diabetic neuropathy: pathogenesis
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Diabetic Neuropathy: PathogenesisTRANSCRIPT
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5/22/14, 6:51 AMDiabetic Neuropathy: Pathogenesis
Page 1 of 3http://www.medscape.com/viewarticle/510707_2
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Seminars in Neurology
Diabetic NeuropathyPraful Kelkar, MD Disclosures
Over the past 20 years there have been three main theories to explaindiabetic neuropathy: the polyol pathway theory, the microvascular theory,
and the glycosylation end-product theory. It has become increasinglyapparent that several pathophysiological factors probably operate
Semin Neurol. 2005;25(2):168-173.
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5/22/14, 6:51 AMDiabetic Neuropathy: Pathogenesis
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simultaneously, and it may be too simplistic to attempt to explain the manyclinical 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 viathe polyol pathway through a series of reactions catalyzed by aldose
reductase. Nerve fructose levels are also increased. The excess fructose andsorbitol 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 anddecreases 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 vascularrelaxation, which can cause chronic ischemia.[2]
Pathological changes in diabetic nerves include capillary basement membrane thickening, endothelial cell hyperplasia, andneuronal ischemia and infarction.[3]
Chronic intracellular hyperglycemia leads to generation of a family of glycating agents known as advanced glycosylation endproducts, 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 NADPHoxidase, contributing to hydrogen peroxide formation and further oxidative stress.[4]
There is increasing evidence that asymmetrical neuropathies, diabetic amyotrophy, and mononeuritis multiplex forms ofdiabetic 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, immunoglobulindeposition, 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 levelsof 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 ofneuropathy.[11]
Abnormal calcium channel activity plays a critical role in cellular injury and death in a variety of disorders. Increased activityof 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 arederanged 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 ofaffected nerves ( Table 1 ).
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Semin Neurol. 2005;25(2):168-173. 2005 Thieme Medical Publishers
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