Alteration of Phosphoinositide Metabolism, Protein Phosphorylation, and Carbohydrate Levels in Sciatic Nerve From Wistar Fatty Diabetic Rats

Sciatic nerve from the Wistar fatty diabetic (FD) rat, a prospective model for non-insulin-dependent diabetes mellitus, was investigated to determine the content of carbohydrates and to measure the incorporation of ³²P into phosphoinositides and proteins. This strain has been shown to develop structural abnormalities in nerves and to exhibit reduced conduction velocity. Males became diabetic between the ages of 8 and 10 wk and were maintained together with lean sibling controls until the animals were either 22 or 44 wk old. Throughout this period, FD rats displayed moderate hyperglycemia. The carbohydrate profile of FD rat sciatic nerve exhibited modest increases in glucose, fructose, and sorbitol levels and significantly reduced myo-inositol concentrations, which were comparable at both ages. When nerves from 22-wk-old animals were incubated with [³²P]orthophosphate and incorporation of radioactivity into phospholipids was measured, an increase in isotope uptake into phosphatidylinositol-4,5-bisphosphate and phosphatidylinositol-4-phosphate in the distal portions of tissue from the FD rat was observed. This effect was more pronounced in nerves from 44-wk-old rats. Phosphorylation of the major myelin protein P₀ was 70% higher in the most distal portion of FD sciatic nerve from 22-wk-old animals. A comparable rise in phosphorylation of P₀ as well as the large (P₁,) and small (P_r) myelin basic proteins occurred in nerves from 44-wk-old rats. In these animals, an ∼50% decrease in the uptake of ³²P into P₀ and P, in the most proximal region of FD nerve was also apparent. Thus, peripheral nerve from this genetically diabetic animal model undergoes compositional and metabolic changes that resemble those of the streptozocin-induced diabetic rat. The results suggest that the FD rat could prove useful for future studies of the neuropathic complications of diabetes.