Research output: Contribution to journal › Article › Academic › peer-review
Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects. / Houten, Sander M.; Herrema, Hilde; te Brinke, Heleen et al.
In: Human molecular genetics, Vol. 22, No. 25, 2013, p. 5249-5261.Research output: Contribution to journal › Article › Academic › peer-review
}
TY - JOUR
T1 - Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects
AU - Houten, Sander M.
AU - Herrema, Hilde
AU - te Brinke, Heleen
AU - Denis, Simone
AU - Ruiter, Jos P. N.
AU - van Dijk, Theo H.
AU - Argmann, Carmen A.
AU - Ottenhoff, Roelof
AU - Müller, Michael
AU - Groen, Albert K.
AU - Kuipers, Folkert
AU - Reijngoud, Dirk-Jan
AU - Wanders, Ronald J. A.
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
U2 - 10.1093/hmg/ddt382
DO - 10.1093/hmg/ddt382
M3 - Article
C2 - 23933733
VL - 22
SP - 5249
EP - 5261
JO - Human molecular genetics
JF - Human molecular genetics
SN - 0964-6906
IS - 25
ER -
ID: 2243407