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Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase.

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.

Pubmed ID: 20670938


  • Li C
  • Chen P
  • Palladino A
  • Narayan S
  • Russell LK
  • Sayed S
  • Xiong G
  • Chen J
  • Stokes D
  • Butt YM
  • Jones PM
  • Collins HW
  • Cohen NA
  • Cohen AS
  • Nissim I
  • Smith TJ
  • Strauss AW
  • Matschinsky FM
  • Bennett MJ
  • Stanley CA


The Journal of biological chemistry

Publication Data

October 8, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK 53761
  • Agency: NIDDK NIH HHS, Id: DK19525
  • Agency: NIDDK NIH HHS, Id: DK22122
  • Agency: NIDDK NIH HHS, Id: DK53012
  • Agency: NHLBI NIH HHS, Id: HL075421
  • Agency: NIDDK NIH HHS, Id: R01 DK053761
  • Agency: NCRR NIH HHS, Id: UL1-RR-024134

Mesh Terms

  • 3-Hydroxyacyl CoA Dehydrogenases
  • Amino Acids
  • Animals
  • Blood Glucose
  • Carbohydrate Metabolism, Inborn Errors
  • Enzyme Activation
  • Glutamate Dehydrogenase
  • Hyperinsulinism
  • Insulin
  • Insulin-Secreting Cells
  • Ketoglutaric Acids
  • Mice
  • Mice, Knockout