Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects.
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.
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry.
Sander M
SM
Houten
Hilde
H
Herrema
Heleen
H
Te Brinke
Simone
S
Denis
Jos P N
JP
Ruiter
Theo H
TH
van Dijk
Carmen A
CA
Argmann
Roelof
R
Ottenhoff
Michael
M
Müller
Albert K
AK
Groen
Folkert
F
Kuipers
Dirk-Jan
DJ
Reijngoud
Ronald J A
RJ
Wanders
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism; D008112:Liver Glycogen / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction
D000596:Amino Acids; D005227:Fatty Acids; D008112:Liver Glycogen; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D005947:Glucose