title: Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase.
abstract: The mechanism of insulin dysregulation in children with hyperinsulinism associated with inactivating mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) was examined in mice with a knock-out of the hadh gene (hadh(-/-)). The hadh(-/-) mice had reduced levels of plasma glucose and elevated plasma insulin levels, similar to children with SCHAD deficiency. hadh(-/-) mice were hypersensitive to oral amino acid with decrease of glucose level and elevation of insulin. Hypersensitivity to oral amino acid in hadh(-/-) mice can be explained by abnormal insulin responses to a physiological mixture of amino acids and increased sensitivity to leucine stimulation in isolated perifused islets. Measurement of cytosolic calcium showed normal basal levels and abnormal responses to amino acids in hadh(-/-) islets. Leucine, glutamine, and alanine are responsible for amino acid hypersensitivity in islets. hadh(-/-) islets have lower intracellular glutamate and aspartate levels, and this decrease can be prevented by high glucose. hadh(-/-) islets also have increased [U-(14)C]glutamine oxidation. In contrast, hadh(-/-) mice have similar glucose tolerance and insulin sensitivity compared with controls. Perifused hadh(-/-) islets showed no differences from controls in response to glucose-stimulated insulin secretion, even with addition of either a medium-chain fatty acid (octanoate) or a long-chain fatty acid (palmitate). Pull-down experiments with SCHAD, anti-SCHAD, or anti-GDH antibodies showed protein-protein interactions between SCHAD and GDH. GDH enzyme kinetics of hadh(-/-) islets showed an increase in GDH affinity for its substrate, α-ketoglutarate. These studies indicate that SCHAD deficiency causes hyperinsulinism by activation of GDH via loss of inhibitory regulation of GDH by SCHAD.
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Palladino
authors.forename: Srinivas
authors.initials: S
authors.lastname: Narayan
authors.forename: Laurie K
authors.initials: LK
authors.lastname: Russell
authors.forename: Samir
authors.initials: S
authors.lastname: Sayed
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Xiong
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Stokes
authors.forename: Yasmeen M
authors.initials: YM
authors.lastname: Butt
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Jones
authors.forename: Heather W
authors.initials: HW
authors.lastname: Collins
authors.forename: Noam A
authors.initials: NA
authors.lastname: Cohen
authors.forename: Akiva S
authors.initials: AS
authors.lastname: Cohen
authors.forename: Itzhak
authors.initials: I
authors.lastname: Nissim
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Smith
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Strauss
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency*; D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D002239:Carbohydrate Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006946:Hyperinsulinism / Q000201:enzymology* / Q000235:genetics; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D007656:Ketoglutaric Acids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D007328:Insulin; D007656:Ketoglutaric Acids; D015094:3-Hydroxyacyl CoA Dehydrogenases; D005969:Glutamate Dehydrogenase