Diabetic neuropathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

Diabetic neuropathy can be classified into two main types:

• Sensorimotor
• Autonomic

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

1. Microvascular disease,
2. Advanced Glycation Endproduct,
3. Protein kinase C, and the
4. Polyol pathway.

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., angiotensin-converting-enzyme 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.

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

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.

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 which also have lots of microvasculature themselves.

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 (Diabetes), 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.

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.

Experimental evidence has yet to confirm that the polyol pathway actually is responsible for microvasculature damage in the retina, kidney and/or neurons of the body. However, physiologists are fairly certain that it plays some role in neuropathy.

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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.

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 largest group of neuropathy patients are of unknown cause, referred to as idiopathic in origin. Of the roughly 100 known causes, diabetes is by far the largest. Other known causes include genetic factors, damaging chemical agents such as chemotherapy drugs, and HIV.

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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.

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.

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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 (skin and soft tissue breakdown) and this may require amputation. In addition, motor nerve damage can lead to psychotic breakdown and imbalance.

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.

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