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Guide To Beating Hypoglycemia

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Hypoglycemia

For many years (for review, see Auer 1986; 2004), it was believed that hypoglycemia was a form of ischemia (Courville 1957; Brierley et al. 1971a). Part of the reason for this was the belief that low oxygen and low glucose had the same potential to cause neurons to perish. We now know (see above) that hypoxia alone is incapable of causing neuronal necrosis in organisms with an intact beating heart. Rather, ischemia is necessary, not merely hypoxia. Thus, the idea that hypoxia and hypoglycemia have identical consequences within the nervous system was flawed from the beginning.

The second flaw in this argument became apparent when the biochemistry of hypoglycemia was worked out by Siesjo and colleagues in Sweden. Salient neurochemical features of hypoglycemic brain damage contrast sharply with those of ischemia (Auer and Siesjo 1993). These include an alkalosis, caused by both increased ammonia production during hypoglycemia and the lack of production of metabolic acids such as lactate, which would normally drive the pH downward. In addition to tissue alkalosis, hypoglycemia is characterized by increased, not decreased cerebral blood flow, again contrasting sharply with ischemia.

The amino acid perturbations in the neurochem-istry of hypoglycemic brain damage also contrast with ischemia. Excitatory amino acids are known to play a pathophysiologic role in neuronal death in both conditions of hypoglycemia and ischemia. However, in ischemia, the release of synaptic glutamate (Benveniste et al. 1984) has been shown to be the culprit, whereas in hypoglycemia, the predominant excitatory amino acid released seems to be aspartate (Sandberg et al. 1986). It is the lack of glycolytic flux that drives aspartate production in hypoglycemia. The paltry glycolysis in turn leads to a shortage of pyruvate and, because decarboxylation to acetate is slowed, acetate is in short supply. Since oxaloac-etate lacks acetate to condense with, to form citrate in normal quantities, oxaloacetate builds up before the block. The increased tissue oxaloacetate, in turn, drives the aspartate-glutamate transaminase reaction towards aspartate and away from glutamate. Thus, tissue amino acid levels of aspartate rise, and glutamate is actually lowered in the tissue during hy-poglycemia. The extracellular aspartate increases to 10-20 times the normal concentration. Aspartate is a potent activator of NDMA receptors on neurons. In this fashion, aspartate, not glutamate, kills the neurons in hyperglycemia. The chain of pathophysiolog-ic events leading to neuronal death is thus much longer than would be expected with the cursory thought that glucose deprivation directly starves the neuron

Fig. 13.9a, b. Hypoglycemic versus ischemic brain damage. a heads), while b in ischemia the dentate gyrus is not involved (H&E Hypoglycemic damage of the hippocampal dentate gyrus (arrow stain; magnification a, b X200)

and kills it. Hypoglycemia is, rather, an excitotoxic death of hyperexcitation. This active neuronal killing contrasts sharply with the old, outmoded concept of neuronal starvation. The idea that neurons can be killed by a negative phenomenon of oxygen or glucose deprivation is an obsolete one. Indeed, even the neuropathology of hypoglycemia can, on occasion, show differences that can be clearly delineated from ischemia.

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