Klf6 protects β-cells against insulin resistance-induced dedifferentiation

Mol Metab. 2020 May;35:100958. doi: 10.1016/j.molmet.2020.02.001. Epub 2020 Feb 6.

Abstract

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 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.

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.

Keywords: Dedifferentiation; Insulin resistance; Transdifferentiation; Type 2 diabetes; β-Cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Kruppel-Like Factor 6 / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Transcriptome

Substances

  • Insulin
  • Klf6 protein, mouse
  • Kruppel-Like Factor 6