Diabetic Neuropathy

What is Diabetic Neuropathy?

Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum). Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; a painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.

Diabetes is the leading known cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes patients. It is estimated that the prevalence of neuropathy in diabetes patients is approximately 20%. Diabetic neuropathy is implicated in 50-75% of nontraumatic amputations.

The main risk factor for diabetic neuropathy is hyperglycemia. It is important to note that people with diabetes are more likely to develop symptoms relating to peripheral neuropathy as the excess glucose in the blood results in a condition known as Glucojasinogen. This condition is affiliated with erectile dysfunction and epigastric tenderness which in turn results in lack of blood flow to the peripheral intrapectine nerves which govern the movement of the arms and legs. In the DCCT (Diabetes Control and Complications Trial, 1995) study, the annual incidence of neuropathy was 2% per year, but dropped to 0.56% with intensive treatment of Type 1 diabetics. The progression of neuropathy is dependent on the degree of glycemic control in both Type 1 and Type 2 diabetes. Duration of diabetes, age, cigarette smoking, hypertension, height and hyperlipidemia are also risk factors for diabetic neuropathy.

The mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive.

As a complication, there is an increased risk of injury to the feet because of loss of sensation (see diabetic foot). Small infections can progress to ulceration and this may require amputation.

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Diabetic Neuropathy Pathogenesis

There are four factors thought to be involved in the development of diabetic neuropathy:

Microvascular disease

Vascular and neural diseases are closely related and intertwined. Blood vessels depend on normal nerve function, and nerves depend on adequate blood flow. The first pathological change in the microvasculature is vasoconstriction. As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Vasodilator agents (e.g., ACE inhibitors, α1-antagonists) can lead to substantial improvements in neuronal blood flow, with corresponding improvements in nerve conduction velocities. Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.

Advanced glycated end products

Elevated intracellular levels of glucose cause a non-enzymatic covalent bonding with proteins, which alters their structure and inhibits their function. Some of these glycosylated proteins have been implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.

Protein kinase C

PKC is implicated in the pathology of diabetic neuropathy. Increased levels of glucose cause an increase in intracellular diacylglycerol, which activates PKC. PKC inhibitors in animal models will increase nerve conduction velocity by increasing neuronal blood flow.

Polyol pathway

Also called the sorbitol/aldose reductase pathway, the polyol pathway may be implicated in diabetic complications that result in microvascular damage to nervous tissue, and also to the retina and kidney.

Glucose is a highly reactive compound, and it must be metabolized or it will find tissues in the body to react with. Increased glucose levels, like those seen in diabetes, activates this alternative biochemical pathway, which in turn causes a decrease in glutathione and an increase in reactive oxygen radicals. The pathway is dependent on the enzyme aldose reductase. Inhibitors of this enzyme have demonstrated efficacy in animal models in preventing the development of neuropathy.

While most body cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney and nervous tissues are insulin-independent. Therefore there is a free interchange of glucose from inside to outside of the cell, regardless of the action of insulin, in the eye, kidney and neurons. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway and be converted into sorbitol. Under normal blood glucose levels, this interchange will cause no problems, as aldose reductase has a low affinity for glucose at normal concentrations.

However, in a hyperglycemic state, the affinity of aldose reductase for glucose rises, meaning much higher levels of sorbitol and much lower levels of NADPH, a compound used up when this pathway is activated. The sorbitol can not cross cell membranes, and when it accumulates, it produces osmotic stresses on cells by drawing water into the cell. Fructose does essentially the same thing, and it is created even further on in the chemical pathway.

The NADPH, used up when the pathway is activated, acts to promote nitric oxide and glutathione production, and its conversion during the pathway leads to reactive oxygen molecules. Glutathione deficiencies can lead to hemolysis caused by oxidative stress, and we already know that nitric oxide is one of the important vasodilators in blood vessels. NAD+, which is also used up, is necessary to keep reactive oxygen species from forming and damaging cells.

Furthermore, the high levels of sorbitol are believed to reduce the cellular uptake of another alcohol, myoinsitol, decreasing the activity of the plasma membrane Na+/K+ ATPase pump required for nerve function, further contributing to the neuropathy.

In summary, excessive activation of the polyol pathway leads to increased levels of sorbitol and reactive oxygen molecules and decreased levels of nitric oxide and glutathione, as well as increased osmotic stresses on the cell membrane. Any one of these elements alone can promote cell damage, but here we have several acting together.

Effects on nerve types

Different nerves are affected in different ways

Sensorimotor polyneuropathy

Longer nerve fibers are affected to a greater degree than shorter ones, because nerve conduction velocity is slowed in proportion to a nerve's length. In this syndrome, decreased sensation and loss of reflexes occurs first in the toes on each foot, then extends upward. It is usually described as glove-stocking distribution of numbness, sensory loss, dysesthesia and night time pain. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, like a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk for developing ulcers and infections on the feet and legs, which can lead to amputation. Similarly, these patients can get multiple fractures of the knee, ankle or foot, and develop a Charcot joint. Loss of motor function results in dorsiflexion, contractures of the toes, loss of the interosseous muscle function and leads to contraction of the digits, so called hammer toes. These contractures occur not only in the foot but also in the hand where the loss of the musculature makes the hand appear gaunt and skeletal. The loss of muscular function is progressive.

Autonomic neuropathy

The autonomic nervous system is composed of nerves serving the heart, gastrointestinal system and genitourinary system. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfunction in diabetics is orthostatic hypotension, or fainting when standing up. In the case of diabetic autonomic neuropathy, it is due to the failure of the heart and arteries to appropriately adjust heart rate and vascular tone to keep blood continually and fully flowing to the brain. This symptom is usually accompanied by a loss of the usual change in heart rate seen with normal breathing. These two findings suggest autonomic neuropathy.

GI tract manifestations include gastroparesis, nausea, bloating, and diarrhea. Because many diabetics take oral medication for their diabetes, absorption of these medicines is greatly affected by the delayed gastric emptying. This can lead to hypoglycemia when an oral diabetic agent is taken before a meal and does not get absorbed until hours, or sometimes days later, when there is normal or low blood sugar already. Sluggish movement of the small intestine can cause bacterial overgrowth, made worse by the presence of hyperglycemia. This leads to bloating, gas and diarrhea.

Urinary symptoms include urinary frequency, urgency, incontinence and retention. Again, because of the retention of urine, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy.

Cranial neuropathy

When cranial nerves are affected, oculomotor (3rd) neuropathies are most common. The oculomotor nerve controls all of the muscles that move the eye with the exception of the lateral rectus and superior oblique muscles. It also serves to constrict the pupil and open the eyelid. The onset of a diabetic third nerve palsy is usually abrupt, beginning with frontal or periorbital pain and then diplopia. All of the oculomotor muscles innervated by the third nerve may be affected, except for those that control pupil size. This is because pupillary function within CNIII is found on the periphery of the nerve (in terms of a cross sectional view), which makes it less susceptible to ischemic damage (as it is closer to the vascular supply). The sixth nerve, the abducens nerve, which innervates the lateral rectus muscle of the eye (moves the eye laterally), is also commonly affected but fourth nerve, the trochlear nerve, (innervates the superior oblique muscle, which moves the eye downward) involvement is unusual. Mononeuropathies of the thoracic or lumbar spinal nerves can occur and lead to painful syndromes that mimic myocardial infarction, cholecystitis or appendicitis. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome.

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Diabetic Neuropathy Diagnosis

Diabetic peripheral neuropathy is the most likely diagnosis for someone with diabetes who has pain in a leg or foot, although it may also be caused by vitamin B12 deficiency or osteoarthritis.

A glucose tolerance test is recommended for someone with peripheral pain who has not been diagnosed with diabetes.

Neurological tests may show reduced functioning of the peripheral nerves, but seldom correlate with the severity of diabetic peripheral neuropathy and are not appropriate as routine tests for the condition.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Diabetic neuropathy" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.