Enhanced
polyol pathway activity resulting in an accumulation of
sorbitol and a depletion of
myoinositol in nervous tissues has been proposed to be important in development of
diabetic neuropathies. This investigation demonstrated that in two models of
diabetic complications,
streptozocin (STZ)-induced diabetic rats and
galactose-fed rats, 5 weeks of disease led to an accumulation of
sorbitol or
galactitol, respectively, in three cranial nerves (the optic (II), trigeminal (V), and vagus (X) nerves), as well as the sciatic nerve, cerebral cortex, and retina. In both models, the cranial nerves and cerebral cortex contained lower levels of accumulated
polyol than the sciatic nerve. In addition,
myoinositol depletion was observed in the sciatic nerve only. In a second
galactose-fed rat study, returning 5-week
galactose-fed rats to a normal diet for 6 weeks led to complete elimination of
galactitol from the optic nerve, sciatic nerve, and retina and normalization of the sciatic nerve
myoinositol concentration. Similarly, continuing the
galactose diet for 6 more weeks (ie, a total of 11 weeks) as well as administration of the
aldose reductase inhibitor (ARI)
tolrestat (20 and 40 mg/kg/day), caused the sciatic nerve to contain a normal
myoinositol concentration and a
galactitol concentration that was 95% below the level observed in
galactose-fed controls. In the optic nerve and retina,
tolrestat was less effective, resulting in 69-78% lower
galactitol levels. In conclusion, these findings indicate that
sorbitol and
galactitol accumulate in cranial nerves, brain, and retina without a concomitant decrease in
myoinositol. Either withdrawal of the
galactose diet or intervention with
tolrestat normalized
polyol levels in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)