Diabetic Neuropathy Pathogenesis

Diabetic neuropathy affects a large proportion of individuals with long-term diabetes and may often go unnoticed in the early stages of the condition.

As the condition progresses, severe pain and other symptoms may manifest. Several factors are thought to be involved in the progression of diabetic neuropathy.

These include:

Damage to the small blood vessels

Diabetes mellitus causes a persistently high blood sugar level. Over time, this high blood glucose leads first to damage of the smaller blood vessels and later to major blood vessels and the heart. The damage to small blood vessels is termed microvascular disease. Microvascular disease is thought to underlie the complications of diabetes such as nephropathy, neuropathy and retinopathy. The increased blood glucose causes narrowing of the blood vessels that supply nerve endings with vital nutrients and oxygen and their constriction results in the nerves being deprived of these.

Other effects of diabetes

When glucose levels in cells are high, glucose may bond with cell proteins and alter their structure and these glycosylated proteins have been implicated in diabetic neuropathy. Protein kinase C has also been implicated, as animal models have shown that inhibitors of protein kinase C increase neuronal blood flow and the speed of nerve conduction. High blood glucose levels increase the amount of intracellular diacylglycerol which activates protein kinase C.

A metabolic pathway called the polyol pathway is also thought to play a role in diabetic neuropathy. Excess glucose in the body can cause activation of this pathway which, in turn, causes a decrease in glutathione and an increase in reactive oxygen radicals which damage cells. Activation of the pathway is dependent on the enzyme aldose reductase and inhibition of this enzyme has been shown to prevent neuropathy in animal studies.