and the array of contributing factors, such as oxidative stress, peripheral circulation, accumulation of irritants in the tissues, and enzyme functions.

Research is proving that an array of treatments in Complementary and Integrative Medicine and Traditional Chinese Medicine (CIM/TCM) are effective in a broad number of ways to both relieve symptoms and, more importantly, to restore function and tissue health in diabetic peripheral neuropathy. Some of this emerging research is available at the end of this article and in Additional Information, and persistence with short courses of acupuncture and physiotherapy, with individualized step-by-step protocol with herbal and nutrient medicine, is necessary to achieve a reversal of this slowly developing pathology.

Diabetic peripheral neuropathy is considered primarily an imbalance or dysfunction of the autonomic nervous system, with denervation hypersensitivity a predominant concern. It is estimated that 30-40 percent of patients with diabetic peripheral neuropathy experience painful symptoms. Neuropathic pain in diabetic neuropathy is still a poorly understood and complex condition, though, although nerve damage in type 1 diabetes, or Diabetes Mellitus, is better understood, with sustained high blood sugars in circulation accelerating nerve cell death and decreasing normal maintenance. The nerve cell, or neuron, is a particularly long cell, often extending from the spinal cord plexus to the peripheral extremities. Lesions anywhere along this cell may cause pain in neuropathy, while poor overall maintenance may cause paresthesia, typically felt as numb tingling sensation.To properly treat this condition, a more comprehensive and restorative holistic protocol is needed, and evidence that a combination of therapies in Complementary and Integrative Medicine and Traditional Chinese Medicine (CIM/TCM) is effective is emerging. Short courses of acupuncture and physiotherapy with a more persistent herbal and nutrient medicine course could be essential to reversing this nerve damage. A quick fix with a single pill is not realistic.

According to experts at the University of Manchester, United Kingdom, in 2008 (Mitra Tavaloki and Dr. Moaz Mojaddidi, with Dr. Rayaz Malik) the pathophysiology of painful diabetic neuropathy (PDN) involves oxidative stress, advanced glycation, polyol accumulation (sorbitol accumulation in hyperglycemia, glutathione and myoinositol deficiency), decreased nitric oxide, and impaired sodium-potassium ATP-ase metabolism (Academia.edu). Reduced insulin-like growth factors and nerve growth factors are also seen in this pathology. Oxidative stress, which may be induced by even short periods of hyperglycemia, are a principle concern. Small fiber neuropathy is also a focus of chronic painful diabetic neuropathy in recent years, and involves the unmyelinated fibers of the nervous system, called C-fibers and A-delta fibers. Complicating this pathology is the fact that nerve lesions causing pain in the lower extremities may come from a central and/or peripheral location, making diagnosis and treatment very difficult. In other words, even when the causative factors are decreased, healing of neural lesions causing painful neuropathy may take time and persistence, addressing neural health in the brain to the foot. These lesions do not heal quickly, either, so the process of healing may be frustrating. While standard medicine continues to treat these conditions by trying to block the pain signal, this does not address the causative problems. Even if the patient chooses to take medication to try to block painful diabetic neuropathy, or PDN, which is rarely successful in the long-term, the task of restoring the health to the nervous system still needs to be addressed. Symptoms are merely signals of dysfunction, and the patient that believes that the dysfunction is gone when the pain signal is diminished by chemical block of the pain signal is not being objective. The underlying degeneration of the small fiber peripheral nerves and arterioles needs to be restored.

For patients afflicted with diabetic peripheral neuropathy and vascular disease, which often go hand-in-hand, the symptoms are often slowly progressing and poorly treated, until one day they become debilitating. The gut reaction is to think "what can I take to just relieve these symptoms and get back to work, sports activities, and even normal sleep". Unfortunately, there is almost nothing that will relieve symptoms of diabetic peripheral neuropathy in the short term. To truly address these issues, a persistent proactive approach by the patient is needed, with steady therapeutic work and patience. The key to this process is understanding of the pathology.

Our cells use glucose for energy, and glucose is the sugar, or carbohydrate, that we measure in blood sugar. Unused glucose is reduced to a molecule called sorbitol in the polyol pathway, and excess glucose in circulation leads to increased sorbitol, which may accumulate or oxidize to fructose. Of course, in the diabetic state, where blood sugars are high, either constantly, or in a fluctuating manner that is abnormal, there is excess glucose at the cell, even the nerve cell. Normally, the homeostatic mechanism may return the peripheral fructose to a form called fructose-6-phosphate, and this may be utilized. In the hyperglycemic state, though, the stress of this metabolic process is too high, and gradually the process creates an excess of sorbitol instead of converting the excess glucose to fructose-6-phosphate. This process also creates excess oxidative stress and a decrease in the cellular fuel NADPH (nicotinamide adenine dinucleotide phosphate), a charged coenzyme of anabolic reactions, such as the creation of healthy lipoprotein membranes and DNA. NADPH also provides the antioxidant and detoxifying potential in the cell, allowing regeneration of glutathione and antioxidant mechanisms of oxidation-reduction (redox), as well as promoting more of the vasodilating chemical nitric oxide. The hyperglycemic state thus creates sorbitol accumulation, decreased NADH, deficient glutathione detoxification, increased oxidative stress, and decreased vasodilation and circulation. To fix this array of problems at the peripheral nerve cells, a number of therapeutic aids may be needed, such as antioxidants, aids to glutathione production (B12, active folate (5MTHF), N-acetylcysteine, zinc monomethionine, and methylselenocysteine), and aids to nitric oxide synthesis (B3 niacins and L-arginine with active Vitamin B6 (P5P)). Alpha lipoic acid (ALA) is one of the targeted antioxidants that have been proven to work to correct painful diabetic neuropathy in randomized controlled human clinical trials (PMID: 25381809).

Reduced NADPH in this polyol pathway may also decrease essential metabolites like myo-inositol and taurine, and create an excess of complex molecules called advanced glycation endproducts (AGEs), altering collagen fibers, and creating fibrosis. Myo-inositol is particularly essential for the normal function of nerves. Inositol is also a sugar, or carbohydrate, and myo-inositol is an important signaling molecule, or second messenger, in nerve membranes, as well as an important component of the important membrane molecule phosphotidylinositol. Much research has advanced knowledge of what our bodies need to clear excess AGEs and block excess production of AGEs, and formulation of herbal and nutrient medicines may be taken to aid this aspect of the pathology. Myo-inositol may be aided in the body through the diet, eating more inositol-rich foods, such as cantalope, seeds, whole grain bran, nuts and beans, as well as supplements such as inositol hexacotinate (B3) and inositol hexakisphosphate (IP6), as well as D-chiro inositol, a nutrient medicine proven valuable to treat insulin resistance and polycystic ovarian syndrome. We see that just this peripheral aspect of diabetic peripheral neuropathy may require a period of treatment that is somewhat complex to restore function and health of the peripheral nerves.

According the the experts cited above (a link to this paper is provided below in additional information) the pathophysiology of diabetic peripheral neuropathy involves 6 essential dysfunctions: 1) increased DAG (diaglycerol) and decreased PKC (protein kinase C), 2) high triglycerides and LDL, 3) impaired omega-6 fatty acid metabolism (GLA, CLA), 4) dysfunction of the polyol pathway, 5) sugar oxidation and oxidant stress, and 6) excess creation of advanced glycation endproducts (AGEs). These dysfunctions lead to excess oxidative stress and membrane endothelial dysfunction, which then leads to decreased capillary blood flow and hypoxia, nerve damage and dysfunction, and decreased nerve repair and regeneration. The longer the pathology is allowed to progress the more damage is created to the structure of these peripheral nerves and blood vessels. To regenerate healthy nerves, nerve fibers, and small blood vessels, time and persistent treatment protocol is needed. We have no prosthetic surgery to replace severely damaged nerves and blood vessels. Both the cessation of harmful factors inhibiting this healthy regeneration, and promotion of the factors that create regeneration are needed. Obviously, a long-term holistic treatment protocol is needed, whether the patient utilizes neural blocking or modulating drugs or not.

Another important aspect of the pathology of diabetic peripheral neuropathy is denervation hypersensitivity. This is also a hallmark of chronic myofascial pathology, which requires a sustained treatment protocol to both restore muscle function, clear tissues around the innervation of affected muscles, and promote healthy regeneration of nerve receptors and pathways. If needed, treatment to address myofascial pathology as well peripheral neuropathy may be needed to correct denervation hypersensitivity. Hypersensitivity in diabetic peripheral neuropathy is usually referred to as allodynia, a term that refers to pain where the usual direct stimulus of the pain is not apparent, yet the body still receives the pain signal. Allodynia is a hallmark of neuropathies, fibromyalgia, migraines, postherpetic neuralgia (chronic shingles pain), and the complex regional pain syndromes of causalgia and reflex sympathetic dystrophy. When denervation occurs, or the death of nerve endings, the remaining nerve endings become hypersensitive to stimulation to compensate. This causes an eventual hypersensitivity in the feet and ankles that persists even after the tissues, blood vessels and nerves start regenerating and oxidant stress is decreased. Hypersensitivity can also lead to an altered perception to pain and discomfort in the brain, with symptoms persisting even when the peripheral problems are restored. This is called central sensitization. When denervation occurs, increased expression of sodium channels results, and eventually this express expression of sodium channels in the cells and membranes needs to be normalized. These hypersensitive peripheral nerves become more sensitive to adrenaline (epinephrine) as well, and thus increased stress and adrenaline may increase the symptoms. Studies also show that when peripheral neuropathy persists that fibers of the local sympathetic nervous system grow excess terminals that surround small nerve fibers (A-delta and C), which release more substance P into the neurons and amplify allodynia. Also, hyperexcitable peripheral nerves stimulate increased central nerve NMDA (glutamate) receptors, which may be involved in pathologies such as nocturnal bruxism, sleep movement disorders, and ADHD.

Treatment of diabetic peripheral neuropathy in standard medicine is often limited to control of blood sugar levels and harsh medications to block nerve signaling, such as gabapentin (an antiseizure medication), or antidepressants (SSNRI medications such as Cymbalta). Only 2 FDA approved drugs exist, though, pregabalin (Lyrica, an antiseizure medication) and duloxetine (Cymbalta). Pain relieving drugs seldom work to decrease neuralgia, and so are usually taken to obtain sleep in this protocol. Capsaicin ointments and creams are found effective, but need frequent application, and are seldom prescribed. Researchers have also recommended alpha-lipoic acid (ALA), an antioxidant proven to help in human studies, or the more active R-lipoic acid (RLA). Experts generally agree that allopathic standard medicine has provided no effective licensed treatment for diabetic peripheral neuropathy other than glycemic control, though. Obviously, this is a realm that requires the integration of Complementary Medicine, and a persistent restoration of health of this system or systems with holistic protocol.

A number of therapeutic aids has shown promising results in studies of the treatment of painful diabetic peripheral neuropathy. As mentioned, alpha lipoic acid (ALA, or the more potent and active RLA) has shown benefits in clinical trials, but studied nutrient medicines also include the potent antioxidant CoQ10 (ubiquitone) and the hormone Vitamin D, as well as the Vitamins B1 (benfotiamine), B6 (P5P) and B12 (liquid methocobalamin), and the amino acids taurine and Acetyl-L-Carnitine (ALC). A 2013 study at the University of Miami Miller School of Medicine, in Miami, Florida (see study link below) showed that CoQ10 shows promise in inhibiting oxidative stress and reducing inflammation in animals with painful diabetic peripheral neuropathy at a prolonged low dose. Inhibition of allodynia and hyperalgesia, as well as measurable benefits with inflammatory cytokines and decreased lipid peroxidation were noted. Studies of standard antioxidants, such as a combination of Vitamins C, A and E, showed no benefit in a large clinical trial. A low-dose CoQ10-H2, or more active form of CoQ10 is thus recommended in the treatment protocol. The neuroprotective and neurotrophic supplement Acetyl-L-Carnitine (ALC) has also demonstrated positive effects on the peripheral nervous system, and studies of ALC use in diabetic neuropathy have demonstrated benefit with sustained use. Besides RLA, ALC, CoQ10-H2 and Vitamin D3, a number of herbs have demonstrated benefit as adjuncts in prevention and treatment, and nutrient formulas to aid glutathione metabolism and clear AGEs also show significant promise in the overall treatment strategy, as well as acupuncture. While no individual therapy is expected to produce dramatic results, a comprehensive treatment protocol, combined with improved health and circulation, as well as control of hyperglycemia, shows great promise in reversal of this slowly developing and debilitating disease.

A newer treatment protocol for diabetic peripheral neuropathy in standard medicine, aldose reductase inhibitors, is showing some promise to address the underlying aspect of the disease associated with the dysfunction of the polyol pathway and accumulation of sorbitol. Clinical trials in Japan are showing much promise for this protocol, but as always, there are side effects to pharmaceutical aldose reductase inhibitors (Epairestat). A number of Chinese herbal chemicals have been found to be effective as aldose reductase inhibitors as well, such as baicalein and skullcapflavone II in Scutellaria baicalensis (Huang qin), chemicals in Sophora flavscens (Ku shen), and Paeonia suffruticosa (Mu dan pi), explaining their efficacy to treat diabetic complications, such as diabetic retinopathy and peripheral neuropathy (see study links below). Mu dan pi is also shown to inhibit AGEs (advanced glycation endproducts), and Huang qin provides strong anti-inflammatory and antioxidant activities. As these drugs present the first pharmaceuticals that actually address the underlying causes of diabetic complications, they may be integrated in therapy with appropriate Chinese herbs to either increase effectiveness or decrease the need of high dosage when side effects are a problem. Such research continues to support the integration of Complementary Medicine for the treatment of difficult diseases. In 2015, expert at the Beijing University of Chinese Medicine, the China Academy of Chinese Medical Sciences, and the Hong Kong Baptist University School of Medicine, in China, showed that a simple Chinese herbal formula, long used to treat diabetic neuropathy, Guizhi Shaoyao Zhimu Tang (decoction) provides and array of chemicals that target a variety of important pathways involved in repair and restoration of peripheral nerves and nerve function, especially on the hydrocarbon receptor signaling and apoptosis signaling pathways that are key to the slowly progressive disease. To see a study summary, click here: http://www.ncbi.nlm.nih.gov/pubmed/25948477. Other studies of acupuncture stimulation in the treatment of peripheral neuropathy, a the Sun Yat-Sen University School of Medicine, and the Southern Medical University in Dongguan, China, showed that acupuncture at both the spinal points of the Du meridian and the peripheral meridian points resulted in significant improvement in nerve conduction velocity measured with EMG. The short course of acupuncture was performed daily. To see the study summar, click here: http://www.ncbi.nlm.nih.gov/pubmed/25788933. More research supporting acupuncture, herbal and nutrient medicine is available in the section of this article entitled Additional Information. This type of study design is not typical of pharmaceutical clinical trials, which are designed for a single chemical molecule and a single measured effect, but this type of scientific study clearly proves the effectiveness of herbal medicine as part of a more holistic treatment protocol.