Klf6 protects ß-cells against insulin resistance-induced dedifferentiation.

OBJECTIVES: 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. METHODS: We used a ß-cell specific Klf6 knockout mouse model to investigate whether Klf6 may be a potential regulator of ß-cell adaptation to a metabolic stress. RESULTS: We show that inactivation of Klf6 in 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 α-cells. CONCLUSION: Our study identifies a new transcription factor that protects ß-cells against dedifferentiation, and which may be targeted to prevent diabetes development.