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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
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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.
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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
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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


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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, anti-

synapatophysin, 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


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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,
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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
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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
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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.