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

Changhong Li, Pan Chen, Andrew Palladino, Srinivas Narayan, Laurie K. Russell, Samir Sayed, Guoxiang Xiong, Jie Chen, David Stokes, Yasmeen M. Butt, Patricia M. Jones, Heather W. Collins, Noam A. Cohen, Akiva S. Cohen, Itzhak Nissim, Thomas J. Smith, Arnold W. Strauss, Franz M. Matschinsky, Michael J. Bennett, Charles A. Stanley

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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- 14C]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.

Original languageEnglish (US)
Pages (from-to)31806-31818
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number41
DOIs
StatePublished - Oct 8 2010

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3-Hydroxyacyl-CoA Dehydrogenase
Glutamate Dehydrogenase
Hyperinsulinism
Chemical activation
Insulin
Amino Acids
Glucose
Glutamine
Leucine
Hypersensitivity
Fatty Acids
Plasmas
Enzyme kinetics
Gene Knockout Techniques
Palmitates
Aspartic Acid
Alanine
Insulin Resistance
Glutamic Acid
Anti-Idiotypic Antibodies

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. / Li, Changhong; Chen, Pan; Palladino, Andrew; Narayan, Srinivas; Russell, Laurie K.; Sayed, Samir; Xiong, Guoxiang; Chen, Jie; Stokes, David; Butt, Yasmeen M.; Jones, Patricia M.; Collins, Heather W.; Cohen, Noam A.; Cohen, Akiva S.; Nissim, Itzhak; Smith, Thomas J.; Strauss, Arnold W.; Matschinsky, Franz M.; Bennett, Michael J.; Stanley, Charles A.

In: Journal of Biological Chemistry, Vol. 285, No. 41, 08.10.2010, p. 31806-31818.

Research output: Contribution to journalArticle

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 2010, 'Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase', Journal of Biological Chemistry, vol. 285, no. 41, pp. 31806-31818. https://doi.org/10.1074/jbc.M110.123638
Li, Changhong ; Chen, Pan ; Palladino, Andrew ; Narayan, Srinivas ; Russell, Laurie K. ; Sayed, Samir ; Xiong, Guoxiang ; Chen, Jie ; Stokes, David ; Butt, Yasmeen M. ; Jones, Patricia M. ; Collins, Heather W. ; Cohen, Noam A. ; Cohen, Akiva S. ; Nissim, Itzhak ; Smith, Thomas J. ; Strauss, Arnold W. ; Matschinsky, Franz M. ; Bennett, Michael J. ; Stanley, Charles A. / Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 41. pp. 31806-31818.
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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- 14C]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.",
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T1 - Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase

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AU - Chen, Pan

AU - Palladino, Andrew

AU - Narayan, Srinivas

AU - Russell, Laurie K.

AU - Sayed, Samir

AU - Xiong, Guoxiang

AU - Chen, Jie

AU - Stokes, David

AU - Butt, Yasmeen M.

AU - Jones, Patricia M.

AU - Collins, Heather W.

AU - Cohen, Noam A.

AU - Cohen, Akiva S.

AU - Nissim, Itzhak

AU - Smith, Thomas J.

AU - Strauss, Arnold W.

AU - Matschinsky, Franz M.

AU - Bennett, Michael J.

AU - Stanley, Charles A.

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N2 - 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- 14C]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.

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