Overt diabetic neuropathy: repair of axo-glial dysjunction and axonal atrophy by aldose reductase inhibition and its correlation to improvement in nerve conduction velocity.
Clinically overt diabetic neuropathy is characterized by neuroanatomical changes of the node of Ranvier and myelinated axons, and by decreased nerve conduction velocity. Sural nerve biopsies were obtained from 16 neuropathic diabetic patients participating in a 12-month randomized, placebo-controlled, double-blind clinical trial of the aldose reductase inhibitor sorbinil. One sural nerve biopsy was obtained at baseline and a second biopsy at the termination of the trial. Ten sorbinil-treated patients showed significant improvement in axo-glial dysjunction, a characteristic lesion of the node of Ranvier. Axonal atrophy assessed by three independent morphometric techniques also exhibited significant recovery in the sorbinil-treated patients. No change was demonstrated in any of these structural parameters in six placebo-treated patients. The improvement in sural nerve conduction velocity in sorbinil-treated patients correlated with the product of the quantitative improvements in axo-glial dysjunction and axonal atrophy. We conclude that the activated polyol-pathway plays a sustaining role in nerve fibre damage in diabetic neuropathy, and that structural lesions such as axo-glial dysjunction and axonal atrophy which are reversible following intervention with an aldose reductase inhibitor, constitute the morphological basis for nerve conduction slowing in overt diabetic neuropathy.
Sima
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AA
Michigan Diabetes Research and Training Center, University of Michigan, Ann Arbor 48109.
Prashar
A
A
Nathaniel
V
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Bril
V
V
Werb
M R
MR
Greene
D A
DA
D000328:Adult; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D001284:Atrophy; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure*; D001706:Biopsy; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D008875:Middle Aged; D009186:Myelin Sheath / Q000187:drug effects / Q000648:ultrastructure; D009431:Neural Conduction / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology*; D013497:Sural Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
D007093:Imidazoles; D048289:Imidazolidines; D000449:Aldehyde Reductase; C026411:sorbinil