Cdk2-Dependent Activation of ß-Cell Metabolism Is Eclipsed by Its Inhibitory Effect on Plasma Membrane Excitability and Insulin Secretion

Abstract

The loss of insulin secretion is a hallmark of diabetes, and it is becoming clear that cell cycle regulators control insulin secretion as well as proliferation. It was recently reported that embryonic deletion of cyclin-dependent kinase 2 (Cdk2) in β-cells (Pdx1-Cre:Cdk2-/-) results in impaired glucose tolerance due to defective insulin secretion (Kim et al., J Biol Chem, 2017), revealing a developmental or perinatal requirement of Cdk2. Here, we show that tamoxifen-inducible deletion of Cdk2 in adult β-cells (MIP-CreER:Cdk2-/-) enhances insulin secretion. Despite these differences, both models of Cdk2 depletion exhibited a strong increase in the glucose dependence of β-cell calcium oscillations. This effect is likely due to the loss of ATP-sensitive K+ (KATP) channels, since kir6.2 transcript was reduced in Cdk2-null β-cells, and pharmacological inhibition of Cdk2 correspondingly reduced KATP channel conductance. These results reveal that Cdk2 inhibits insulin secretion by limiting plasma membrane excitability via KATP. In adult β-cells lacking Cdk2, we also observed a 45% reduction in depolarization-induced exocytosis, indicating that Cdk2 is required for the metabolic amplification of insulin secretion. Within the intermediary metabolic pathways, Cdk2-null β-cells exhibited reductions in glucose-dependent lactate accumulation, mitochondrial membrane potential, and mitochondrial NADH utilization. Together, these studies reveal that Cdk2 transcriptionally limits β-cell membrane excitability and the insulin secretory response, and is required to maintain proper metabolic function. Disclosure S. Sdao: None. C. Poudel: None. K.M. Mortensen: None. M.J. Merrins: None.