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dc.contributor.authorSt-Louis, Johanna L.
dc.contributor.authorel Jellas, Khadija
dc.contributor.authorVelasco, Kelly
dc.contributor.authorSlipp, Brittany A.
dc.contributor.authorHu, Jiang
dc.contributor.authorHelgeland, Geir
dc.contributor.authorSteine, Solrun
dc.contributor.authorDe Jesus, Dario F.
dc.contributor.authorKulkarni, Rohit N.
dc.contributor.authorMolven, Anders
dc.description.abstractCongenital hyperinsulinism of infancy (CHI) can be caused by a deficiency of the ubiquitously expressed enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD). To test the hypothesis that SCHAD-CHI arises from a specific defect in pancreatic β-cells, we created genetically engineered β-cell-specific (β-SKO) or hepatocyte-specific (L-SKO) SCHAD knockout mice. While L-SKO mice were normoglycemic, plasma glucose in β-SKO animals was significantly reduced in the random-fed state, after overnight fasting, and following refeeding. The hypoglycemic phenotype was exacerbated when the mice were fed a diet enriched in leucine, glutamine, and alanine. Intraperitoneal injection of these three amino acids led to a rapid elevation in insulin levels in β-SKO mice compared to controls. Consistently, treating isolated β-SKO islets with the amino acid mixture potently enhanced insulin secretion compared to controls in a low-glucose environment. RNA sequencing of β-SKO islets revealed reduced transcription of β-cell identity genes and upregulation of genes involved in oxidative phosphorylation, protein metabolism, and Ca2+ handling. The β-SKO mouse offers a useful model to interrogate the intra-islet heterogeneity of amino acid sensing given the very variable expression levels of SCHAD within different hormonal cells, with high levels in β- and δ-cells and virtually absent α-cell expression. We conclude that the lack of SCHAD protein in β-cells results in a hypoglycemic phenotype characterized by increased sensitivity to amino acid-stimulated insulin secretion and loss of β-cell identity.en_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleDeficiency of the metabolic enzyme SCHAD in pancreatic β-cells promotes amino acid–sensitive hypoglycemiaen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.rights.holderCopyright 2023 the authorsen_US
dc.source.journalJournal of Biological Chemistryen_US
dc.identifier.citationJournal of Biological Chemistry. 2023, 299 (8), 104986.en_US

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Navngivelse 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse 4.0 Internasjonal