Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats

J Pharmacol Exp Ther. 1998 Dec;287(3):897-902.


To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcarnitine / therapeutic use
  • Aldehyde Reductase / antagonists & inhibitors
  • Aldehyde Reductase / metabolism*
  • Animals
  • Body Weight
  • Carnitine / analysis
  • Carnitine / deficiency*
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / complications
  • Diabetic Neuropathies / blood
  • Diabetic Neuropathies / drug therapy
  • Diabetic Neuropathies / etiology*
  • Enzyme Inhibitors / therapeutic use
  • Hemodynamics / drug effects
  • Male
  • Neural Conduction / drug effects
  • Polymers / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve / blood supply
  • Tetrazoles / therapeutic use
  • Thiophenes / therapeutic use


  • Enzyme Inhibitors
  • Polymers
  • Tetrazoles
  • Thiophenes
  • polyol
  • (5-(3-thienyl)tetrazol-1-yl)acetic acid
  • Acetylcarnitine
  • Aldehyde Reductase
  • polyol dehydrogenase (NADP)
  • Carnitine