Vascular and metabolic factors in the pathogenesis of experimental diabetic neuropathy in mature rats

The complex interrelationships between metabolic factors (increased nerve glucose, fructose and sorbitol and decreased nerve myo-inositol levels) and ischaemic-hypoxic vascular factors [decreased nerve blood flow (NBF) and increased nerve vascular resistance (NVR)] in the pathogenesis of diabetic neuropathy are incompletely understood. This study evaluates, in mature animals, the time course and magnitude of changes in factors postulated to be of importance in the pathogenesis of experimental diabetic neuropathy (EDN). Hyperglycaemia was induced in mature 9-month-old male Sprague-Dawley rats with streptozocin (as in studies utilizing immature rats it has been difficult to separate effects which are due to the growth retardation and maturational delay induced by hyperglycaemia from those arising from diabetes per se). Groups of age-matched control and diabetic animals were compared 1, 2, 4, 8, 16 and 24 weeks after injection. In diabetic animals NBF was decreased and NVR was increased after 1 week (P < 0.05); sciatic nerve glucose, sorbitol and fructose levels were increased after 1 week (P < 0.05). These changes were maintained for the duration of the experiment. Sciatic and caudal nerve conduction velocities were significantly decreased after 16 weeks (P < 0.05), although trends were apparent after 4 weeks. Diabetic animals showed decreased sciatic nerve myo-inositol levels between 2 and 16 weeks (P < 0.05), but there was no significant difference at 24 weeks. There were no significant differences in sciatic nerve total (Na+K+)ATPase concentrations. Early and sustained alterations in vascular indices (NBF and NVR) support the postulate that ischaemic-hypoxic factors may play a role in the causation of EDN. The ischaemic-hypoxic postulates do not, however, diminish the obvious importance of the multitude of metabolic alterations which also occur very early after the onset of hyperglycaemia.