Streptozotocin-diabetic rats were maintained on a 72% fructose diet for 4 weeks or 6-8 mos and some were treated with an aldose reductase inhibitor (ONO-2235: 50 mg·kg-1·day-1).
Fructose feeding significantly influenced the development of impaired motor nerve conduction velocity in the diabetic rats and this effect was positively correlated with sorbitol accumulation and myo-inositol decrease in the sciatic nerve of diabetic rats maintained on fructose-rich diet. Treatment with ONO-2235 prevented both slowing of the motor nerve conduction velocity and elevation of sorbitol and decrease in myo-inositol in the sciatic nerve.
A morphometric study of the treatment with aldose reductase inhibitor for 8 months was performed in the sural nerve of diabetic rats maintained on a fructose-rich diet, and these microscopic observations were confirmed by morphometric analysis of the myelinated fibers by using a computer. The axonal area of fructose-fed diabetic rats (21.6±4.1μm2) was significantly less than that of normal fructose-fed rats (27.8±3.6μm2, p<0.05), and this reduction of the axonal area was reversed by treatment with the aldose reductase inhibitor (26.5±2.4μm2, p<0.05 versus fructose-fed diabetic rats). In the linear regression of myelin thikness on fiber diameter, the myelin thickness of aldose reductase inhibitor treated rats was larger in both small (x=4) and large (x=8) myelinated fibers than that of fructose-fed diabetic rats not treated with ONO-2235. These changes in myelinated fibers were also confirmed by determination of the index of circularity (IC). The mean IC of fructosefed diabetic rats (72.9±6.0%) was significantly less than that of fructose-fed normal rats (86.5±2.0%, p<0.001). However, this reduction in IC in fructose-fed diabetic rats was completely reversed by the treatment with the aldose reductase inhibitor (86.8±3.6%, p<0.001 versus fructose-fed diabetic rats).
Thus, our findings suggest that increased polyol pathway activity and decreased myo-inositol levels in the nerves may be related to the pathogenesis of diabetic neuropathy and the aldose reductase inhibitor may be a useful treatment for it.
