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

摘要

The importance of mitochondrial fatty acid β-oxidation (FAO) as a glucose-sparing process is illustrated by patients with inherited defects inFAO,whomaypresentwith life-threatening fasting-induced hypoketotic hypoglycemia. It isunknownwhy peripheral glucose demand outpaces hepatic gluconeogenesis in these patients. In this study, we have systematically addressed the fasting response in long-chain acyl-CoA dehydrogenasedeficient (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 glucogeniccapacity but rathercausedbyashortage in thesupply 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. Weconclude 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.