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

Autor:	St-Louis JL; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, USA; Department of Clinical Medicine, Gade Laboratory for Pathology, University of Bergen, Bergen, Norway., El Jellas K; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, USA; Department of Clinical Medicine, Gade Laboratory for Pathology, University of Bergen, Bergen, Norway., Velasco K; Department of Clinical Medicine, Gade Laboratory for Pathology, University of Bergen, Bergen, Norway., Slipp BA; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, USA., Hu J; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, USA., Helgeland G; Department of Clinical Medicine, Gade Laboratory for Pathology, University of Bergen, Bergen, Norway., Steine SJ; Department of Clinical Medicine, Gade Laboratory for Pathology, University of Bergen, Bergen, Norway., De Jesus DF; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Harvard Stem Cell Institute, Boston, USA., Kulkarni RN; Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Harvard Stem Cell Institute, Boston, USA., Molven A; Department of Clinical Medicine, Gade Laboratory for Pathology, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway; Section for Cancer Genomics, Haukeland University Hospital, Bergen, Norway. Electronic address: anders.molven@uib.no.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Aug; Vol. 299 (8), pp. 104986. Date of Electronic Publication: 2023 Jun 29.
DOI:	10.1016/j.jbc.2023.104986
Abstrakt:	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 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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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