5/22/14, 6:51 AM Diabetic Neuropathy: Pathogenesis

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Seminars in Neurology
Diabetic Neuropathy
Praful Kelkar, MD Disclosures
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
Semin Neurol. 2005;25(2):168-173.
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5/22/14, 6:51 AM Diabetic Neuropathy: Pathogenesis
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Comment Comment
simultaneously, and it may be too simplistic to attempt to explain the many
clinical presentations and pathological ndings 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 inammatory 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 deciency 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 uid abnormalities,
changes in red blood cell membrane, and decreased prostaglandin E2, a potent vasodilator.
[14,15]
Diabetic neuropathy can be classied by multiple schemes. A practical classication is based on the pattern of distribution of
affected nerves ( Table 1 ).
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Semin Neurol. 2005;25(2):168-173. 2005 Thieme Medical Publishers
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