Effectively truncated TCA cycle during profound hypoglycemia

Background

In the medical, scientific and legal communities, it is now widely understood that hypoglycemic brain damage occurs in the presence of coma (flat EEG), a prerequisite for brain damage signaled by excitatory amino acid release. Alterations must take place, however, allowing most brain tissue to survive hypoglycemic coma.

Methods

Brain metabolism was interrogated in rats during and following recovery from 40 min of profound hypoglycemia using ex vivo 1 H MR spectroscopy.

Results

A time-dependent increase in aspartate was equaled by a reciprocal decrease in glutamate/glutamine. The kinetics of aspartate formation during the first 30 min (0.36 ± 0.03 μmol g⁻¹ min⁻¹) showed that glutamate, via aspartate aminotransferase, becomes the primary source of carbon when glucose-derived pyruvate is unavailable. Oxaloacetate is produced directly from á-ketoglutarate, so that reactions involving the six-carbon intermediates of the tricarboxylic acid cycle are bypassed (figure 1).

Figure 1

Conclusions

We demonstrate for the first time that the Krebs cycle is effectively truncated from a tricarboxylic to a dicarboxylic acid cycle during hypoglycemia, allowing it to still turn. This fundamental alteration in basic metabolic pathways explains the partial preservation of energy charge during periods of glucose deficiency. The results may explain how most brain neurons, and all glia, survive profound hypoglycemia accompanied by electrocerebral silence.