Recurrent hypoglycemia: boosting the brain’s metabolic flexibility
Marina Litvin, … , Amy L. Clark, Simon J. Fisher
Marina Litvin, … , Amy L. Clark, Simon J. Fisher
Published April 1, 2013
Citation Information: J Clin Invest. 2013;123(5):1922-1924. https://doi.org/10.1172/JCI69796.
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Commentary

Recurrent hypoglycemia: boosting the brain’s metabolic flexibility

Abstract

For people with diabetes, recurrent episodes of hypoglycemia limit the brain’s ability to sense dangerously low blood sugar levels. In this issue of the JCI, the mechanisms behind this clinical problem of hypoglycemia unawareness are addressed by Herzog et al. The authors provide compelling evidence that recurrent hypoglycemia enhances transport of lactate into the brain and, although not itself a major alternative fuel source, lactate may preserve neuronal function during hypoglycemia by maintaining neuronal glucose metabolism. These findings redefine our understanding of the brain’s metabolic adaptations that result from recurrent hypoglycemia.

Authors

Marina Litvin, Amy L. Clark, Simon J. Fisher

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Figure 1

Recurrent hypoglycemia preconditioning increases the brain’s capacity for glucose and lactate uptake during hypoglycemia.

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Recurrent hypoglycemia preconditioning increases the brain’s capacity fo...
Herzog et al. (15) traced the metabolic fate of infused lactate during insulin-induced hypoglycemia in the brains of rats. The figure depicts neuronal cells during conditions of acute hypoglycemia and lactate infusion either (A) without or (B) with antecedent hypoglycemic preconditioning. During acute hypoglycemia, intracellular glucose levels decline markedly and limit glucose oxidation and ATP generation, even in the presence of lactate infusion. With very low intracellular glucose levels, there is a relatively large transmembrane glucose gradient, consistent with the notion that glucose transport is the rate-limiting step for brain glucose metabolism during hypoglycemia. The normal responses to hypoglycemia include symptoms of hypoglycemia (e.g., hypoglycemia awareness) associated with a brisk counterregulatory response. If hypoglycemia is severe, however, neuronal function can be impaired. The recurrent hypoglycemia-preconditioned brain, on the other hand, demonstrated an increased capacity for glucose transport (as depicted by bold arrow), which prevented such a marked decline in intracellular glucose. Preconditioning thus maintains neuronal glucose oxidation and preserves brain function during hypoglycemia but consequently leads to the clinical problem of hypoglycemia unawareness and impaired sympathoadrenal responses. Preconditioning also increased the capacity for lactate transport via monocarboxylic acid transporters (MCT) as depicted by bold arrows. Although, with only a small lactate gradient in the brain, increased lactate influx was matched by lactate efflux, and lactate was not a significant alternative fuel substrate. The authors’ propose that the infused lactate may have acted as a metabolic regulator that helped to preserve glucose metabolism during hypoglycemia. A better understanding of the brain’s adaptations to recurrent hypoglycemia may help prevent the clinical conditions of hypoglycemia unawareness and impaired stress responses and that occur in patients with diabetes. Glut, glucose transporter.