Diabetic Neuropathy

Praful Kelkar, MD


Semin Neurol. 2005;25(2):168-173. 

In This Article


Over the past 20 years there have been three main theories to explain diabetic neuropathy: the polyol pathway theory, the microvascular theory, and the glycosylation end-product theory. It has become increasingly apparent that several pathophysiological factors probably operate simultaneously, and it may be too simplistic to attempt to explain the many clinical presentations and pathological findings of diabetic neuropathy by a single theory.

Glucose uptake in peripheral nerves is not dependent on insulin. Therefore, high blood glucose levels in diabetes lead to high nerve glucose concentrations. This, in turn, leads to conversion of glucose to sorbitol via the polyol pathway through a series of reactions catalyzed by aldose reductase. Nerve fructose levels are also increased. The excess fructose and sorbitol decrease the expression of the sodium/myoinositol cotransporter, leading to decreases in myoinositol levels. This causes decreased levels of phosphoinositide, which interferes with activation of the Na pump and decreases Na/K ATPase activity. Activation of aldose reductase depletes its cofactor, NADPH, which results in decreased levels of nitric oxide and glutathione, which buffer against oxidative injury. Lack of nitric oxide also inhibits vascular relaxation, which can cause chronic ischemia.[2]

Pathological changes in diabetic nerves include capillary basement membrane thickening, endothelial cell hyperplasia, and neuronal ischemia and infarction.[3]

Chronic intracellular hyperglycemia leads to generation of a family of glycating agents known as advanced glycosylation end products, which deposit within and around peripheral nerves. Advanced glycosylation end products can interfere with axonal transport, leading to slowing of nerve conduction velocities. They can also deplete NADPH by activation of NADPH oxidase, contributing to hydrogen peroxide formation and further oxidative stress.[4]

There is increasing evidence that asymmetrical neuropathies, diabetic amyotrophy, and mononeuritis multiplex forms of diabetic neuropathies are caused by inflammatory vasculopathy or vasculitis.[5,6,7,8] Diabetic nerves appear to have an increased susceptibility to both cellular and humoral immune factors, including activation of lymphocytes, immunoglobulin deposition, and complement activation.[5,9,10]

Neurotrophic factors are essential for maintenance of nerve structure and function as well as repair after an injury. Low levels of nerve growth factor and insulin-like growth factors 1 have been shown to correlate with the severity of the diabetic neuropathy in animal models. Insulin itself has neurotrophic effects and its deficiency may contribute to the development of neuropathy.[11]

Abnormal calcium channel activity plays a critical role in cellular injury and death in a variety of disorders. Increased activity of voltage-dependent calcium channels has been demonstrated in diabetic neuropathy, which may lead to tissue injury.[12] Sodium channel dysfunction has an important role in the genesis of painful neuropathy, which is common in diabetes.[13]

It has been suggested that the essential fatty acid pathways from linolenic acid to prostaglandins and thromboxane are deranged in diabetic patients, which lead to multiple areas of cellular dysfunction such as membrane fluid abnormalities, changes in red blood cell membrane, and decreased prostaglandin E2, a potent vasodilator.[14,15]

Diabetic neuropathy can be classified by multiple schemes. A practical classification is based on the pattern of distribution of affected nerves ( Table 1 ).


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