title: Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study.
abstract: OBJECTIVE
  Studies of the role of sorbitol dehydrogenase in nerve functional deficits induced by diabetes reported contradictory results. We evaluated whether sorbitol dehydrogenase inhibition reduces metabolic abnormalities and enhances oxidative stress characteristic of experimental diabetic neuropathy.
  
  
  METHODS
  Control and streptozotocin-diabetic rats were treated with or without sorbitol dehydrogenase inhibitor (SDI)-157 (100 mg x kg(-1) x day(-1), in the drinking water, for 3 weeks). Sciatic nerve free mitochondrial (cristae and matrix) and cytosolic NAD(+): NADH ratios were calculated from the beta-hydroxybutyrate, glutamate and lactate dehydrogenase systems. Concentrations of metabolites, e. g. sorbitol pathway intermediates and variables of energy state were measured in individual nerves spectrofluorometrically by enzymatic procedures.
  
  
  RESULTS
  The flux through sorbitol dehydrogenase (manifested by nerve fructose concentrations) was inhibited by 53 % and 74 % in control and diabetic rats treated with SDI compared with untreated control and diabetic groups. Free NAD(+):NADH ratios in mitochondrial cristae, matrix and cytosol were decreased in diabetic rats compared with controls and reduction in either of the three variables was not prevented by sorbitol dehydrogenase inhibitor. Phosphocreatine concentrations and phosphocreatine:creatine ratios were decreased in diabetic rats compared with controls and were further reduced by the inhibitor. Malondialdehyde plus 4-hydroxyalkenals concentration was increased and reduced gluthathione concentration was reduced in diabetic rats compared with the control group, and changes in both variables were further exacerbated by sorbitol dehydrogenase inhibitor. Neither NAD-redox and energy states nor lipid aldehyde and reduced gluthathione concentrations were affected by treatment with the inhibitor in control rats.
  
  
  CONCLUSIONS
  Inhibition of sorbitol dehydrogenase does not offer an effective approach for prevention of oxidation and metabolic imbalances in the peripheral nerve that is induced by diabetes and is adverse rather than beneficial. [Diabetologia (1999) 42: 1187-1194]
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354, USA.
authors.forename: I G
authors.initials: IG
authors.lastname: Obrosova
authors.forename: L
authors.initials: L
authors.lastname: Fathallah
authors.forename: H J
authors.initials: HJ
authors.lastname: Lang
authors.forename: D A
authors.initials: DA
authors.lastname: Greene
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D005632:Fructose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013050:Spectrometry, Fluorescence
chemical_list: D004791:Enzyme Inhibitors; D009243:NAD; D005632:Fructose; D008315:Malondialdehyde; D007064:L-Iditol 2-Dehydrogenase; D005978:Glutathione