@article{dumayne_klf6_2020, title = {Klf6 protects β-cells against insulin resistance-induced dedifferentiation}, issn = {2212-8778}, url = {http://www.sciencedirect.com/science/article/pii/S2212877820300302}, doi = {10.1016/j.molmet.2020.02.001}, 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 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.}, journaltitle = {Molecular Metabolism}, shortjournal = {Molecular Metabolism}, author = {Dumayne, Christopher and Tarussio, David and Sanchez-Archidona, Ana Rodriguez and Picard, Alexandre and Basco, Davide and Berney, Xavier Pascal and Ibberson, Mark and Thorens, Bernard}, urldate = {2020-02-13}, date = {2020-02-06}, langid = {english}, keywords = {Type 2 diabetes, {WP}5, dedifferentiation, insulin resistance, transdifferentiation, β-cell proliferation}, }