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Truncation of the krebs cycle during hypoglycemic coma
Garnette R Sutherland1, Randy L Tyson, Roland N Auer
1Seaman Family MR Research Centre, Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada. garnette@ucalgary.ca
Medicinal Chemistry (Shariqah (United Arab Emirates))
|August 5, 2008
Summary
Hypoglycemic coma is necessary for brain cell death, which is prevented by a metabolic shift. This shift redraws the Krebs cycle, allowing brain cells to survive glucose deficiency.
Area of Science:
- Neuroscience
- Biochemistry
- Metabolic pathways
Background:
- Hypoglycemia can cause brain damage, but the mechanisms of neuronal survival are not fully understood.
- Neuronal death during hypoglycemia is incorrectly thought to occur without coma.
- Coma is a prerequisite for neuronal death, mediated by metabolic excitatory amino acid release.
Purpose of the Study:
- To investigate brain metabolism during and after profound hypoglycemia in rats.
- To identify metabolic alterations that account for brain tissue survival during glucose deficiency.
- To clarify the role of the tricarboxylic acid cycle in maintaining brain energy homeostasis during hypoglycemia.
Main Methods:
- Ex vivo (1)H MR spectroscopy was used to analyze brain metabolism in rats.
- Metabolic changes were assessed during and following 40 minutes of profound hypoglycemia.
- Changes in amino acid concentrations and metabolic flux were quantified.
Main Results:
- A time-dependent increase in aspartate and a reciprocal decrease in glutamate/glutamine were observed.
- Glutamate, via aspartate aminotransferase, became the primary carbon source when glucose was unavailable.
- The tricarboxylic acid cycle was altered to a dicarboxylic acid cycle, bypassing six-carbon intermediates.
- A truncated Krebs cycle continued to function, preserving energy charge and promoting cell survival.
Conclusions:
- Profound hypoglycemia induces a metabolic shift that preserves brain energy charge and cell survival.
- The altered metabolic pathway effectively redraws the Krebs cycle, enabling continued function during glucose deficiency.
- These findings challenge misconceptions about hypoglycemic neuronal death and explain brain cell resilience.
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