{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:52:50Z","timestamp":1790373170338,"version":"4.1.0"},"reference-count":35,"publisher":"American Diabetes Association","issue":"7","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,7,1]]},"abstract":"<jats:p>The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR\u2212\/\u2212) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR+\/+) and AR\u2212\/\u2212 mice. Under short-term diabetic conditions, AR\u2212\/\u2212 mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR+\/+ mice. Sorbitol levels in the sciatic nerves of diabetic AR+\/+ mice were increased significantly, whereas sorbitol levels in the diabetic AR\u2212\/\u2212 mice were significantly lower than those in diabetic AR+\/+ mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH2-terminal kinase (JNK), depletion of reduced glutathione, increase of superoxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR+\/+ mice were not observed in the diabetic AR\u2212\/\u2212 mice, indicating that the diabetic AR\u2212\/\u2212 mice were protected from oxidative stress in the sciatic nerve. The diabetic AR\u2212\/\u2212 mice also excreted less 8-hydroxy-2\u2032-deoxyguanosine in urine than diabetic AR+\/+ mice. The structural abnormalities observed in the sural nerve of diabetic AR+\/+ mice were less severe in the diabetic AR\u2212\/\u2212 mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI fidarestat in diabetic AR+\/+ nerves, similar to those in diabetic AR\u2212\/\u2212 mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage.<\/jats:p>","DOI":"10.2337\/db05-1497","type":"journal-article","created":{"date-parts":[[2006,6,27]],"date-time":"2006-06-27T18:39:44Z","timestamp":1151433584000},"page":"1946-1953","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":126,"title":["Aldose Reductase\u2013Deficient Mice Are Protected From Delayed Motor Nerve Conduction Velocity, Increased c-Jun NH2-Terminal Kinase Activation, Depletion of Reduced Glutathione, Increased Superoxide Accumulation, and DNA Damage"],"prefix":"10.2337","volume":"55","author":[{"given":"Eric C.M.","family":"Ho","sequence":"first","affiliation":[{"name":"Institute of Molecular Biology, The University of Hong Kong, Hong Kong, Special Administrative Region (SAR), China"},{"name":"Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen S.L.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Hong Kong, Hong Kong, SAR, China"},{"name":"Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong, SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuk Shan","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, The University of Hong Kong, Hong Kong, Special Administrative Region (SAR), China"},{"name":"Department of Anatomy, The University of Hong Kong, Hong Kong, SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny C.W.","family":"Yip","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, The University of Hong Kong, Hong Kong, Special Administrative Region (SAR), China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meena","family":"Arvindakshan","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, The University of Hong Kong, Hong Kong, Special Administrative Region (SAR), China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Ichiro","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soroku","family":"Yagihashi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Oates","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig A.","family":"Ellery","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S.M.","family":"Chung","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, The University of Hong Kong, Hong Kong, Special Administrative Region (SAR), China"},{"name":"Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong, SAR, China"},{"name":"Department of Physiology, The University of Hong Kong, Hong Kong, SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sookja K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, The University of Hong Kong, Hong Kong, Special Administrative Region (SAR), China"},{"name":"Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong, SAR, China"},{"name":"Department of Anatomy, The University of Hong Kong, Hong Kong, SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031209324993100_R1","doi-asserted-by":"crossref","unstructured":"Thomas PK: Diabetic peripheral neuropathies: their cost to patient and society and the value of knowledge of risk factors for development of interventions. 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