AN ALDOSE REDUCTASE INHIBITOR BUT NOT MYOINOSITOL BLOCKS ENHANCED POLYPHOSPHOINOSITIDE TURNOVER IN PERIPHERAL-NERVE FROM DIABETIC RATS

Experimental diabetic neuropathy, whether chemically induced or presen t in several spontaneously diabetic animal models, is characterized by sorbitol accumulation and myo-inositol depletion and usually also by enhanced turnover of the monoesterified moieties of polyphosphoinositi des, particularly phosphatidylinositol-4,5-bisphosphate (PIP2). This s tudy examined the relationship of these alterations by assessing the e ffects of myo-inositol and the aldose reductase inhibitor, sorbinil, s upplied as dietary supplements, on sorbitol and myo-inositol concentra tions and incorporation of P-32 into polyphosphoinositides in sciatic nerve from rats killed 8 weeks after induction of diabetes with strept ozotocin. Nerves from diabetic rats killed after 8 weeks of disease ex hibited 52% to 76% greater PIP2 labeling, markedly elevated sorbitol l evels, and 30% less myo-inositol when compared with age-matched normal rats. Incorporation of isotope into PIP2 in nerves from animals fed a myo-inositol supplement, added to either a high-sucrose diet or stand ard rat chow beginning immediately after induction of diabetes, remain ed substantially elevated, whereas myo-inositol levels were corrected to normal. Essentially the same results were obtained when rats were f ed the myo-inositol-containing diet beginning 4 weeks after streptozot ocin injection. In contrast, PIP2 labeling in nerves from diabetic rat s that received the sorbinil supplemented diet for either 4 or 8 weeks was not different from that in controls. myo-Inositol levels in these animals were also restored to normal, whereas sorbitol levels remaine d elevated, albeit reduced by approximately 30%. These results indicat e that myo-inositol administration is unable to completely counteract the impact of diabetes on the turnover of monoesterified phosphate gro ups in PIP2. In contrast, sorbinil can correct this abnormality, but t his beneficial effect is not dependent on the presence of normal sorbi tol concentrations. Copyright (C) 1996 by W.B. Saunders Company