| First Author | St-Louis JL | Year | 2023 |
| Journal | J Biol Chem | Volume | 299 |
| Issue | 8 | Pages | 104986 |
| PubMed ID | 37392854 | Mgi Jnum | J:339012 |
| Mgi Id | MGI:7517588 | Doi | 10.1016/j.jbc.2023.104986 |
| Citation | St-Louis JL, et al. (2023) Deficiency of the metabolic enzyme SCHAD in pancreatic beta-cells promotes amino acid-sensitive hypoglycemia. J Biol Chem 299(8):104986 |
| abstractText | 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 beta-cells, we created genetically engineered beta-cell-specific (beta-SKO) or hepatocyte-specific (L-SKO) SCHAD knockout mice. While L-SKO mice were normoglycemic, plasma glucose in beta-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 beta-SKO mice compared to controls. Consistently, treating isolated beta-SKO islets with the amino acid mixture potently enhanced insulin secretion compared to controls in a low-glucose environment. RNA sequencing of beta-SKO islets revealed reduced transcription of beta-cell identity genes and upregulation of genes involved in oxidative phosphorylation, protein metabolism, and Ca(2+) handling. The beta-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 beta- and delta-cells and virtually absent alpha-cell expression. We conclude that the lack of SCHAD protein in beta-cells results in a hypoglycemic phenotype characterized by increased sensitivity to amino acid-stimulated insulin secretion and loss of beta-cell identity. |
