Pluto Bioinformatics

GSE137187: Klf6 protects -cells against insulin resistance-induced dedifferentiation

Bulk RNA sequencing

In the pathogenesis of type 2 diabetes development of insulin resistance triggers an increase in pancreatic -cell insulin secretion capacity and -cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of -cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The -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 -cell adaptation to metabolic stress. We show that inactivation of Klf6 in mouse -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 -cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature -cell identity and the induction of disallowed genes that impair insulin secretion; its expression also limits the transdifferentiation of -cells into alpha cells. Our study identifies a new transcription factor that protects -cells against dedifferentiation and which may be targeted to prevent diabetes development. SOURCE: Ana Rodriguez Sanchez-Archidona (arsanchezarchidona@gmail.com, Ana.Rodriguez.1@unil.ch) - Bernard Thorens University of Lausanne