A genetic screen identifies Crat as a regulator of pancreatic beta-cell insulin secretion.

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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_E7C44B7C6874
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A genetic screen identifies Crat as a regulator of pancreatic beta-cell insulin secretion.
Journal
Molecular metabolism
Author(s)
Berdous D., Berney X., Sanchez-Archidona A.R., Jan M., Roujeau C., Lopez-Mejia I.C., Mynatt R., Thorens B.
ISSN
2212-8778 (Electronic)
ISSN-L
2212-8778
Publication state
Published
Issued date
07/2020
Peer-reviewed
Oui
Volume
37
Pages
100993
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Glucose-stimulated insulin secretion is a critical function in the regulation of glucose homeostasis, and its deregulation is associated with the development of type 2 diabetes. Here, we performed a genetic screen using islets isolated from the BXD panel of advanced recombinant inbred (RI) lines of mice to search for novel regulators of insulin production and secretion.
Pancreatic islets were isolated from 36 RI BXD lines and insulin secretion was measured following exposure to 2.8 or 16.7 mM glucose with or without exendin-4. Islets from the same RI lines were used for RNA extraction and transcript profiling. Quantitative trait loci (QTL) mapping was performed for each secretion condition and combined with transcriptome data to prioritize candidate regulatory genes within the identified QTL regions. Functional studies were performed by mRNA silencing or overexpression in MIN6B1 cells and by studying mice and islets with beta-cell-specific gene inactivation.
Insulin secretion under the 16.7 mM glucose plus exendin-4 condition was mapped significantly to a chromosome 2 QTL. Within this QTL, RNA-Seq data prioritized Crat (carnitine O-acetyl transferase) as a strong candidate regulator of the insulin secretion trait. Silencing Crat expression in MIN6B1 cells reduced insulin content and insulin secretion by ∼30%. Conversely, Crat overexpression enhanced insulin content and secretion by ∼30%. When islets from mice with beta-cell-specific Crat inactivation were exposed to high glucose, they displayed a 30% reduction of insulin content as compared to control islets. We further showed that decreased Crat expression in both MIN6B1 cells and pancreatic islets reduced the oxygen consumption rate in a glucose concentration-dependent manner.
We identified Crat as a regulator of insulin secretion whose action is mediated by an effect on total cellular insulin content; this effect also depends on the genetic background of the RI mouse lines. These data also show that in the presence of the stimulatory conditions used the insulin secretion rate is directly related to the insulin content.
Keywords
Insulin secretion, beta-cells, carnitine acetyltransferase, diabetes, genetics, recombinant inbred mice, Beta-cells, Carnitine acetyltransferase, Diabetes, Genetics, Recombinant inbred mice
Pubmed
Web of science
Open Access
Yes
Create date
25/04/2020 20:07
Last modification date
01/08/2020 6:26
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