Is resistance to ischaemia of motor axons in diabetic subjects due to membrane depolarization?

Abstract

SUMMARYThe reasons for the resistance to ischaemia of peripheral nerves in diabetics are not well understood. We have now explored whether axonal depolarization underlies this phenomenon, as has previously been proposed. Resistance to ischaemia was determined by the new method of "threshold tracking". This method revealed an increase in excitability of the peroneal nerve at the popliteal fossa during ischaemia, and a decrease in excitability in the post-ischaemic period. The extent of these alterations in 28 type 1 diabetics without peripheral neuropathy showed a strong correlation with the mean blood glucose concentrations during the last 24 h before examination. To test whether the ischaemic resistance was related to membrane potential, we also measured axonal superexcitability in 11 selected diabetics, since it has been shown that post-spike changes in excitability depend on membrane potential. Changes in excitability of the peroneal nerve were measured in the period between 10 and 30 msec following a conditioning supramaximal compound action potential. Under resting conditions, no differences in the post-spike superexcitability were found between controls and diabetics, despite striking differences in their responses to a 10-min pressure cuff. These observations indicate that membrane depolarization is not involved in the resistance to ischaemia of motor axons in diabetic subjects.

The paradox between resistance to hypoxia and liability to hypoxic damage in hyperglycemic peripheral nerves. Evidence for glycolysis involvement

“…Another possibility underlying the abnormal sensitivity to hypoxia of hyperglycemic nerves is enhanced glycolysis, as suggested previously (8)(9)(10)(11)(12). The possible importance of this mechanism is strongly supported by the effects of D-mannose seen in this study.…”

“…However, the precise mechanisms underlying these alterations are not yet clear. Resistance to ischemia was first described by Steiness (3), and several hypotheses have attempted to explain this phenomenon (4): 1) a decrease in the accumulation of extracellular K + during ischemia caused by a change of a nodal diffusion barrier (5) or an enlarged interstitial endoneurial space (6); 2) changes in the internodal length of myelinated axons (7); 3) increased availability of energy sources for anaerobic glycolysis in diabetic nerve (8)(9)(10)(11)(12); 4) other alterations in neuronal metabolism such as inhibition of inositol uptake, accumulation of polyols, and/or reduced activity of the Na"7K + -ATPase (13), and 5) adaptation to chronic hypoxemia (14)(15)(16).…”

Intra-axonal recording from large sensory myelinated axons: Demonstration of impaired membrane conductances in early experimental diabetes

“…However, this decrease is not only due to membrane depolarization but rather consistent with altered kinetics of sodium channel activation, as shown by the difference in correlation between the membrane potential and the rate of rise. The membrane depolarization of peripheral nerves in diabetic neuropathy has recently been discounted on the basis of the indirect but sensitive threshold tracking technique [43].…”

Changes in excitability and accommodation of human motor axons following brief periods of ischaemia.

“…ischaemia (Strupp, Bostock, Weigl, Piwernetz, Renner & Grafe, 1990). In that study, the axons were stimulated at the knee (fibular head), and compound muscle action potentials (CMAP) recorded from extensor digitorum brevis (EDB).…”

“…On the other hand, the relative insensitivity to ischaemia of the distal, compared with the proximal parts of an axon (Fig. 1 A) is reminiscent of the relative insensitivity of diabetic nerves, which appears to be determined by the substrate levels for anaerobic metabolism (Strupp et al 1990). Groat & Koenig proposed a proximo-distal gradient of substrates (1946 a), but also considered a relationship to the newly discovered phenomenon of axoplasmic flow (1946 b).…”