Increased nerve polyol levels in experimental diabetes and their reversal by Sorbinil.
Sciatic nerve glucose, sorbitol, fructose and myo-inositol levels were measured over a 24-week period in rats made diabetic using a single intraperitoneal injection of streptozotocin at 45 mg kg-1 body weight. In addition, the effect of the aldose reductase inhibitor Sorbinil (Pfizer Ltd) at 25 mg kg-1 day-1 in reversing the accumulation of nerve polyols following 8 weeks of diabetes was investigated. Following induction of diabetes 47, 471 and 456% increases and a 43% decrease in sciatic nerve glucose, sorbitol, fructose and myo-inositol concentrations (mumol g-1 wet weight) respectively, were observed by day 14. Over the remainder of the experimental course untreated diabetic control animals demonstrated relatively consistent elevations in sciatic nerve glucose, sorbitol and fructose. Although a significant, progressive reduction in sciatic nerve myo-inositol to 30% of onset values was observed over the first 84 days of the study, this was followed by a spontaneous partial recovery (31%) over the remainder of the experimental course. However, sciatic nerve myo-inositol levels at the end of the study were still significantly lower than onset values (P less than 0.01). Sorbinil treatment, initiated after 8 weeks of diabetes, and without effect on sciatic nerve glucose levels, normalized sorbitol concentrations following 4, 8, or 12 weeks of treatment but only partially reversed the accumulation of fructose by 368, 161 and 199%, compared to age-matched non-diabetic control values, at the above times, respectively. Mean myo-inositol levels were progressively increased following Sorbinil treatment over the experimental period, although the increase was only significant, compared to results from untreated diabetic animals, at weeks 4 and 16.(ABSTRACT TRUNCATED AT 250 WORDS)
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007294:Inositol / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D013997:Time Factors
D007093:Imidazoles; D048289:Imidazolidines; D005632:Fructose; D007294:Inositol; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; C026411:sorbinil; D005947:Glucose