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Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Hypoglycaemia is characterized by decreased blood glucose levels and is associated with different pathologies (e.g. diabetes, inborn errors of metabolism). Depending on its severity, it might affect cognitive functions, including impaired judgment and decreased memory capacity, which have been linked to alterations of brain energy metabolism. Glucose is the major cerebral energy substrate in the adult brain and supports the complex metabolic interactions between neurons and astrocytes, which are essential for synaptic activity. Therefore, hypoglycaemia disturbs cerebral metabolism and, consequently, neuronal function. Despite the high vulnerability of neurons to hypoglycaemia, important neurochemical changes enabling these cells to prolong their resistance to hypoglycaemia have been described. This review aims at providing an overview over the main metabolic effects of hypoglycaemia on neurons, covering in vitro and in vivo findings. Recent studies provided evidence that non-glucose substrates including pyruvate, glycogen, ketone bodies, glutamate, glutamine, and aspartate, are metabolized by neurons in the absence of glucose and contribute to prolong neuronal function and delay ATP depletion during hypoglycaemia. One of the pathways likely implicated in the process is the pyruvate recycling pathway, which allows for the full oxidation of glutamate and glutamine. The operation of this pathway in neurons, particularly after hypoglycaemia, has been re-confirmed recently using metabolic modelling tools (i.e. Metabolic Flux Analysis), which allow for a detailed investigation of cellular metabolism in cultured cells. Overall, the knowledge summarized herein might be used for the development of potential therapies targeting neuronal protection in patients vulnerable to hypoglycaemic episodes.

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Acknowledgments

Dr. Ana P. Teixeira, Dr. Paula M. Alves (IBET, Portugal) and Prof. Ursula Sonnewald (NTNU, Norway) are gratefully acknowledged for fruitful discussions and all the support and scientific contribution to the MFA studies. Prof Ursula Sonnewald is further acknowledged for the critical reading of the manuscript.

Details of funding

Part of the experimental work described in this review was supported by the Fundação para a Ciência e Tecnologia (FCT), Portugal (project ref. PTDC/BIO/69407/2006 and PhD fellowship SFRH/BD/29666/2006 to A. Amaral), and the Norwegian Research Council.

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  1. Anne McLaren Laboratory for Regenerative Medicine, Department of Clinical Neurosciences, MRC Centre for Stem Cell Biology and Regenerative Medicine, University of Cambridge, West Forvie Building, Robinson Way, CB2 0SZ, Cambridge, UK

    Ana I. Amaral

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  1. Ana I. Amaral
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Correspondence to Ana I. Amaral.

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Communicated by: Francois Feillet

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Amaral, A.I. Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose. J Inherit Metab Dis 36, 621–634 (2013). https://doi.org/10.1007/s10545-012-9553-3

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  • DOI: https://doi.org/10.1007/s10545-012-9553-3

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