Glucose-induced Alterations in Nerve Metabolism: Current Perspective on the Pathogenesis of Diabetic Neuropathy and Future Directions for Research and Therapy

Greene, Douglas A.; Lattimer, S. A.; Ulbrecht, Jan S.; Carroll, P. B.

doi:10.2337/diacare.8.3.290

Cited by 204 publications

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“…They are also improved by aldose reductase inhibition and dietary myoinositol supplementation [1]. Thus, it is unlikely that the deficits themselves resulted from a direct action of streptozotocin on axons or Schwann cells.…”

Section: Resultsmentioning

confidence: 93%

“…One viewpoint is that neuropathy results from hyperglycaemia stimulating the polyol pathway, which leads to loss of myo-inositol from nerve fibres. This in turn reduces nerve Na-K ATPase pump activity: fibres become Na loaded, Na channels inactivate, and NCV decreases [1]. Another hypothesis suggests that reduced nerve blood flow caused by rheological changes coupled with vasa nervosum microangiopathy leads to endoneurial hypoxia sufficient to impair function [21. In this communication we present data demonstrating that chronic nerve stimulation normalises NCV in streptozotocin-diabetic rats.…”

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confidence: 99%

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Chronic low frequency electrical activation for one week corrects nerve conduction velocity deficits in rats with diabetes of three months duration

Cameron

Robertson

1989

Diabetologia

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Summary. This study examined the effect of chronic electrical activation on conduction velocity deficits after three months of streptozotocin-induced diabetes. There were 30% and 20% reductions in conduction velocity in diabetic animals for tibialis anterior and saphenous nerves, respectively (p <0.01). Unilateral electrical stimulation of the common peroneal nerve, which contains axons supplying tibialis anterior but not saphenous nerve, was carried out in a group of diabetic and a group of normal control rats. Stimulation was given over seven days, at 10 Hz for 8 h/day. Final experiments were carried out at least 17 h after the last stimulation session. In normal rats stimulation had no effect on conduction velocity in either nerve. In diabetic animals, however, tibialis anterior conduction was within the normal control range for the stimulated nerve. In contrast, the contralateral unstimulated nerve had reduced conduction velocity (p < 0.001), which was within the unoperated diabetic control range. There were no effects on saphenous nerve conduction, comparing stimulated and unstimulated legs. We conclude that chronic increases in nerve electrical activation promote mechanisms that reverse conduction deficits in diabetic rats.Key words: Diabetic neuropathy, chronic electrical stimulation, nerve conduction, streptozotocin-diabetes.Reduced nerve conduction velocity (NCV) is an early neuropathic change in diabetic patients and animals. Its aetiology is unclear although several hypotheses have been considered. One viewpoint is that neuropathy results from hyperglycaemia stimulating the polyol pathway, which leads to loss of myo-inositol from nerve fibres. This in turn reduces nerve Na-K ATPase pump activity: fibres become Na loaded, Na channels inactivate, and NCV decreases [1]. Another hypothesis suggests that reduced nerve blood flow caused by rheological changes coupled with vasa nervosum microangiopathy leads to endoneurial hypoxia sufficient to impair function [21.In this communication we present data demonstrating that chronic nerve stimulation normalises NCV in streptozotocin-diabetic rats. We employed nerve stimulation to activate skeletal muscles as part of an investigation into changes in capillarisation and oxidative potential [3]. We also monitored NCV in stimulated and unstimulated nerve branches, and this previously unreported effect of electrical activation may have some beating on the mechanisms underlying diabetic neuropathy. Materials and methodsMale Sprague-Dawley rats aged 19 weeks, obtained from the Aberdeen University breeding colony, were divided into normal and diabetic groups. Normal animals acted as ,onset controls and were studied in final experiments one week later. A further group of normal rats was not subjected to stimulation or any operative procedures but was left for a further three months to act as unstimulated age-matched controls. The other animals were given a single i.p. injection of streptozotocin (45 mg/kg) in 20 mmol/1 sodium citrate buffer (pH 4.5). Diabetes was verified...

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Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 99%

Chronic low frequency electrical activation for one week corrects nerve conduction velocity deficits in rats with diabetes of three months duration

Cameron

Robertson

1989

Diabetologia

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“…Vascular endothelial growth factor/vascular permeability factor (VEGF) 1 is an endothelial cell-specific mitogen (15), but also displays other biologically relevant activities, such as the ability to increase blood vessel permeability (16) and to induce vascular relaxation (17). It is well documented that hypoxia, both in vitro and in vivo, is a potent inducer of VEGF (18)(19)(20), which is one potential mediator of the increases in blood flow and vascular hyperpermeability caused by hypoxia.…”

Section: Introductionmentioning

confidence: 99%

“…A large body of evidence indicates that multiple metabolic imbalances associated with elevated tissue glucose levels contribute to the pathogenesis of diabetic vascular complications (reviewed in [1][2][3][4][5]. Many of these metabolic perturbations have been linked to increased flux of glucose via the sorbitol pathway, a two-step enzymatic process in which D -glucose is reduced to sorbitol (coupled to oxidation of NADPH to NADP ϩ ) by aldose reductase followed by the subsequent oxidation of sorbitol to fructose (coupled to reduction of NAD ϩ to NADH) by sorbitol dehydrogenase.…”

Section: Introductionmentioning

confidence: 99%

Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.

Tilton¹,

Kawamura²,

Chang³

et al. 1997

J. Clin. Invest.

175

143

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The purpose of these experiments was to investigate a potential role for vascular endothelial growth factor (VEGF) in mediating vascular dysfunction induced by increased glucose flux via the sorbitol pathway. Skin chambers were mounted on the backs of Sprague-Dawley rats and 1 wk later, granulation tissue in the chamber was exposed twice daily for 7 d to 5 mM glucose, 30 mM glucose, or 1 mM sorbitol in the presence and absence of neutralizing VEGF antibodies. Albumin permeation and blood flow were increased two-to three-fold by 30 mM glucose and 1 mM sorbitol; these increases were prevented by coadministration of neutralizing VEGF antibodies. Blood flow and albumin permeation were increased ‫ف‬ 2.5-fold 1 h after topical application of recombinant human VEGF and these effects were prevented by nitric oxide synthase (NOS) inhibitors (aminoguanidine and N G -monomethyl L -arginine). Topical application of a superoxide generating system increased albumin permeation and blood flow and these changes were markedly attenuated by VEGF antibody and NOS inhibitors. Application of sodium nitroprusside for 7 d or the single application of a calcium ionophore, A23187, mimicked effects of glucose, sorbitol, and VEGF on vascular dysfunction and the ionophore effect was prevented by coadministration of aminoguanidine. These observations suggest a potentially important role for VEGF in mediating vascular dysfunction induced by "hypoxia-like" cytosolic metabolic imbalances (reductive stress, increased superoxide, and nitric oxide production) linked to increased flux of glucose via the sorbitol pathway. ( J. Clin. Invest. 1997. 99:2192-2202.)

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“…Effects of aldose reductase inhibitors on the muscarinic responses of DM rats, especially on those of the urinary bladder, have not been reported in the context of the polyol pathway, although there have been reports on the changes in the function of muscarinic receptors induced by drug treatments (14,16,18,26) and on the changes in the polyol pathway activities responsible for the DM neu ropathy (27)(28)(29)(30). Our data showed an increase of mus carinic receptor function in DM rats, and this response was attenuated by the treatment with a potent aldose reductase inhibitor, ONO-2235.…”

Section: Discussionmentioning

confidence: 99%

Effects of ONO-2235, an Aldose Reductase Inhibitor, on Muscarinic Receptors and Contractile Response of the Urinary Bladder in Rats with Streptozotocin-Induced Diabetes

Kanda¹,

Eto

Tanabe³

et al. 1997

Japanese Journal of Pharmacology

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ABSTRACT-This study was conducted to evaluate effects of the aldose reductase inhibitor ONO-2235 on the contractile response to acetylcholine of the urinary bladder dome of streptozotocin-induced diabetes mellitus (DM) rats and simultaneously observe the changes in the function and number of muscarinic receptors and the sorbitol content of the bladder. The contractile response to acetylcholine increased 51 % in the DM rat bladder dome compared to the normal rats; however, this was attenuated to a 10% increase by administration of 100 mg/kg ONO-2235 for 2 weeks. Treatment with ONO-2235 significantly decreased the specific [3H]quinuclidinyl benzilate binding in DM rats. However there was no significant dose-dependency among the ONO-2235-treated groups. The sorbitol levels of the sciatic nerve and the bladder were higher in the DM rats compared to the control rats; ONO-2235 decreased the level, although it did not completely reverse them to the control level. These results suggest that an aldose reductase inhibitor attenuates the in crease of the muscarinic receptor number and normalizes the enhanced contractile response to acetylcholine caused by hyperglycemia and diuresis, probably through suppression of the polyol-pathway in the DM rat bladder dome.

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Glucose-induced Alterations in Nerve Metabolism: Current Perspective on the Pathogenesis of Diabetic Neuropathy and Future Directions for Research and Therapy

Cited by 204 publications

References 0 publications

Chronic low frequency electrical activation for one week corrects nerve conduction velocity deficits in rats with diabetes of three months duration

Chronic low frequency electrical activation for one week corrects nerve conduction velocity deficits in rats with diabetes of three months duration

Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.

Effects of ONO-2235, an Aldose Reductase Inhibitor, on Muscarinic Receptors and Contractile Response of the Urinary Bladder in Rats with Streptozotocin-Induced Diabetes

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