Deficiency of the metabolic enzyme SCHAD in pancreatic β-cells promotes amino acid–sensitive hypoglycemia

• Published in: The Journal of biological chemistry 2023-08, Vol.299 (8), p.104986, Article 104986
• Main Authors: St-Louis, Johanna L., El Jellas, Khadija, Velasco, Kelly, Slipp, Brittany A., Hu, Jiang, Helgeland, Geir, Steine, Solrun J., De Jesus, Dario F., Kulkarni, Rohit N., Molven, Anders
• Format: Article
• Language: English
• Subjects: 3-Hydroxyacyl-CoA Dehydrogenase - deficiency; 3-Hydroxyacyl-CoA Dehydrogenase - genetics; amino acids; Amino Acids - metabolism; Amino Acids - pharmacology; Animals; Congenital Hyperinsulinism - genetics; congenital hyperinsulinism of infancy; HADH; hypoglycemia; Hypoglycemia - enzymology; Hypoglycemia - genetics; Insulin - metabolism; insulin secretion; Insulin Secretion - drug effects; Insulin-Secreting Cells - enzymology; islets; knockout mouse model; Mice; Mice, Knockout; SCHAD; short-chain 3-hydroxyacyl-CoA dehydrogenase; transcriptomics; β-cell; β-cell dedifferentiation
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2023.104986

Congenital 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.