{"doi":"10.1016/j.jbc.2023.104986","title":"Deficiency of the metabolic enzyme SCHAD in pancreatic β-cells promotes amino acid–sensitive hypoglycemia","abstract":"Congenital hyperinsulinism of infancy (CHI) can be caused by 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. Whereas 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 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 Ca 2+ 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.","journal":"Journal of Biological Chemistry","year":2023,"id":378744,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":720905,"name":"Khadija El Jellas","orcid":"0000-0003-4473-1422","position":1,"is_corresponding":false},{"id":694746,"name":"Kelly Velasco","orcid":"0000-0002-9376-6034","position":2,"is_corresponding":false},{"id":735548,"name":"Brittany A. Slipp","orcid":null,"position":3,"is_corresponding":false},{"id":748784,"name":"Jiang Hu","orcid":"0000-0003-4284-2575","position":4,"is_corresponding":false},{"id":1143266,"name":"Geir Helgeland","orcid":null,"position":5,"is_corresponding":false},{"id":902546,"name":"Solrun J. Steine","orcid":null,"position":6,"is_corresponding":false},{"id":294804,"name":"Dario F. De Jesus","orcid":"0000-0001-8826-9095","position":7,"is_corresponding":false},{"id":269959,"name":"Rohit Kulkarni","orcid":"0000-0001-5029-6119","position":8,"is_corresponding":false},{"id":240406,"name":"Anders Molven","orcid":"0000-0003-1847-3079","position":9,"is_corresponding":false},{"id":1143265,"name":"Johanna L. St‐Louis","orcid":null,"position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:16:48.594070Z","pmid":"37392854","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}