PubMed:37392854 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/37392854","sourcedb":"PubMed","sourceid":"37392854","source_url":"https://www.ncbi.nlm.nih.gov/pubmed/37392854","text":"Deficiency of the metabolic enzyme SCHAD in pancreatic β-cells promotes amino acid-sensitive hypoglycemia.\nCongenital 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.","tracks":[{"project":"NCBITAXON","denotations":[{"id":"T1","span":{"begin":466,"end":470},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":484,"end":488},"obj":"OrganismTaxon"},{"id":"T3","span":{"begin":694,"end":698},"obj":"OrganismTaxon"},{"id":"T4","span":{"begin":865,"end":869},"obj":"OrganismTaxon"},{"id":"T5","span":{"begin":1253,"end":1258},"obj":"OrganismTaxon"}],"attributes":[{"id":"A1","pred":"db_id","subj":"T1","obj":"10088"},{"id":"A2","pred":"db_id","subj":"T2","obj":"10088"},{"id":"A3","pred":"db_id","subj":"T3","obj":"10088"},{"id":"A4","pred":"db_id","subj":"T4","obj":"10088"},{"id":"A5","pred":"db_id","subj":"T5","obj":"10088"},{"id":"A6","pred":"db_id","subj":"T5","obj":"10090"},{"subj":"T1","pred":"source","obj":"NCBITAXON"},{"subj":"T2","pred":"source","obj":"NCBITAXON"},{"subj":"T3","pred":"source","obj":"NCBITAXON"},{"subj":"T4","pred":"source","obj":"NCBITAXON"},{"subj":"T5","pred":"source","obj":"NCBITAXON"}]},{"project":"mondo_disease","denotations":[{"id":"T1","span":{"begin":93,"end":105},"obj":"Disease"},{"id":"T2","span":{"begin":107,"end":133},"obj":"Disease"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/MONDO_0004946"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/MONDO_0017182"},{"id":"A3","pred":"mondo_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/MONDO_0019010"},{"subj":"T1","pred":"source","obj":"mondo_disease"},{"subj":"T2","pred":"source","obj":"mondo_disease"}]},{"project":"GlyCosmos6-Glycan-Motif-Structure","denotations":[{"id":"T1","span":{"begin":516,"end":523},"obj":"https://glytoucan.org/Structures/Glycans/G15021LG"},{"id":"T2","span":{"begin":1031,"end":1038},"obj":"https://glytoucan.org/Structures/Glycans/G15021LG"}],"attributes":[{"subj":"T1","pred":"source","obj":"GlyCosmos6-Glycan-Motif-Structure"},{"subj":"T2","pred":"source","obj":"GlyCosmos6-Glycan-Motif-Structure"}]},{"project":"GlyCosmos6-Glycan-Motif-Image","denotations":[{"id":"T1","span":{"begin":516,"end":523},"obj":"Glycan_Motif"},{"id":"T2","span":{"begin":1031,"end":1038},"obj":"Glycan_Motif"}],"attributes":[{"id":"A1","pred":"image","subj":"T1","obj":"https://api.glycosmos.org/wurcs2image/0.10.0/png/binary/G15021LG"},{"id":"A2","pred":"image","subj":"T2","obj":"https://api.glycosmos.org/wurcs2image/0.10.0/png/binary/G15021LG"},{"subj":"T1","pred":"source","obj":"GlyCosmos6-Glycan-Motif-Image"},{"subj":"T2","pred":"source","obj":"GlyCosmos6-Glycan-Motif-Image"}]},{"project":"Anatomy-UBERON","denotations":[{"id":"T1","span":{"begin":423,"end":433},"obj":"Body_part"},{"id":"T2","span":{"begin":509,"end":515},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"uberon_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL_0000182"},{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/UBERON_0001969"},{"subj":"T1","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T2","pred":"source","obj":"Anatomy-UBERON"}]},{"project":"HP-phenotype","denotations":[{"id":"T1","span":{"begin":93,"end":105},"obj":"Phenotype"}],"attributes":[{"id":"A1","pred":"hp_id","subj":"T1","obj":"HP:0001943"},{"subj":"T1","pred":"source","obj":"HP-phenotype"}],"namespaces":[{"prefix":"HP","uri":"http://purl.obolibrary.org/obo/HP_"}]},{"project":"CL-cell","denotations":[{"id":"T1","span":{"begin":423,"end":433},"obj":"Cell"}],"attributes":[{"id":"A1","pred":"cl_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL:0000182"},{"subj":"T1","pred":"source","obj":"CL-cell"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"NCBITAXON","color":"#b1ec93","default":true},{"id":"mondo_disease","color":"#ec93cb"},{"id":"GlyCosmos6-Glycan-Motif-Structure","color":"#93e6ec"},{"id":"GlyCosmos6-Glycan-Motif-Image","color":"#ecd893"},{"id":"Anatomy-UBERON","color":"#be93ec"},{"id":"HP-phenotype","color":"#93eca4"},{"id":"CL-cell","color":"#ec939b"}]}]}}