Exploring Diabetic Neuropathy

Pickering 1 Leticia Pickering UH 267- Dr. Twardosz 15 April 2007

Diabetes Mellitus: A Disease of the Nervous System? Diabetes mellitus is a disease that affects the body in many devastating ways. Of the potential side effects, diabetic neuropathy is the most dangerous, as it often exhibits no symptoms. Once thought to be a delayed affect of diabetes, peripheral neuropathy is shown to be associated with glucose intolerance and may be, in fact, used as a diagnostic symptom for diabetes mellitus (Freeman et al 333). “Diabetes may affect both the central and peripheral nervous systems” and may be exhibited in one of four ways: chronic diabetic polyneuropathy, acute diabetic polyneuropathy, proximal diabetic neuropathy, or diabetic radiopathy and mononeuropathy (Macleod et al 126). Before delving into the complexities of diabetic neuropathy, it is important to first understand diabetes, along with its risks. Diabetes mellitus is defined as “a metabolic disorder characterized by abnormal carbohydrate, fat, and protein metabolism, which is clinically diagnosed on the basis of hyperglycemia”, or elevated blood glucose levels (Barb et al 136). Diabetes is further classified into Type I and Type II. Type I, or insulin dependent diabetes, is either caused by an autoimmune reaction of the pancreas or due to genetic inheritance. This type of diabetes requires that the hormone insulin be injected into the body. One might wonder why insulin might not be taken orally. The insulin must be injected because of its chemical structure. Hormones are composed of protein structures, which are sensitive to

Pickering 2 adverse conditions, such as extreme temperatures, change in pH levels, and enzymatic activity. If the hormone were ingested, the delicate protein structure would be denatured in the acidic environment of the stomach before it could be absorbed into the blood stream and utilized for glucose control. Type II or insulin-independent diabetes is associated with obesity and insulin resistance. Unlike Type I diabetes, Type II patients typically produce sufficient amounts of insulin. Rather, the insulin does not effectively bond to the glucose molecules in the blood, therefore does not maintain blood glucose at consistent levels. Type II patients generally do not require insulin therapy but it is often controlled with a nutritious diet and exercise regimen (Barb et al 137). If needed, an oral medication can be taken in order to improve the insulin’s ability to bind to the glucose molecules in the blood, therefore maintaining blood glucose at a safe level. Diabetes, when left uncontrolled carries serious risks including retinopathy, nephropathy, renal disease, and neuropathy. While each complication takes a different toll on the body, few affect the body like the peripheral neuropathy that plagues approximately fifty percent of diabetics. When it becomes clear that neuropathy has begun to develop, it is imperative that its etiology, or underlying cause, be determined. This means classifying the neuropathy as acute, chronic, spontaneous, or entrapment neuropathy. The most common of these is chronic. Its prevalence increases to approximately fifty percent twenty five years after initial diagnosis, but is also attributed to older age, height, genetic history, history of smoking, and long term retinopathy (Freeman 333). The risk for neuropathy also appears to be greater for those patients with Type II diabetes and may have an association to obesity.

Pickering 3 Additionally, in respect to neuronal transmission, both large and small myelinated and unmyelinated nerve fibers are affected, which can seriously impair the speed at which electrical impulses are conducted along the nerves. A condition known as chronic inflammatory demyelinating polyradialneuropathy has recently been linked to diabetes and studies show that the illness’ symptoms might be accelerated in diabetic patients (Freeman et al 335). This problem is further aggravated by the fact that nerve growth factors are suppressed in the presence of elevated blood glucose levels. The second most common neuropathy is sensory polyneuropathy. This is characterized by a painful burning sensation, followed by the inability to perceive pain and temperature changes. This type of neuropathy is tested with a small vibrator applied to the sole of the foot and is usually accompanied by difficulty with balance and loss of involuntary reflexes. “When a patient with diabetes has significant weakness, diagnostic considerations include proximal diabetic neuropathy, acquired demyelinating polyneuropathy, anterior horn cell loss from recurring treatment-induced hypoglycemia, and coincidental motor neuronopathy”(Freeman et al 335). Proximal neuropathy is a rare condition, and occurs in less than one percent of diabetic patients. This facet of diabetic neuropathy shows prevalence in men with Type II diabetes, and is often preceded by significant weight loss and, in extreme cases, anorexia. The characteristic weight loss makes diagnosis difficult, as this usually causes blood glucose levels to stabilize. Symptoms generally include thigh and back pain, distal muscle weakness, and an absence of the knee jerk reflex. Symptoms often do not occur symmetrically, but rather begin on one side and progress to the other. Treatment options include prescribed anti-inflammatory drugs. Another option is to regain the weight lost as

Pickering 4 a result of the neuropathy. The pain is generally resolved, followed by a gradual improvement in strength (Freeman et al 343). The final category of diabetic neuropathy is radiculopathy and mononeuropathy. These neuropathies are most often associated with acute pain, and occur many years after the diabetes is diagnosed. This type of neuropathy, similar to proximal neuropathy, is coincided with unusual weight loss and, in the case of adult onset diabetes, be used as diagnostic symptom. This category is broken up into three subcategories: limb mononeuropathy, cranial mononeuropathy, and truncal mononeuropathy. Because of the many different problems diabetes can cause for the nervous system, along with its contribution to the morbidity of diabetic patients, there is a great deal of research concerning diabetic neuropathy. One study, conducted in Japan on a set of lab rats, sought to illustrate just how powerful hyperglycemia, characteristic of diabetes, could be in altering the function of the brain. It is becoming increasingly evident that hyperglycemia may be directly toxic to the nerve cells by prompting the conversion of glucose into the sugar alcohol sorbitol as a means of restoring normal blood glucose levels. This is possible because sugar alcohols do not cause a rapid increase in blood glucose levels, which is the earmark of hyperglycemia. If prolonged, this displacement reaction could cause a reduction in adenosine triphosphate (ATP) which would cause all of the major systems of the body to shut down. Neurotrophins, including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin- 4/5, were closely observed and measured in this experiment. While the scientists monitored the change in all of the major neurotrophins, they paid particular attention to the levels of brain-derived neurotrophic factor (BDNF). BDNF is responsible for the “maintenance of

Pickering 5 neuronal functions including synapse function and neuronal transmissions” (Furukawa et al 61). In order to judge the effect of peripheral neuropathy on the brain’s activity and the nervous system, the scientists evaluated the rats based on five stages of experimentation: immunoblots of the hippocampus, y-maze tasks, measurement of BDNF contents, semiquantification of BDNF mRNA expression, and Golgi staining (Furukawa et al 64). During the first phase of the experiment, the researchers induced diabetes in the Wistar rats by injecting streptozotocin, a chemical commonly used to induce diabetes for experimental purposes. The rats were diagnosed after four weeks of careful observation and lab tests. A control group of non-treated rats was similarly monitored (Furukawa et al 63). After confirming that the streptozotocin successfully induced the diabetes, the scientists examined the rats’ behavior as they were placed in a Y-Maze composed of gray wood. Their movement was observed and recorded in order to measure short term memory. This test revealed a reduced capacity for short term memory in the diabetic rats when compared to the control group. Following the Y-Maze task, the scientists examined the rats’ hippocampus by extracting the protein membrane and washing it in a solution with anti- calbindin, antisynapatophysin, and anti- syntaxin antibodies. This allowed each protein to be observed. “The expressions of calbindin, synaptophysine and syntaxin were significantly reduced in the diabetic hippocampus. These proteins are synaptospme- associated proteins, and relate to the secretion of neuronal transmitters such as glutamate, dopamine and acetylcholine” (Furukawa et al 66). These neurotransmitters are responsible for a number of crucial functions in the body, including but not limited to memory and pleasure. The absence of acetylcholine is being studied in association with Alzheimer’s disease. This

Pickering 6 has been illustrated by researchers who have observed that the occurrence of diabetes in Alzheimer’s patients is relatively high. It has been suggested that a diet sufficient in choline, along with its cofactor lethicin, might help to compensate for this deficiency. Additionally, the BDNF mRNA expressions in the hippocampus were measured. In the diabetic rats, these levels were found to be significantly lower when compared to the levels of the control group. After realizing the potential for devastation caused by diabetic neuropathy, one might wonder; what can be done to treat these side effects of diabetes? As with any disease, the focus of treatment is prevention. The primary means of prevention of neuropathy development is, of course, management of the diabetes. To do this, the patient must be aware of blood glucose testing methods and should be instructed in proper diabetic nutrition by a registered dietician. This will allow the patient to achieve and maintain healthy blood glucose levels. When treating diabetes the key to success is consistency of diet, exercise, and medication, when necessary. Sadly, despite careful treatment of diabetes, the condition can sometimes worsen and lead to neuropathy. While there is no cure, a variety of treatments are available to treat the symptoms. In order to treat the pain that occurs as a result of damaged nerves, doctors can prescribe trycyclic antidepressants. The pain relieving effects of the drugs usually begin within forty eight hours and generally precede the antidepressant function of the drug (Macleod et al 136). In addition to peripheral neuropathy, diabetes has been known to cause autonomic neuropathy. This type of neuropathy occurs in less than forty percent of patients, and is characterized by interference with the vital organs and other regulatory functions of the body. This type of neuropathy can be treated in a variety of ways. For example,

Pickering 7 disruption of the bowel movement might be addressed with a high fiber diet eaten in small, frequent intervals. Quite conflictingly, if a patient experiences difficulties with gastroparesis, they should consider eating a diet low in fiber. Complications involving the urinary tract should be addressed with antibiotics in order to prevent a urinary tract infection from developing and to maintain bladder control. Problems concerning hypertension, or high blood pressure, can be easily treated with oral medications. Perhaps the most important treatment for diabetic neuropathy, particularly peripheral neuropathy is the meticulous care of the feet. While it may seem an insignificant step in treatment, the diabetic foot is an area that demands careful attention. Any injury at all could lead to serious consequences; something as small as a paper cut, or even an ingrown toenail can lead to an emergency amputation of the foot. Does this seem a bit extreme? Examining the physiology of the foot can allow for a better understanding. When the circulation of blood becomes limited, as with diabetic patients, the nerve endings begin to die, leaving an area of neurons that no longer function. The next time the foot incurs a small injury, the patient may assume that the wound will heal on its own, when in fact the foot no longer has this capability. If not treated immediately, the tissues of the foot will begin to be destroyed. “The diabetic foot can be divided into two entities: the neuropathic foot in which neuropathy predominates and there is a good circulation, and the neuroischaemic foot where there is both neuropathy and absence of foot pulses” (Edmonds et al 149). If an ulcer does develop, treatment is a three step process. First, the callus should be removed and an antibiotic ointment should be applied. Secondly, and most importantly, the infection must be treated and healed. Finally, weight and pressure should be removed from the foot, and the patient should limit stress on the

Pickering 8 foot until it is fully healed. If these steps are not taken, the possibility for damage is almost endless. Left untreated the ulcer will develop into gangrene, a condition in which the nerves, capillaries, and blood vessels no longer function. If the gangrene affected foot is not removed, the condition could spread to other parts of the body. Fortunately, with the medical advances and research conducted in the diabetic field of medicine, this extreme measure is often avoided. Diabetes mellitus was once thought to be a disease solely concerned with dietary control and its effects on the body’s blood glucose levels. While the control of blood glucose levels is an integral part of diabetes, the problems it can cause extend to the other systems of the body. The central nervous system is drastically affected by hyperglycemia, and the symptoms of neuropathy can be painful and cause interference with patients’ lives. Not only is the nervous system affected on the peripheral level, the function of the brain is actually changed. In examining the different types of neuropathy possible as a result of diabetes, it is clear that their effects on the body are complex and profound. The hyperglycemia that is so characteristic of diabetes can actually cause the body to synthesize a substance that is known to be directly toxic to nerve cells. With a reduced level of nerve growth hormone, the chances for repair are minimal. As discovered in the experiment with the lab rats, the hyperglycemia associated with diabetes can have drastic effects on the function of the brain, especially in respect to short term memory by restricting the synthesis and distribution of essential neurotransmitter. Because one of these neurotransmitters, acetylcholine, has been linked to short term memory as it relates to the etiology of Alzheimer’s disease, this information

Pickering 9 has the potential to prevent this devastating illness from seizing any more lives. Diabetes is a disease, that, when regulated through proper diet and medication, can be controlled.