Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat.

Abstract

Biochemical abnormalities in peripher, nerve are thought to precede and condition the development of diabetic neuropathy, but metabolic intervention in chronic diabetic neuropathy produces only limited acute clinical response. The residual, metabolically unresponsive neurological deficits have never been rigorously defined in terms of either persistent metabolic derangements or irreversible structural defects because (a) human nerve tissue is rarely accessible for anatomical and biochemical study and (b) experimentally diabetic animals do not develop the structural hallmarks of human diabetic neuropathy. Detailed neuroanatomical-functional-biochemical correlation was therefore undertaken in long-term spontaneously diabetic BB-Wistar rats that functionally and structurally model human diabetic neuropathy. Vigorous insulin replacement in chronically diabetic BB rats essentially normalized both the sural nerve fiber caliber spectrum and the decreased sciatic nerve myo-inositol and (Na,K)-ATPase levels generally associated with conduction slowing in diabetic animals; yet, nerve conduction was only partially restored toward normal. Morphometric analysis revealed a striking disappearance of paranodal axo-glial junctional complexes that was not corrected by insulin replacement. Loss of these strategic junctional complexes, which are thought to limit lateral migration of axolemmal Na channels away from nodes of Ranvier, correlates with and can account for the diminished nodal Na permeability and resultant nodal conduction delay characteristic of chronic diabetic neuropathy in this animal model.

The correlation between sensory nerve conduction velocities and three metabolic indices in rats treated with streptozotocin

“…Also a closer relationship between CVs and plasma glucose than with HbA1 or dW would be expected in such a situation. The myo-inositol and Na+-K + ATPase mechanisms [3,4,25,26] were unlikely to be responsible for similar reasons. The latter two mechanisms are probably not important in the pathogenesis of diabetic neuropathy in distal cutaneous nerves in man [10], and in rats treated with streptozotocin [27].…”

“…The latter two mechanisms are probably not important in the pathogenesis of diabetic neuropathy in distal cutaneous nerves in man [10], and in rats treated with streptozotocin [27]. Reduced Na + -K + ATPase activity leading to intracellular accumulation of Na + as suggested in [4], should cause a measurable reduction in the amplitudes of CAPs. There were no significant differences in the amplitudes of CAPs of all the classes of nerve fibres in this study.…”

“…There was a good correlation between A-fibre conduction velocity and levels of glycosylated haemoglobin but no significant relationship between C-fibre conduction velocity and this metabolic index. A-fibre conduction velocity was statistically more correlated with levels of glycosylated haemoglobin than the other two metabolic indices (p < 0.01).Key words: Diabetes, streptozotocin, A-fibres, C-fibres, conduction velocity, glycosylated haemoglobin, random plasma glucose, body weight.It is now well established that peripheral nerve conduction velocity (CV) is slowed in experimental diabetes mellitus [1][2][3][4]. Of the various animal models used, motor nerve CV has been studied most.…”

“…It is now well established that peripheral nerve conduction velocity (CV) is slowed in experimental diabetes mellitus [1][2][3][4]. Of the various animal models used, motor nerve CV has been studied most.…”

C-Peptide Replacement Therapy and Sensory Nerve Function in Type 1 Diabetic Neuropathy

“…Specifically, neuropathy in type 1 diabetes progresses more rapidly and shows a more marked decline of nerve conduction velocity than neuropathy in type 2 diabetes (1-4). The basis for the fall in conduction velocity are reduced endoneurial blood flow and diminished Na ϩ ,K ϩ -ATPase activity in the nerve (5)(6)(7)(8), causing sodium ion accumulation, axonal swelling, and, subsequently, a disruption of the paranodal-axoglial junctions and the paranodal ion-channel barrier (9,10). This phenomenon, termed axoglial dysjunction, is a characteristic finding in type 1 diabetes but occurs rarely or not at all in type 2 diabetes (1).…”