The Polyol Pathway in the Neuropathy of Early Diabetes

Ward, J. D.

doi:10.1016/b978-0-12-027362-1.50050-9

Cited by 9 publications

(11 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human trials using various aldose reductase inhibitors also have proved inconsistent, with effects varying from no change in conduction velocities to improvement in both sensory and motor conduction [32][33][34][35]. However, analysis of post-mortem material [36,37] and human nerve biopsies [38] suggests that alterations of polyol pathway activity and myo-inositol metabolism occur in nerves from human diabetics and encourages further experiments with these treatments.…”

Section: Discussionmentioning

confidence: 99%

Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: The effect of aldose reductase inhibition

Gillon¹,

Hawthorne²,

Tomlinson³

1983

Diabetologia

118

View full text Add to dashboard Cite

A possible relationship between increased sorbitol concentration and decreased myo-inositol concentration in peripheral nerves of diabetic rats has been examined. To this end, sorbinil, an aldose reductase inhibitor, was used either to prevent or reverse elevation of nerve sorbitol concentration in diabetic rats. Sorbinil treatment at 20 mg . kg-1 . day-1 prevented elevation of nerve sorbitol levels in early diabetes and reduced sorbitol concentration from 2.38 to 0.51 mumol/g in rats diabetic for 10 weeks. This treatment reduced the increase in nerve fructose concentration and prevented the reduced myo-inositol concentration found in diabetic rat nerve (control 3.63, diabetic 2.40, diabetic/sorbinil, 3.56 mumol/g). Sorbinil treatment did not prevent a significant slowing of motor-nerve conduction velocity at 10 weeks although treatment reduced the extent of slowing. Sorbinil treatment at 25 mg . kg-1 . day-1 reduced elevated sorbitol and fructose concentrations in diabetic in diabetic rat nerve and normalised myo-inositol concentration. Myo-Inositol treatment at 650 mg . kg-1 . day-1 did not affect the elevated concentrations of sorbitol, fructose or glucose in peripheral nerves of diabetic rats, but it did restore reduced myo-inositol concentration. Both sorbinil and myo-inositol treatment partially reversed the slowing of motor-nerve conduction velocity in diabetic rats. These results are discussed in relation to the involvement of sorbitol and myo-inositol metabolism in the aetiology of diabetic neuropathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: The effect of aldose reductase inhibition

Gillon¹,

Hawthorne²,

Tomlinson³

1983

Diabetologia

118

View full text Add to dashboard Cite

show abstract

“…1 -14 Under normal circumstances, the concentration of free myo-inositol within the rat sciatic nerve is approximately thirty times higher than that of the plasma. 7~9>15 ' 16 Neither the mechanisms responsible for the maintenance of this gradient nor the relative contribution of the axons, the Schwann cells, the epineurial space, and the endoneurial space to the total free myo-inositol content of nerve homogenates are known. Similarly, the significance of this gradient with regard to peripheral nerve function is unclear.…”

mentioning

confidence: 98%

Abnormal Sciatic Nerve Myo-inositol Metabolism in the Streptozotocin-diabetic Rat: Effect of Insulin Treatment

Clements

Stockard

1980

Diabetes

View full text Add to dashboard Cite

The metabolism of myo-inositol and its phospholipids has been studied in the sciatic nerves of control, two weeks' streptozotocin-diabetic, and insulin-treated diabetic rats. The concentrations of glucose, fructose, and sorbitol were increased and the concentration of myo-inositol was decreased in the sciatic nerves of the diabetic animals; these abnormalities were only partially corrected by insulin therapy that was adequate to obviate hyperglycemia. Whereas the space of distribution of 2-3 H-myo-inositol was found to exceed the total water space of the nerves of control animals, the 2-3 H-myo-inositol space approximated the water space in the nerves of diabetic animals and was only slightly increased after insulin therapy. During the first 2 h after the intraperitoneal injection of 2-3 H-myo-inositol, the recovery of radioactivity in nerve lipids was decreased by 69% in the untreated diabetics and by 77% in the insulin-treated diabetics. Analysis of the individual phosphoinositides revealed a proportional increase in the radioactivity recovered with phosphatidylinositol and a decrease in the recovery with triphosphatidylinositol in the diabetic nerves. CDP-diglyceride:inositol transferase activity was decreased by 44% in homogenates of sciatic nerves from untreated diabetic rats, but it was normal in nerve homogenates from insulin-treated diabetics. The pattern of incorporation of radioactivity into phospholipids after 1 h of incubation of nerve homogenates with 2-3 H-myo-inositol was similar to that observed in vivo. The fractional recovery of radioactivity with phosphatidylinositol was increased, whereas the recovery of label as triphosphatidylinositol was decreased by 11% in the presence of homogenates of sciatic nerves from diabetic rats.These observations indicate that 2 wk of acute streptozotocin diabetes results in a decrease in the sciatic nerve content and space of distribution of myoinositol and suggests that nerve myo-inositol transport may be defective in the diabetic animal. The observed abnormalities in the amount and pattern of incorporation of 2-3 H-myo-inositol into diabetic nerve phospholipids could be explained, in part, by decreased activities of CDP-diglyceride:inositol transferase and phosphatidylinositol 4-phosphate kinase activities in the diabetic nerves. However, the fact that the incorporation of 2-3 H-myo-inositol into phospholipids was decreased in the nerves of insulin-treated-diabetic animals despite a normal CDP-diglyceride:inositol transferase activity suggests that defective myo-inositol transport may also contribute to the abnormal neural phosphoinositide metabolism in this model. The possibility that these abnormalities are related to the development of the structural and functional changes associated with diabetic neuropathy requires further investigation. DIABETES 29:227-235, March 1980. D uring the past decade, considerable evidence has accumulated to suggest that the metabolism of myo-inositol and its phospholipid derivatives may play an important role in peripheral nerve...

show abstract

“…(The clinical efficacy of aldose reductase inhibitors or MI supplementation await large scale, long-term, randomized, controlled clinical trials with these drugs [10,16,17]). The conflicting and fragmentary reports of measurements of whole nerve MI content in diabetic humans (11,(18)(19)(20)(21) and the reported lack of an effect thereon of aldose reductase inhibitor therapy (1 1,21) has recently been used to argue that altered MI metabolism is irrelevant to the pathogenesis of diabetic neuropathy (1 1, 22, 23). This view has been disputed (24,25) partly on the basis of the fact that MI metabolism is now thought to be highly compartmentalized, and that depletion of a putative small metabolically labile MI pool by glucose during in vitro incubation of aortic intima-media preparations impairs tissue function (including sodium-potassium ATPase activity) in the absence of detectable changes in tissue MI content (26).…”

Section: Introductionmentioning

confidence: 99%

A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.

Greene¹,

Lattimer²,

Carroll³

et al. 1990

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

The Polyol Pathway in the Neuropathy of Early Diabetes

Cited by 9 publications

References 4 publications

Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: The effect of aldose reductase inhibition

Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: The effect of aldose reductase inhibition

Abnormal Sciatic Nerve Myo-inositol Metabolism in the Streptozotocin-diabetic Rat: Effect of Insulin Treatment

A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.

Contact Info

Product

Resources

About