DIABETES
October 20, 2010

Diabetic Neuropathy

John W. Wiley, M.D., and Roberto Towns, Ph.D.
Uncontrolled blood sugar can wreak havoc on diabetics' nervous systems. Learn the signs and symptoms.
Dr. Wiley is Professor, Internal Medicine and Director, Michigan Clinical Research Unit, and Dr. Towns is Research Assistant Professor, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI.

Diabetes, formally known as diabetes mellitus, affects 171 million people worldwide, according to the World Health Organization. Type I diabetes usually starts in childhood or early adulthood, while the onset of type 2 diabetes is typically much later, often in middle-age.

Diabetes affects many of the body’s systems and functions, not the least of which may be the nervous system. When the nervous system is affected, diabetic neuropathy can result. This occurs when too much sugar (hyperglycemia) circulates in the blood stream over a long period of time.

Some people with neuropathy may not have any symptoms at all, while others will experience pain, tingling, or numbness in their hands, arms, feet, or legs. Many patients will first notice numbness, tingling, or pain in the feet. These symptoms are usually mild in the beginning but may worsen over the years, and then actually decrease in later years, as the nerve damage gets worse.

It is thought that 60-70% of people with diabetes will develop some form of neuropathy over their lifetimes. While it is still somewhat unclear, diabetic neuropathy tends to occur after about five years of high blood sugar, and it usually peaks after about 25 years. Some people with neuropathy may not have any symptoms at all, while others will experience pain, tingling, or numbness in their hands, arms, feet, or legs. Diabetic neuropathy can also affect different organ systems, including the cardiovascular, genital-urinary, digestive, and vision.

Though the origin of type 1 and type 2 diabetes is different, the result is the same: chronically high blood sugar. And the long-term effects of high blood sugar can be felt in different ways throughout the body, like increasing oxidative stress (damage to cells) of various organs and the overactivation of other metabolic pathways.

All these effects can lead to problems in the ways that nerve cells (neurons) function. And when neurons don’t functions properly, neuropathy can occur. Neuropathy may affect different parts of the nervous system, including the peripheral nervous system (which is made up of all the nerves outside of the brain and spinal cord, including "automatic" or involuntary processes like heart rate and digestion, and all the nerves that provide us with our sense of touch). This article will outline the symptoms of diabetic neuropathy, as well as how it is diagnosed, and the available treatment options.

Signs and Symptoms of Diabetic Neuropathy

The symptoms of neuropathy that diabetic patients may experience vary, depending on which nerves are involved. For example, many patients will first notice numbness, tingling, or pain in the feet. These symptoms are usually mild in the beginning but may worsen over the years, and then actually decrease in later years, as the nerve damage gets worse. Some people report muscle weakness in their hands or feet, while others have problems in their autonomic or involuntary nervous systems. This can show up in a variety of ways, such as constipation, diarrhea, nausea with or without vomiting, feeling full after eating, dizziness with or without fainting related to a drop in blood pressure after standing or sitting up, erectile problems in men, and vaginal dryness in women, and problems with urination. In other words, there are many different symptoms that may signal that nerve damage as a consequence of diabetes is occuring.

Signs of Peripheral Neuropathy
Neuropathy of the peripheral nervous system usually begins with tingling or numbness in both hands or feet, which may progress "inwards" over time (in other words, it can begin in the fingertips or toes and proceed up the hands and arms or legs). Some people report that their sensations are "hypersensitive", while other report feeling less sensitivity. This difference may depend on how long diabetes has been present. Some individuals will present with problems involving specific nerves and muscles, for example, double vision, pain or weakness in the face, thigh, chest or abdomen.

Signs of Autonomic Neuropathy
As mentioned, autonomic neuropathy involves the branch of the nervous system that controls the heart and blood vessels, the gastrointestinal tract and genital-urinary system, and the system that monitors and balances blood glucose levels after a low blood sugar (hypoglycemic) episodes.

Many patients will first notice numbness, tingling, or pain in the feet. These symptoms are usually mild in the beginning but may worsen over the years, and then actually decrease in later years, as the nerve damage gets worse.

Patients with autonomic neuropathy may be unaware of the heart palpitations, shakiness, and sweating that can occur with episodes of low blood sugar. When nerves that supply the heart and blood vessels are affected, individuals may lose their ability to adjust blood pressure and heart rate when they change in position, which can result in light-headedness and, sometimes, loss of consciousness.

When the gastrointestinal tract is involved, constipation is often a person's first complaint. Later, some people may experience diarrhea associated with bacterial overgrowth in the small intestine or (rarely) large amounts of diarrhea. When the upper GI tract is affected, it can result in nausea with or without vomiting, loss of appetite with bloating of the abdomen, distention, and feeling particularly full after eating sometime even a small amount, and problems swallowing. This constellation of symptoms can be seen in patients who have slow emptying of the stomach, a condition called gastroparesis.

Autonomic neuropathy may also affect a patient’s urinary tract or sexual function. Some patients may not be able to empty their bladders completely, which increases the risk for urinary tract infections. Some people may also experience urinary incontinence (leaking of urine between bathroom visits). Men may have problems with erections, ejaculation, and orgasm, while women may experience problems with arousal, vaginal dryness, and having a normal orgasm.

People with autonomic neuropathy may also develop an abnormal sweat response, which can result in problems regulating body temperature or producing too much sweat at inappropriate times. Vision can be affected as a result of changes in how the pupil responds to light or in the muscles that coordinate eye movements, which can result in blurry or double vision.

How Do Doctors Diagnose Neuropathy?

When checking for neuropathy, a doctor will look at the patient’s clinical history and do a complete physical examination, which will include specific diagnostic tests. The physical examination may show changes in blood pressure, heart rate, muscle strength, reflexes, and changes in how one responds to light touch, position, temperature, and vibration. A doctor will carefully examine the patient’s feet, which is crucial, since diabetic neuropathies often begin there. Additional testing may measure how a patient’s nerves and muscles conduct electricity (nerves and muscle cells communicate via electric impulses), in order to determine the type of nerve damage that has occurred and the extent of it.

A doctor will carefully examine the patient’s feet, which is crucial, since diabetic neuropathies often begin there.

Other methods are used to test how a patient’s heart responds to deep breathing and to changes in his or her posture, which, if abnormal, could suggest the presence of autonomic neuropathy. Some tests measure how much a person sweats in response to a topical stimulant, and others can count the number of sensory nerves on the skin via a biopsy. If the number of sensory nerves in a patient’s skin is lower than normal, this is a strong indication that early sensory neuropathy has occurred.

If a doctor suspects gastroparesis or neuropathy of the urinary tract, specific tests can be performed to verify either of these conditions, too. And finally, it is important for diabetics to have an annual eye exam to check for abnormalities, since the eyes can often be affected by neuropathy.

How Diabetic Neuropathy Develops, The Key Players

The underlying problem in diabetes is simply too much sugar circulating in the blood stream: hyperglycemia. This occurs for slightly different reasons in type 1 vs. type 2 diabetes. With type 1, there is simply not enough insulin in the body because the cells in the pancreas which make insulin have been destroyed (it is thought that the body's immune system actually attacks them, in a haywire autoimmune response).

In type 2 diabetes, on the other hand, insulin is not able to reduce blood sugar as it should by bringing it into the body’s cells because insulin resistance has developed over time, often associated with obesity, poor diet and lack of exercise. In both cases, the high levels of glucose circulating in the blood trigger a variety of problems at the cellular level, which result in many of the complications associated with diabetes.

General Factors
A large body of research on diabetes and diabetic neuropathy has looked into the factors that may play a role in diabetes, like blood fat levels, genetics, and age-related risks (like the natural decrease in metabolism as we age).

A recent study found that high triglycerides in the blood may be a better predictor of diabetic neuropathy than any other variable, including how long one has had diabetes or how well it is controlled.

Problems with the makeup of blood fats is one factor that’s known to contribute to diabetes. In fact, the ways in which various types of fats (lipids and fatty acids) lead to oxidative stress and inflammation in the body is a big area of interest in diabetes research. A recent study found that high triglycerides in the blood may be a better predictor of diabetic neuropathy than any other variable, including how long one has had diabetes or how well it is controlled. Of course, it is also clear that early detection of hyperglycemia and keeping it under good control are critical in preventing the development of diabetic neuropathy as well as other complications related to diabetes.

Stress and Sugar Wreak Havoc on Cells
When hyperglycemia is uncontrolled over time, a variety of changes can occur in the ways cells utilize energy. A high-glucose environment can lead to the generation of destructive molecules called reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can alter the cell’s DNA. The damage that these little compounds can bring about is thought to be perhaps the single most important change to occur leading to cell death and ultimately to diabetic neuropathy. Though the mechanisms behind the changes that lead to cell damage are extraordinarily complex, the bottom line is that too much sugar in the blood can bring about the oxidative stress that leads to serious problems in nerve function.

When sugar levels are too high, both sorbitol and fructose can accumulate inside the nerve cell. This accumulation can lead to a cascade of events and byproducts that result in inflammation that affects the nerve cell. The ultimate result is that damaging stress again results, and neuropathy can now occur. Much research is looking into how targeting the specific pathways involving these sugars might have therapeutic potential.

Enzyme Activity Is Disrupted
Oftentimes in diabetes, the enzymes that help cells function normally are disrupted, and this is what leads to neuropathy. Though there are far too many enzymes to cover here, one of the central players is aldose reductase (AR), which helps convert glucose to sorbitol which ultimately gets converted to fructose.

A high-glucose environment can lead to the generation of destructive molecules which can alter the cell’s DNA. The damage that these little compounds can bring about is thought to be perhaps the single most important change to occur leading to cell death and ultimately to diabetic neuropathy.

As mentioned above, if these two sugars are too high, more oxidative stress (as well as other unwanted effects) can result. In fact, some studies in diabetic lab animals have shown that when AR is inhibited so that glucose can’t be converted into sorbitol, many of the harmful effects on the cell are actually reduced. Investigators are currently studying whether inhibitors of AR as well as other compounds are effective to treat diabetic neuropathy in animals and humans.

Protein kinase C (PKC) is another enzyme that has been shown to play an important role in some of the complications associated with diabetes. This is particularly the case in diabetic retinopathy (damage to the retina of the eye), which seems to occur when the blood supply is reduced.

There are likely many other enzymes and pathways involved in diabetic neuropathy, and as more research is devoted to uncovering and understanding them, this will help gain clues into both the origin and treatment options for neuropathies.

Reduced Blood Supply
Does blood supply affect the development of diabetic neuropathy? The answer appears to be "yes". In fact the relationship between blood vessels and nerve fibers may be more important than nerve function alone, particularly the blood supply to peripheral nerves like those in the hands and feet. And as mentioned, reduced blood flow to the eye seems to play a significant role in the development of damage to the retina. Therapies that are designed to improve blood flow appear to reduce damage to the peripheral nerves.

Preventing Neuropathy

Many studies have shown that the best way to prevent neuropathy is to maintain blood sugar levels as close to the normal range as possible. Research also shows that large-scale fluctuations of blood glucose into the hyperglycemic range are also linked to problems in the function of the autonomic nervous system.

The best strategies to prevent neuropathy from occurring also include:

  • Maintaining a healthy body weight,
  • Not smoking,
  • Avoiding excessive use of alcohol

See the end of the article for more tips and helpful references.

Treatment Options for Neuropathies

So, what happens if you develop neuropathy? How do doctors treat it once it develops? Painful neuropathy will often respond to treatment using the group of antidepressants known as the tricyclics (such as nortriptyline), and to other types of antidepressants (such as duloxetine) or anticonvulsant medications (such as gabapentin). Keep in mind that relatively low doses of these drugs can be very effective in managing neuropathy. Opioid medications may also work, but should be used in moderation because of their side-effects, which can worsen other complications of neuropathy like constipation.

There are also treatments for autonomic neuropathies like gastroparesis,, but again it is important for one’s doctor to consider the side effects that may occur with the various treatments, and as with any drug, to determine whether the benefits outweigh the risks.

Painful neuropathy will often respond to treatment using the group of antidepressants known as the tricyclics (such as nortriptyline), and to other types of antidepressants (such as duloxetine) or anticonvulsant medications (such as gabapentin).

Patients who are suffering from diarrhea as a result of bacterial overgrowth are usually treated with a broad spectrum antibiotic that specifically acts in the digestive tract. Patients with constipation will typically respond to polyethylene glycol (PEG) 3350 products, which can help regulate one’s bowel movements (i.e., Miralax®). People who have problems the genital-urinary tract or trouble with their vision should see the appropriate specialist who will determine the best management options.

Summary

Neuropathy is a complication of diabetes that we want to avoid, if possible. There are some practices that can help delay onset and reduce the level of injury. In particular, patients with diabetes should try to do the following:

  • Maintain blood glucose as close to the normal range as possible.
  • Limit alcohol.
  • Don’t smoke.
  • Take especially good care of your feet and tell your doctor about any skin problems, especially sores that have trouble healing.
  • Tell your doctor about any problems you experience with your:
    • Hands, arms, feet or legs such as changes in sensation or muscle weakness.
    • Stomach, bowels, or bladder such as bloating, distention, constipation, diarrhea or difficulties with urination.
  • Tell the doctor if you:
    • Have problems with sex, such as erectile dysfunction, difficulty achieving an orgasm or vaginal dryness.
    • Cannot always tell when your blood sugar is low.
    • Feel dizzy when you move from lying down to a sitting or standing position.

Online Resources

The sites below are set up by the leading organizations in the field of diabetes, whose goal it is to developing effective new treatment for methods for diabetes and its complications. Please visit these sites to learn more.

American Diabetes Association:
http://www.diabetes.org/diabetes-research/clinical-trials/trials-home.jsp

Juvenile Diabetes Research Foundation:
http://www.jdrf.org

National Institutes of Health:
http://www.diabetes.niddk.nih.gov

Food and Drug Administration:
http://www.fda.gov/diabetes

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