Strengths of this study include the use of parallel in vivo and ex vivo model systems to explore the fundamental biology of how a cell cycle regulator rescues diabetes phenotype in Irs2–/– mice, a careful and comprehensive determination of the CDK4-mediated effect on FOXO1 biology and Pdx1 expression, and the use of primary cells rather than transformed cell lines. Here, CDK4 is linked to diabetes mellitus.