Abnormal Sciatic Nerve Myo-inositol Metabolism in the Streptozotocin-diabetic Rat: Effect of Insulin Treatment

Abstract

The metabolism of myo-inositol and its phospholipids has been studied in the sciatic nerves of control, two weeks' streptozotocin-diabetic, and insulin-treated diabetic rats. The concentrations of glucose, fructose, and sorbitol were increased and the concentration of myo-inositol was decreased in the sciatic nerves of the diabetic animals; these abnormalities were only partially corrected by insulin therapy that was adequate to obviate hyperglycemia. Whereas the space of distribution of 2-3 H-myo-inositol was found to exceed the total water space of the nerves of control animals, the 2-3 H-myo-inositol space approximated the water space in the nerves of diabetic animals and was only slightly increased after insulin therapy. During the first 2 h after the intraperitoneal injection of 2-3 H-myo-inositol, the recovery of radioactivity in nerve lipids was decreased by 69% in the untreated diabetics and by 77% in the insulin-treated diabetics. Analysis of the individual phosphoinositides revealed a proportional increase in the radioactivity recovered with phosphatidylinositol and a decrease in the recovery with triphosphatidylinositol in the diabetic nerves. CDP-diglyceride:inositol transferase activity was decreased by 44% in homogenates of sciatic nerves from untreated diabetic rats, but it was normal in nerve homogenates from insulin-treated diabetics. The pattern of incorporation of radioactivity into phospholipids after 1 h of incubation of nerve homogenates with 2-3 H-myo-inositol was similar to that observed in vivo. The fractional recovery of radioactivity with phosphatidylinositol was increased, whereas the recovery of label as triphosphatidylinositol was decreased by 11% in the presence of homogenates of sciatic nerves from diabetic rats.These observations indicate that 2 wk of acute streptozotocin diabetes results in a decrease in the sciatic nerve content and space of distribution of myoinositol and suggests that nerve myo-inositol transport may be defective in the diabetic animal. The observed abnormalities in the amount and pattern of incorporation of 2-3 H-myo-inositol into diabetic nerve phospholipids could be explained, in part, by decreased activities of CDP-diglyceride:inositol transferase and phosphatidylinositol 4-phosphate kinase activities in the diabetic nerves. However, the fact that the incorporation of 2-3 H-myo-inositol into phospholipids was decreased in the nerves of insulin-treated-diabetic animals despite a normal CDP-diglyceride:inositol transferase activity suggests that defective myo-inositol transport may also contribute to the abnormal neural phosphoinositide metabolism in this model. The possibility that these abnormalities are related to the development of the structural and functional changes associated with diabetic neuropathy requires further investigation. DIABETES 29:227-235, March 1980. D uring the past decade, considerable evidence has accumulated to suggest that the metabolism of myo-inositol and its phospholipid derivatives may play an important role in peripheral nerve...

Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve. Competitive inhibition by glucose and lack of an insulin effect.

“…In contrast, although altered sciatic nerve myo-inositol metabolism in experimental diabetes has been explicitly linked to impairment of nerve conduction (15,16), the mechanism(s) by which experimental diabetes lowers nerve myo-inositol content and alters nerve myo-inositol metabolism is entirely unclear at present (17,18). In contrast to most other carbohydrates, myo-inositol is maintained at high intracellular concentrations by most tissues.…”

“…Active concentration of myo-inositol has been described in kidney (21), small intestine (22), choroid plexus (23), ciliary body (24), and ocular lens (25). It has been postulated (17), but never demonstrated, in peripheral nerve (20). Although myo-inositol synthesis has been observed in crude homogenates of peripheral nerve (26), the relative importance of active concentration, intracellular sequestration (20), and endogenous synthesis in the maintenance of nerve myo-inositol concentrations is unknown (17,18,20).…”

“…It has been postulated (17), but never demonstrated, in peripheral nerve (20). Although myo-inositol synthesis has been observed in crude homogenates of peripheral nerve (26), the relative importance of active concentration, intracellular sequestration (20), and endogenous synthesis in the maintenance of nerve myo-inositol concentrations is unknown (17,18,20). In the studies presented here, we demonstrate that myo-inositol uptake occurs in endoneurial tissue via a sodiumand energy-dependent, ouabain-inhibitable, high affinity, carrier mediated transport system.…”

Impaired rat sciatic nerve sodium-potassium adenosine triphosphatase in acute streptozocin diabetes and its correction by dietary myo-inositol supplementation.

“…acute streptozocin diabetes reduces sciatic nerve MI concentration (3,7,8,26,27), conduction velocity (3, 6, 7) and sodium-potassium ATPase activity. MI administration obviates the fall in tissue MI and prevents the decrease in both nerve conduction velocity (3,7,8) and sodium-potassium ATPase.…”

Effect of Sorbinil and Ascorbic Acid on myo‐Inositol Transport in Cultured Rat Schwann Cells Exposed to Elevated Extracellular Glucose

“…All these tissues, being independent of insulin for glucose transport, accumulate high levels of glucose as a result of chronically elevated circulating glucose levels. Increased glucose concentration leads to a rise in intracellular sorbitol content via induction of aldose reductase (AR) activity, accompanied by decreased inositol uptake, content, and incorporation into phospholipids (Greene et al, 1975;Palmano et al, 1977;Hothersall and Mclean, 1979;Whiting et al, 1979;Clements and Stockard, 1980;Mayhew et al, 1983;Greene and Lattimer, 1984;Bell and Eichberg, 1985;Williamson et al, 1985;MacGregor and Matschinsky, 1986;Lorenzi et al, 1987;Khatami and Rockey, 1988;Hawthorne et al, 1989;Del Monte et al, 1991;Thomas et al, 1994;Shindo et al, 1996), leading to a whole array of dysfunction. All these observations have collectively given rise to the sorbitol theory of diabetic neuropathy, linking the changes in inositol and sorbitol content in a mostly chronic diabetic nerve to its functional alterations, e.g., altered phosphoinositide metabolism, Na+ ,K + -ATPase activity, and nerve conduction velocity.…”