title: Novel insights into fatty acid oxidation, amino acid metabolism, and insulin secretion from studying patients with loss of function mutations in 3-hydroxyacyl-CoA dehydrogenase.
abstract: BACKGROUND
  Mutations causing genetic defects have been described in many of the enzymes involved in mitochondrial fatty acid oxidation (FAO). Recently, mutations in the penultimate enzyme in the FAO chain have been described that result in quite different symptoms from those normally seen. Patients with mutations in 3-hydroxyacyl-CoA dehydrogenase (HADH) present with protein (leucine)-induced hyperinsulinemic hypoglycemia (HH), suggesting a link between FAO, amino acid metabolism, and insulin secretion.
  
  
  METHODS
  Peer-reviewed articles were searched in PubMed with relevance to HADH and disorders of FAO and protein sensitivity. Relevant articles were cited. Recent evidence suggests that mutations in HADH cause HH that is precipitated by protein in a similar manner to the hyperinsulinism/hyperammonemia (HI/HA) syndrome, which is caused by mutations in the GLUD1 gene, encoding the enzyme glutamate dehydrogenase (GDH).
  
  
  CONCLUSIONS
  Current data suggest that the HH observed in patients with mutations in HADH is precipitated by leucine as seen in the HI/HA syndrome. This is caused by a loss of protein/protein interaction between short-chain HADH (SCHAD, the enzyme coded for by HADH) and GDH, causing an overstimulation of GDH and a rise in cellular ATP and up-regulated insulin secretion. These observations provide new mechanistic insights into the regulation of insulin secretion by fatty acid and amino acid metabolism.
authors.affiliation: Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Heslegrave
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050356:Lipid Metabolism / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D007328:Insulin; D015094:3-Hydroxyacyl CoA Dehydrogenases