CDK4 promotes beta cell differentiation
Expanding beta cell mass is a critical goal in the fight against diabetes. CDK4, an extensively characterized cell cycle activator, is required to establish and maintain beta cell number. Beta cell failure in the IRS2-deletion mouse type 2 diabetes model is in part due to loss of CDK4 regulator Cyclin D2. We set out to determine whether replacement of endogenous CDK4 with the inhibitor-resistant mutant CDK4-R24C rescued the loss of beta cell mass in Irs2-deficient mice. Surprisingly, not only beta cell mass but also beta cell dedifferentiation was effectively rescued, despite no improvement in whole body insulin sensitivity. Ex vivo studies in primary islet cells revealed a novel mechanism in which CDK4 intervened downstream in the insulin signaling pathway to prevent FOXO1-mediated transcriptional repression of critical beta cell transcription factor Pdx1. FOXO1 inhibition was not related to E2F1 activity, to FOXO1 phosphorylation, or even to FOXO1 subcellular localization, but rather was related to deacetylation and reduced FOXO1 abundance. Taken together, these results demonstrate a novel differentiation-promoting activity of the classical cell cycle activator CDK4 and support the concept that beta cell mass can be expanded without compromising function. Overall design: Pancreatic islets were isolated from littermate mice of genotypes IRS2+/+;CDK4 wt/wt ("WT"), IRS2-/-;CDK4 wt/wt ("KO"), or IRS2-/-;CDK4 R24C/R24C ("RRKO"), hand picked, and flash frozen for RNA isolation.