%0 Journal Article
%T Klf6 protects β-cells against insulin resistance-induced dedifferentiation
%U http://www.sciencedirect.com/science/article/pii/S2212877820300302
%X Objectives
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.
Methods
We use 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.
Results
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.
Conclusion
Our study identifies a new transcription factor that protects β-cells against dedifferentiation, and which may be targeted to prevent diabetes development.
%G en
%J Molecular Metabolism
%A Dumayne, Christopher
%A Tarussio, David
%A Sanchez-Archidona, Ana Rodriguez
%A Picard, Alexandre
%A Basco, Davide
%A Berney, Xavier Pascal
%A Ibberson, Mark
%A Thorens, Bernard
%D February 6, 2020
%K Type 2 diabetes
WP5
dedifferentiation
insulin resistance
transdifferentiation
β-cell proliferation