The Paradox Between Resistance to Hypoxia and Liability to Hypoxic Damage in Hyperglycemic Peripheral Nerves: Evidence for Glycolysis Involvement

Abstract

Isolated ventral and dorsal rat spinal roots incubated in normal (2.5 mM) or high glucose (25 mM) concentrations or in high concentrations of other hexoses were exposed transiently to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials, extracellular direct current potentials, and interstitial pH were continuously recorded before, during, and after hypoxia. Ventral roots incubated in 25 mM D-glucose showed resistance to hypoxia. Dorsal roots, on the other hand, revealed electrophysiological damage by hyperglycemic hypoxia as indicated by a lack of posthypoxic recovery. In both types of spinal roots, interstitial acidification was most pronounced during hyperglycemic hypoxia. The changes in the sensitivity to hypoxia induced by high concentrations of D-glucose were imitated by high concentrations of D-mannose. In contrast, D-galactose, L-glucose, D-fructose, and L-fucose did not have such effects. Resistance to hypoxia, hypoxia-generated interstitial acidification, and hypoxia-induced electrophysiological damage were absent after pharmacological inhibition of nerve glycolysis with iodoacetate. These observations indicate 1) that enhanced anaerobic glycolysis produces resistance to hypoxia in hyperglycemic peripheral nerves and 2) that acidification may impair the function of peripheral axons when anaerobic glycolysis proceeds in a tissue with reduced buffering power.

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

“…It has been reported that the fast K + channel activity is reduced by 50% at cytoplasmic pH of 6.8 as a result of enhanced anaerobic glycolysis [24,48]. Decreased K channels could also explain our finding of membrane depolarization.…”

Insulin partially reverses deficits in peripheral nerve blood flow and conduction in experimental diabetes

“…In the former, the magnitude of resistance appears to be related to the degree of medium-term metabolic control, rather than the presence or absence of neuropathy (Price et al, 1987). It has been suggested that increased resistance to hypoxia results from increased availability of substrate for anaerobic energy production in the diabetic nerve (Shirabe et al, 1988;Parry and Kohzu, 1990;Schneider et al, 1993). We cannot confirm this suggestion since values in this experiment did not correlate with either those for plasma or nerve glucose in diabetic rats.…”

The effects of hyperglycaemic hypoxia on rectification in rat dorsal root axons.

“…The chain of events by which hyperglycaemia leads to nerve damage, predominantly in sensory fibres, is far from clear but there is much evidence that endoneurial hypoxia due to microangiopathy is involved (for review see Low, 1987;Thomas & Tomlinson, 1993). Using isolated frog nerves, Lorente de N6 (1947) first made the observation that high glucose concentrations cause a lack of functional recovery after hypoxia, and this phenomenon has recently been investigated in rat peripheral nerves and spinal roots in vitro (Strupp, Jund, Schneider & Grafe, 1991;Schneider, Jund, Nees & Grafe, 1992;Schneider, Niedermeier & Grafe, 1993a; Quasthoff, Mitrovic & Grafe, 1993 b). Recovery of membrane and action potentials from hyperglycaemic hypoxia is worse in dorsal than ventral roots (Schneider et al 1992), supporting an association with diabetic neuropathy.…”

“…Recovery of membrane and action potentials from hyperglycaemic hypoxia is worse in dorsal than ventral roots (Schneider et al 1992), supporting an association with diabetic neuropathy. The poor recovery of dorsal roots is probably due to intracellular acidification by anaerobic glycolysis, since (a) it is worse when the buffering power and/or bicarbonatedependent pH-regulating mechanisms of the axons are compromised (Schneider et al 1992), (b) it only occurs with hexoses that can be metabolized rapidly by the glycolytic pathway (Schneider et al 1993a), and (c) it is associated with extracellular release of acid (Strupp et al 1991). It is a welldocumented observation that hypoxia and/or ischaemiainduced decrease in tissue pH is dependent on the preischaemic blood glucose concentration, being greatest in hyperglycaemic and least in hypoglycaemic animals (e.g.…”