Klf6 protects β-cells against insulin resistance-induced dedifferentiation

• Published in: Molecular metabolism (Germany) Vol. 35; p. 100958
• Main Authors: Dumayne, Christopher, Tarussio, David, Sanchez-Archidona, Ana Rodriguez, Picard, Alexandre, Basco, Davide, Berney, Xavier Pascal, Ibberson, Mark, Thorens, Bernard
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01-05-2020; Elsevier
• Subjects: Animals; Cell Dedifferentiation - genetics; Cell Proliferation - genetics; Cell Transdifferentiation; Dedifferentiation; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Female; Gene Expression Regulation; Gene Knockout Techniques; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; Insulin Secretion - genetics; Insulin-Secreting Cells - metabolism; Kruppel-Like Factor 6 - genetics; Kruppel-Like Factor 6 - metabolism; Male; Mice; Mice, Knockout; Original; Transcriptome; Transdifferentiation; Type 2 diabetes; β-Cell proliferation; Type 2 diabetes; β-Cell proliferation; KLF6; Dedifferentiation; Transdifferentiation; RT-PCR; GSIS; HFHS; Insulin resistance; WGCNA
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2020.02.001

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.
•Absence of Klf6 in β-cells leads to a reduction in their proliferation and mass during insulin resistance development.•Insulin receptor blockade by S961 leads to a greater dedifferentiation state in β-cell-specific Klf6 knockout mice.•Insulin receptor antagonism leads to enhanced β-cell to α-cell transdifferentiation in β-cell-specific Klf6 knockout mice.