Klf6 protects ß-cells against insulin resistance-induced dedifferentiation

In the pathogenesis of type 2 diabetes development of insulin resistance triggers an increase in pancreatic ß-cell insulin secretion capacity and ß-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of ß-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The ß-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 ß-cell adaptation to metabolic stress. We show that inactivation of Klf6 in mouse ß-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 ß-cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature ß-cell identity and the induction of disallowed genes that impair insulin secretion; its expression also limits the transdifferentiation of ß-cells into alpha cells. Our study identifies a new transcription factor that protects ß-cells against dedifferentiation and which may be targeted to prevent diabetes development. Overall design: Islet transcriptomic analysis, searching for genes differentially expressed between Ctrl and ßKlf6KO mouse islets in saline or S961 treated mice. 12 mice were treated with saline (6 Ctrl and 6 ßKlf6KO mice), and 16 with S961 (8 Ctrl and 8 ßKlf6KO mice) Ins1Cre/+ mice were crossed with Klf6flox/flox mice to generate Klf6flox/flox;Ins1Cre/+ mice (ßKlf6KO) and Klf6flox/flox;Ins1+/+mice l (CTL).