Experimental diabetic neuropathy, whether chemically induced or present 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 polyphosphoinositides, particularly phosphatidylinositol-4,5-bisphosphate (PIP 2 ). This study examined the relationship of these alterations by assessing the effects of myo-inositol and the aldose reductase inhibitor, sorbinil, supplied as dietary supplements, on sorbitol and myo-inositol concentrations and incorporation of 3 2 P into polyphosphoinositides in sciatic nerve from rats killed 8 weeks after induction of diabetes with streptozotocin. Nerves from diabetic rats killed after 8 weeks of disease exhibited 52% to 76% greater PIP 2 labeling, markedly elevated sorbitol levels, and 30% less myo-inositol when compared with age-matched normal rats. Incorporation of isotope into PIP 2 in nerves from animals fed a myo-inositol supplement, added to either a high-sucrose diet or standard rat chow beginning immediately after induction of diabetes, remained substantially elevated, whereas myo-inositol levels were corrected to normal. Essentially the same results were obtained when rats were fed the myo-inositol-containing diet beginning 4 weeks after streptozotocin injection. In contrast, PIP 2 labeling in nerves from diabetic rats 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 remained elevated, albeit reduced by approximately 30%. These results indicate that myo-inositol administration is unable to completely counteract the impact of diabetes on the turnover of monoesterified phosphate groups in PIP 2 . In contrast, sorbinil can correct this abnormality, but this beneficial effect is not dependent on the presence of normal sorbitol concentrations.