Klf6 protects β-cells against insulin resistance-induced dedifferentiation.
Animals
Cell Dedifferentiation
/ genetics
Cell Proliferation
/ genetics
Cell Transdifferentiation
Diabetes Mellitus, Type 2
/ metabolism
Disease Models, Animal
Female
Gene Expression Regulation
Gene Knockout Techniques
Insulin
/ metabolism
Insulin Resistance
/ genetics
Insulin Secretion
/ genetics
Insulin-Secreting Cells
/ metabolism
Kruppel-Like Factor 6
/ genetics
Male
Mice
Mice, Knockout
Transcriptome
Dedifferentiation
Insulin resistance
Transdifferentiation
Type 2 diabetes
β-Cell proliferation
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
12
12
2019
revised:
30
01
2020
accepted:
02
02
2020
pubmed:
4
4
2020
medline:
15
4
2021
entrez:
4
4
2020
Statut:
ppublish
Résumé
In the pathogenesis of type 2 diabetes, development of insulin resistance triggers an increase in pancreatic β-cell insulin secretion capacity and β-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of β-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The β-cell factors that normally protect against dedifferentiation remain poorly defined. Here, through a systems biology approach, we identify the transcription factor Klf6 as a regulator of β-cell adaptation to metabolic stress. We used a β-cell specific Klf6 knockout mouse model to investigate whether Klf6 may be a potential regulator of β-cell adaptation to a metabolic stress. We show that inactivation of Klf6 in β-cells blunts their proliferation induced by the insulin resistance of pregnancy, high-fat high-sucrose feeding, and insulin receptor antagonism. Transcriptomic analysis showed that Klf6 controls the expression of β-cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature β-cell identity and the induction of disallowed genes that impair insulin secretion. Its expression also limits the transdifferentiation of β-cells into α-cells. Our study identifies a new transcription factor that protects β-cells against dedifferentiation, and which may be targeted to prevent diabetes development.
Identifiants
pubmed: 32244185
pii: S2212-8778(20)30030-2
doi: 10.1016/j.molmet.2020.02.001
pmc: PMC7093812
pii:
doi:
Substances chimiques
Insulin
0
Klf6 protein, mouse
0
Kruppel-Like Factor 6
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100958Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.
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