Free and lipid inositol, sorbitol and sugars in sciatic nerve obtained post-mortem from diabetic patients and control subjects

Mayhew, John; Gillon, K. R. W.; Hawthorne, J. N.

doi:10.1007/bf00275940

Cited by 105 publications

(48 citation statements)

References 14 publications

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“…In the diabetic rat these complications can be ameliorated by aldose reductase inhibition [10,17], thus demonstrating a reversible component, at least over a relatively short period in this species. In man, elevated sorbitol and fructose concentrations are found in the nerves of diabetic patients [18] and the reduction of erythrocyte sorbitol levels by sorbinil in diabetic patients [19] suggests a possible role for this agent in the treatment of diabetic neuropathy. In normal subjects, sorbinil is eliminated slowly from the circulation with a half-time of disappearance of 34-52h.…”

Section: Discussionmentioning

confidence: 99%

Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy

et al. 1984

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Summary. The effect of sorbinil (200 mg daily for 4 weeks) was examined in 13patients, mean age 59.7years (range 42-72 years), with symptomatic diabetic neuropathy of mean duration 6years (range 1-18years). In this double-blind, placebo-controlled crossover trial, studies were made of motor, sensory and autonomic nerve function, severity of painful symptoms and duration of sleep. One patient was withdrawn because of an adverse reaction to sorbinil. In the other 12, constant mean values for glycosylated haemoglobin A1 between 11% and 12% indicated stable though not ideal diabetic control throughout the study. Example values for nerve conduction velocity on placebo and active treatment were: 44.3 +_ 5.9 and 44.8 + 5.1 metres/s (mean + SD) for median motor nerve, 38.4+8.2 and 37.2+7.7metres/s for median sensory nerve. Thus there was no significant effect of sorbinil on conduction velocity in these or any other of the motor and sensory nerves tested. Abnormal autonomic function was not improved by sorbinil. Subjective pain scores on a 10 cm visual analogue scale were 4.2 + 2.4 on placebo and 4.3 + 2.4 after sorbinil. Duration of sleep on placebo and active treatment was 6.1 _+ 1.6 and 6.2 + 1.7 h/night, respectively. We were not able to detect any beneficial effect of sorbinil on painful diabetic neuropathy in our patients.Key words: Aldose reductase inhibitor, sorbinil, diabetic neuropathy.Peripheral neuropathy is a common complication of diabetes mellitus and in some patients severe pain may be experienced which is refractory to conventional treatments. Impaired nerve function may be related to inadequate control of blood glucose levels [1,2]. Recently, improvement in glycaemic control using continuous subcutaneous insulin infusion [3,4] and intensive intermittent subcutaneous insulin injections [5] have been associated with an observed improvements in neurophysiological function. Unfortunately, there are many difficulties in implementing such regimens so that normal or near normal blood glucose levels cannot be achieved in many patients. Effective alternative treatments for symptomatic diabetic neuropathy would therefore be valuable.Sorbitol and fructose accumulate in the nerves of diabetic animals and man in proportion to the degree of hyperglycaemia [6,7] and have been implicated in the impaired nerve conduction [8,9]. Inhibition of aldose reductase, the first and rate-limiting enzyme in the polyol pathway, has a beneficial effect on nerve conduction in rats with spontaneous galactosaemia and with streptozotocin-induced diabetes [6,/0]. Sorbinil, a non-competitive inhibitor of aldose reductase, has recently become available for use in man. Initial reports have suggested that treatment with this inhibitor may improve motor and sensory nerve conduction velocities [11] and reduce painful symptoms and weakness [12] in patients with diabetic neuropathy. In the present study we have examined the effects of this drug in patients with symptomatic diabetic neuropathy. Subjects and methods Subjects and study designA ran...

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Section: Discussionmentioning

confidence: 99%

Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy

et al. 1984

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“…In the diabetic rat, metabolism of excess glucose to sorbitol by aldose reductase (AR2)' and then to fructose by sorbitol dehydrogenase (SDH) has been associated with reciprocal depletion of myoinositol (MI) and other intracellular organic osmolytes (8), altered phosphoinositide metabolism, and reduced (Na+,K+)-ATPase activity in nerve; these metabolic derangements, alone or in concert, have been invoked in the aldose reductase inhibitor (ARI)-sensitive slowing of nerve conduction velocity (NCV) in acute experimental (1,9) and (by analogy) human diabetes (2,10). Because AR2 and SDH are NADPH:NADP+ and NAD+:NADH coupled, respectively, glucose-induced flux through these enzymes is associated with increased oxidative stress (secondary to diminished NADPH-dependent reduction of glutathione) (11) and a putative state of "pseudohypoxia"…”

Section: Introductionmentioning

confidence: 99%

The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat.

Stevens¹,

Dananberg²,

Feldman³

et al. 1994

J. Clin. Invest.

200

125

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Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na',K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na',K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolicischemic pathogenesis. (J. Clin. Invest. 1994. 94:853-859.)

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“…(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.

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Free and lipid inositol, sorbitol and sugars in sciatic nerve obtained post-mortem from diabetic patients and control subjects

Cited by 105 publications

References 14 publications

Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy

Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy

The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat.

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

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