title: Pathogenesis and prevention of diabetic neuropathy.
abstract: Diabetic neuropathy, long-recognized as an important but complex and poorly understood clinical complication of diabetes, is finally yielding to more than a decade of intense clinical and laboratory investigation. At least one basic biochemical mechanism involving sorbitol and MI metabolism, phosphoinositides, protein kinase C, and the (Na,K)-ATPase has been identified that can rationally account for the neurotoxicity of glucose. This biochemical sequence has been examined in some detail in vitro, but some of its elements, such as the link between abnormal sorbitol and MI metabolism, and between protein kinase C and the (Na,K)-ATPase, remain the subject of ongoing investigation. Through its effect on the (Na,K)-ATPase, this metabolic sequence can explain both the rapidly-reversible functional impairment and the early structural lesions of nerve fibers, such as paranodal swelling in acute diabetes. Extrapolation of early paranodal swelling to the more advanced stages of nerve fiber damage remains somewhat speculative, although axo-glial dysjunction is a likely intermediate step. Impaired axonal transport or microvascular dysfunction may be additional contributing factors, possibly also related to abnormal sorbitol and MI metabolism. Blunted phosphoinositide-mediated signal transduction could potentially explain a putative insensitivity to neurotrophic factors and a diminished regenerative response in diabetic neuropathy. Human morphometric studies and ARI trials support the relevance of these pathogenetic processes to human diabetic neuropathy, and suggest that specific metabolic therapy with agents such as ARIs hold promise as important new elements in the treatment and possibly prevention of diabetic neuropathy.
authors.affiliation: Diabetes Research and Training Center, University of Michigan, Ann Arbor 48109.
authors.forename: D A
authors.initials: DA
authors.lastname: Greene
authors.forename: S A
authors.initials: SA
authors.lastname: Lattimer
authors.forename: A A
authors.initials: AA
authors.lastname: Sima
mesh_terms: D003929:Diabetic Neuropathies / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D006801:Humans