Truncation of the Krebs Cycle During Hypoglycemic Coma

Author(s): Garnette R. Sutherland , Randy L. Tyson , Roland N. Auer .

Journal Name: Medicinal Chemistry

Volume 4 , Issue 4 , 2008

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Abstract:

There is a misconception that hypoglycemic nerve cell death occurs easily, and can happen in the absence of coma. In fact, coma is the prerequisite for neuronal death, which occurs via metabolic excitatory amino acid release. The focus on nerve cell death does not explain how most brain neurons and all glia survive. Brain metabolism was interrogated in rats during and following recovery from 40 min of profound hypoglycemia using ex vivo 1H MR spectroscopy to determine alterations accounting for survival of brain tissue. As previously shown, a time-dependent increase in aspartate was equaled by a reciprocal decrease in glutamate/glutamine. We here show that the kinetics of aspartate formation during the first 30 min (0.36 ± 0.03 μmol g-1 min-1) are altered such that glutamate, via aspartate aminotransferase, becomes the primary source of carbon when glucose-derived pyruvate is unavailable. Oxaloacetate is produced directly from α- ketoglutarate, so that reactions involving the six-carbon intermediates of the tricarboxylic acid cycle are bypassed. These fundamental observations in basic metabolic pathways in effect redraw the tricarboxylic acid cycle from a tricarboxylic to a dicarboxylic acid cycle during hypoglycemia. The basic neurochemical alterations according to the chemical equilibrium of mass action augments flux through a truncated Krebs cycle that continues to turn during hypoglycemic coma. This explains the partial preservation of energy charge and brain cell survival during periods of glucose deficiency.

Keywords: Magnetic Resonance Spectrscopy, isoelectric EEG changes, guanosine, TCA cycle, Amino Acid Metabolism, NADH production

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Article Details

VOLUME: 4
ISSUE: 4
Year: 2008
Page: [379 - 385]
Pages: 7
DOI: 10.2174/157340608784872235
Price: $58

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