Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects

Houten, Sander M, Herrema, Hilde, Te Brinke, Heleen, Denis, Simone, Ruiter, Jos P N, van Dijk, Theo H, Argmann, Carmen A, Ottenhoff, Roelof, Müller, Michael ORCID: https://orcid.org/0000-0002-5930-9905, Groen, Albert K, Kuipers, Folkert, Reijngoud, Dirk-Jan and Wanders, Ronald J A (2013) Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects. Human Molecular Genetics, 22 (25). pp. 5249-5261. ISSN 0964-6906

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Abstract

The importance of mitochondrial fatty acid β-oxidation (FAO) as a glucose-sparing process is illustrated by patients with inherited defects in FAO, who may present with life-threatening fasting-induced hypoketotic hypoglycemia. It is unknown why peripheral glucose demand outpaces hepatic gluconeogenesis in these patients. In this study, we have systematically addressed the fasting response in long-chain acyl-CoA dehydrogenase-deficient (LCAD KO) mice. We demonstrate that the fasting-induced hypoglycemia in LCAD KO mice was initiated by an increased glucose requirement in peripheral tissues, leading to rapid hepatic glycogen depletion. Gluconeogenesis did not compensate for the increased glucose demand, which was not due to insufficient hepatic glucogenic capacity but rather caused by a shortage in the supply of glucogenic precursors. This shortage in supply was explained by a suppressed glucose-alanine cycle, decreased branched-chain amino acid metabolism and ultimately impaired protein mobilization. We conclude that during fasting, FAO not only serves to spare glucose but is also indispensable for amino acid metabolism, which is essential for the maintenance of adequate glucose production.

Item Type:	Article
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	Pure Connector
Date Deposited:	10 Jun 2014 20:30
Last Modified:	06 Jun 2024 14:45
URI:	https://ueaeprints.uea.ac.uk/id/eprint/47634
DOI:	10.1093/hmg/ddt382

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