Klf6 protects β-cells against insulin resistance-induced dedifferentiation

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 show that inactivation of Klf6 in mouse 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 alpha cells. Our study identifies a new transcription factor that protects β-cells against dedifferentiation and which may be targeted to prevent diabetes development. Islet transcriptomic analysis, searching for genes differentially expressed between Ctrl and βKlf6KO mouse islets in saline or S961 treated mice. 12 mice were treated with saline (6 Ctrl and 6 βKlf6KO mice), and 16 with S961 (8 Ctrl and 8 βKlf6KO mice) Ins1Cre/+ mice were crossed with Klf6flox/flox mice to generate Klf6flox/flox;Ins1Cre/+ mice (βKlf6KO) and Klf6flox/flox;Ins1+/+mice l (CTL).