Journal Article

Regeneration and Repair of Myelinated Fibers in Sural-Nerve Biopsy Specimens from Patients with Diabetic Neuropathy Treated with Sorbinil

Bril, Vera, Greene, Douglas A, Lattimer, Sarah A, Sima, Anders A.F, Brown, Morton B, Nathaniel, Virgil, McEwen, Thomas AJ

1988

Overview

There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8±8.0 percent in nerve sorbitol content (P<0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P<0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy. (N Engl J Med 1988; 319:548–55.) THE distal symmetric polyneuropathy that accompanies diabetes mellitus is by far the most common form of peripheral neuropathy in the Western world 1 , 2 and is a major contributor to the overall morbidity associated with diabetes. 3 Although this condition is presumed to reflect a complex interplay among metabolic factors related to hyperglycemia, 1 2 3 4 5 6 7 8 microvascular abnormalities, 1 , 9 10 11 and unidentified independent genetic and environmental variables, its exact pathogenesis remains controversial. 1 , 5 , 6 Effective and specific treatment continues to elude the efforts of both clinicians and investigators in the field. 5 , 12 Investigators searching for specific consequences of hyperglycemia that might initiate or accelerate the development of chronic complications of diabetes, . . .

• Publisher: Massachusetts Medical Society
• Subject: Action Potentials / Aldehyde reductase / Aldehyde Reductase - antagonists & inhibitors / Biopsy / Clinical trials / Clinical Trials as Topic / Demyelinating Diseases - pathology / Demyelination / Diabetes / Diabetes mellitus / Diabetic Neuropathies - drug therapy / Diabetic Neuropathies - metabolism / Diabetic Neuropathies - pathology / Diabetic neuropathy / Double-Blind Method / Fibers / Humans / Hyperglycemia / Imidazoles - therapeutic use / Imidazolidines / Myelin / Nerve conduction / Nerve Fibers - pathology / Nerve Regeneration / Neural Conduction / Patients / Peripheral neuropathy / Placebos / Polyneuropathy / Random Allocation / Regeneration / Sorbitol / Sorbitol - analysis / Sugar Alcohol Dehydrogenases - antagonists & inhibitors / Sural Nerve - pathology