CDK2 Limits the Highly Energetic Secretory Program of Mature Β Cells by Restricting PEP Cycle-Dependent KATP Channel Closure

Hallmarks of mature beta cells are restricted proliferation and a highly energetic secretory state. Paradoxically, cyclin-dependent kinase 2 (CDK2) is synthesized throughout adulthood, its cytosolic localization raising the likelihood of cell cycle-independent functions. In the absence of any changes in beta cell mass, maturity, or proliferation, genetic deletion of Cdk2 in adult beta cells enhanced insulin secretion from isolated islets and improved glucose tolerance in vivo. At the single beta cell level, CDK2 restricts insulin secretion by increasing K-ATP conductance, raising the set point for membrane depolarization in response to activation of the phosphoenolpyruvate (PEP) cycle with mitochondrial fuels. In parallel with reduced beta cell recruitment, CDK2 restricts oxidative glucose metabolism while promoting glucose-dependent amplification of insulin secretion. This study provides evidence of essential, non-canonical functions of CDK2 in the secretory pathways of quiescent beta cells.