Role of sorbitol accumulation and myo-inositol depletion in paranodal swelling of large myelinated nerve fibers in the insulin-deficient spontaneously diabetic bio-breeding rat. Reversal by insulin replacement, an aldose reductase inhibitor, and myo-inositol.

Abstract

Axo-glial dysjunction refers to the disruption of important junctional complexes that anchor terminal loops of myelin to the paranodal axolemma in diabetic human and animal peripheral nerve. Neither axo-glial dysjunction nor the preceeding acute localized paranodal swelling has been specifically attributed to discrete metabolic consequences of insulin deficiency or hyperglycemia. Two metabolic sequelae of hyperglycemia in diabetic nerve, sorbitol accumulation via aldose reductase, and (NaK)-ATPase deficiency related to myo-inositol depletion, were explored as possible underlying causes of acute paranodal swelling in the spontaneously diabetic bio-breeding rat. 3 wk of insulin replacement, or therapy with an aldose reductase inhibitor or myo-inositol completely reversed paranodal swelling in sural nerve fibers after 3 wk of untreated insulin deficiency. These observations suggest that insulin deficiency and hyperglycemia cause reversible paranodal swelling, and ultimately poorly reversible axo-glial dysfunction, via the myo-inositol-related (Na,K)-ATPase defect rather than by the osmotic effects of sorbitol accumulation within nerve fibers.

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

“…The dose of sorbinil used in our studies did not completely prevent the diabetes-induced increase in sorbitol and fructose levels in the sciatic nerve suggesting that we did not achieve total inhibition of aldose reductase activity in our studies, which could have an impact on the differences observed in the efficacy of these treatments. Dietary myo-inositol supplementation also improved the slowing of MNCV as previously reported as well as EBF [18][19][20][21]. The latter result was unexpected since Cameron et al [9] has reported that aldose reductase inhibitor treatment of diabetic rats improves the reduction in EBF and MNCV independent of nerve myo-inositol levels.…”

“…However, clinical trials using aldose reductase inhibitors for treatment of diabetic neuropathy have been disappointing [17]. Treatment of diabetic rats with dietary myo-inositol has also been shown to improve nerve function [18][19][20][21]. This led to speculation 15 years ago that a common mechanism might induce the diverse complications of diabetes [22].…”

Visual evoked potential changes in patients with diabetes mellitus without retinopathy

“…[29][30][31] Kamijo M et al in 1993 documented highly significant correlation of the prolongation of the VEP latencies with the structural lesions, namely, axonal atrophy and axoglial dysjunctions in the optic nerve. 31 A polyol pathway related mechanism has been implicated according to which, increased extracellular glucose concentrations produce a concentration dependent conversion of glucose to sorbitol by the enzyme aldose-reductase.…”

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

“…Hyperglycaemiainduced mitochondrial production of ROS has been shown to induce activation of the polyol pathway [20]. Inhibition of aldose reductase activity has previously been used to inhibit glucose metabolism through the polyol pathway [21,22,23]. In the present study we used AL-1576, which in comparative studies with other aldose reductase inhibitors has been shown to be both highly potent and selective and to lack antioxidant effects [24,25].…”