Diabetic Neuropathy - Pathology
Polyol Pathway -
updated: 15 March 2008
Future prevention and treatment of diabetic neuropathy
Diabetes Metab. 1998 Nov;24 Suppl 3:79-83
Tomlinson DR.
This review orders the likely components of the pathogenesis of diabetic neuropathy into vertical (temporal) and horizontal dimensions. It is argued that the effects of hyperglycaemia are transduced to neuronal dysfunction via at least three secondary biochemical disturbances--the sorbitol (polyol) pathway, non-enzymatic glycation of proteins and oxidative stress--and that there are clear interactions between them. Because of these interactions, interference with one of these biochemical transducers could either worsen or attenuate the effects of the others. Examples of these alternatives are given. It is suggested that the prime goal for pharmacological intervention should be a combined attack on all three sources of disturbance. Interventions further on in the sequence of pathogenesis are also considered, and the arguments for the use of neurotrophic factors are persuasive because of their selectivity for different neuronal phenotypes, even though side-effects may be inevitable. Finally, a novel conjugate of gamma-linolenic acid and alpha-lipoic acid is considered as an agent with the potential to correct effects arising from more than one pathway of disorder in experimental diabetic neuropathy. The preliminary results with this agent have been encouraging.
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Online - Abstract
Physiopathology of diabetic neuropathies. Functional exploration of peripheral involvement
Diabetes Metab. 1998 Nov;24 Suppl 3:73-8
Raccah D.
Neuropathy is a common complication of Type 1 and Type 2 diabetes. In the peripheral nerve, persistent hyperglycaemia leads to metabolic and vascular disorders responsible for nerve fibre abnormalities. Genetic predisposition has been mentioned more recently. Among metabolic factors, an increase of the polyol pathway, a linoleic acid metabolism abnormality, a decrease of carnitine level, an increase of protein glycation, nerve growth factor abnormalities, and high production of oxygen free radicals can be involved. These factors could account for nerve membrane phospholipid pattern disorder, a decrease of Na/K ATPase activity and disequilibrium in prostaglandin production. Vascular factors involve a decrease in nitric oxide production, an abnormality of eicosanoid production, and an increase in the oxidative pathway, inducing vasoconstriction of endoneural microvascularisation and nerve hypoxia. Strong interactions exist between metabolic and vascular factors, making it difficult to distinguish between them. Moreover, a restriction polymorphism in the first intron of the Na/K ATPase ATP1 A1 gene is associated with low enzymatic activity and a relative risk of neuropathy of 6.5. Electromyography determines the myelinisation state of large nerve fibres and the number of functional axons. However, it cannot detect damage to small fibres, and the study of sensitive nerves is difficult. Electromyography is not a systematic examination and should be preceded by a clinical examination of sensitivity.
Publication Types:
Online - Abstract
New concepts and insights on pathogenesis and treatment of diabetic complications: polyol pathway and its inhibition
Nagoya J Med Sci. 1997 Nov;60(3-4):89-100
Hotta N.
The polyol pathway is one of the possible biochemical mechanisms by which hyperglycemia could impair the function and structure of the cells affected by diabetic complications. As possible hypothesis for the pathogenesis of diabetic complications, the polyol osmotic theory, alterations in myo-inositol and sodium metabolism, intermediary metabolites, abnormal changes of the redox state (NADH/NAD+ ratio) and an abnormality of kinase C dependent protein phosphorylation have been proposed. Recently, increasing evidence suggests that glycation and oxidative stress may have a cross-link with polyol pathway, contributing to the development of diabetic complications. If hyperglycemia-induced polyol pathway hyperactivity has an important role in the etiology of late-onset diabetic complications, the inhibition of aldose reductase (AR), a rate-limiting enzyme of the pathway, could become a key element in the prevention and reversal of diabetic complications. Recent evidence from both animal experiments and clinical studies has emerged to support this theory, resulting in the development of drugs available for the clinical treatment of diabetic neuropathy. From the results obtained mainly in animal models of diabetic complications, it is well recognized at present that AR inhibitors have a positive inhibitory effect on neuropathy, retinopathy, nephropathy, keratopathy, cataract-formation, possibly infection and atherosclerosis. It is now clear that AR inhibitors may offer various benefits to patients with diabetic complications. However, more extensive efforts are needed for the evaluation of their effects.
Publication Types:
Online - Abstract
Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism
Crit Rev Neurobiol. 1989;5(2):143-219
Greene DA, Lattimer-Greene S, Sima AA.
A unifying metabolic hypothesis completely accounting for the development of one or more of the chronic complications of diabetes on the basis of a single aspect of disturbed glucose metabolism resulting from insulin deficiency and/or hyperglycemia has been sought by clinical and basic scientists for decades. A growing body of loosely related but internally consistent scientific data obtained from cultured cells, incubated tissue preparations, animal models, and man implicate sorbitol- and glucose-induced myo-inositol depletion and altered phosphoinositide metabolism in a series of secondary biochemical, functional, and architectural abnormalities in the PNS in diabetes. These early metabolically based functional and structural changes simulate those that characterize human diabetic neuropathy. Can abnormal phosphoinositide metabolism in diabetic nerve thereby by itself explain the development of chronic diabetic neuropathy with all of its clinical complexity and heterogeneity? Almost certainly not. Even if the entire contribution of hyperglycemia to the development of diabetic neuropathy were mediated by secondary abnormalities in phosphoinositide metabolism, other factors must also play a role. Witness the differences in the histopathological picture of neuropathy in patients with IDDM and NIDDM despite similar durations and severity of diabetes, the apparent influence of age and gender on the appearance of early neuropathy in patients with IDDM, and the association of alcohol consumption with diabetic neuropathy. While early metabolic and functional disturbances in diabetic nerve such as impaired (Na,K)-ATPase function and paranodal swelling are empirically attributable to abnormal myo-inositol and phosphoinositide metabolism, more advanced abnormalities such as axo-glial dysjunction may reflect superimposed independent biochemical and/or hormonal defects (although, as mentioned previously, aldose reductase inhibition decreases axo-glial dysjunction in diabetic humans). The PNS has only a limited repertoire of responses to a variety of insults, so that Wallerian degeneration, axonal atrophy, impaired axonal transport, and dystrophic changes in diabetic neuropathy may represent multiple factors. On the other hand, the increasingly recognized importance of the phosphoinositide cascade in neuromodulation may attribute a progressively wider range of disturbances in the diabetic PNS to myo-inositol depletion and associated defects in phosphoinositide metabolism. Thus, while all effects of aldose reductase inhibitors in the PNS of diabetic rats have been reproduced by myo-inositol supplementation when this alternative intervention has been tested, the exact role of phosphoinositide metabolism in most of these responses is not well understood
Publication Types:
Online - Abstract
Polyol pathway activity and myo-inositol metabolism. A suggested relationship in the pathogenesis of diabetic neuropathy
Diabetes. 1983 Nov;32(11):988-92
Finegold D, Lattimer SA, Nolle S, Bernstein M, Greene DA.
Two major metabolic perturbations, increased polyol (sorbitol) pathway activity and reduced tissue myo-inositol content, are induced in peripheral nerve by hyperglycemia. Although they are commonly invoked as alternative biochemical pathogenetic mechanisms for diabetic neuropathy, their possible interrelationship has never been adequately explored. Therefore, we studied the effect of polyol pathway blockade with sorbinil, a specific inhibitor of aldose reductase, on nerve myo-inositol content in acutely streptozotocin-diabetic rats. Sorbinil administration completely prevented the fall in nerve myo-inositol, thereby implicating increased polyol pathway activity as a likely factor in the fall in nerve myo-inositol content in experimental diabetes
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Vascular factors in diabetic neuropathy
Diabetologia. 1994 Sep;37(9):847-54
Tesfaye S, Malik R, Ward JD.
Despite considerable research we still do not have a comprehensive explanation for the pathogenesis of diabetic neuropathy. Although chronic hyperglycaemia is almost certainly involved, it is not known whether the primary pathology is metabolic, microvascular, or an interaction between the two. Hyperglycaemia-induced polyol pathway hyperactivity associated with nerve sorbitol accumulation and myo-inositol depletion may play a part in the genesis of diabetic neuropathy. The case for microvascular disease in diabetic neuropathy is now strong. Fibre loss in human sural nerve is multifocal, suggesting ischaemia. The degree of vessel disease has been related to the severity of neuropathy. People with chronic obstructive pulmonary disease develop the so called "hypoxic neuropathy" in which similar microvascular changes occur as in diabetic neuropathy. In rats with experimental diabetic neuropathy nerve blood flow is reduced and oxygen supplementation or vasodilator treatment improved the deterioration in conduction velocity and nerve blood flow. Similarly, in human diabetic neuropathy, there is impaired nerve blood flow, epineurial arterio-venous shunting and a reduction in sural nerve oxygen tension. At what stage during the development of nerve damage these changes occur is yet to be determined.
Publication Types:
Online - Abstract
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