| First Author | Dumayne C | Year | 2020 |
| Journal | Mol Metab | Volume | 35 |
| Pages | 100958 | PubMed ID | 32244185 |
| Mgi Jnum | J:329512 | Mgi Id | MGI:6714513 |
| Doi | 10.1016/j.molmet.2020.02.001 | Citation | Dumayne C, et al. (2020) Klf6 protects beta-cells against insulin resistance-induced dedifferentiation. Mol Metab 35:100958 |
| abstractText | OBJECTIVES: In the pathogenesis of type 2 diabetes, development of insulin resistance triggers an increase in pancreatic beta-cell insulin secretion capacity and beta-cell number. Failure of this compensatory mechanism is caused by a dedifferentiation of beta-cells, which leads to insufficient insulin secretion and diabetic hyperglycemia. The beta-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 beta-cell adaptation to metabolic stress. METHODS: We used a beta-cell specific Klf6 knockout mouse model to investigate whether Klf6 may be a potential regulator of beta-cell adaptation to a metabolic stress. RESULTS: We show that inactivation of Klf6 in beta-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 beta-cell proliferation genes and, in the presence of insulin resistance, it prevents the down-expression of genes controlling mature beta-cell identity and the induction of disallowed genes that impair insulin secretion. Its expression also limits the transdifferentiation of beta-cells into alpha-cells. CONCLUSION: Our study identifies a new transcription factor that protects beta-cells against dedifferentiation, and which may be targeted to prevent diabetes development. |
