CDK8 Regulates Insulin Secretion and Mediates Postnatal and Stress-Induced Expression of Neuropeptides in Pancreatic β Cells

Cyclin-dependent kinases (CDKs) contribute to vital cellular processes including cell cycle regulation. Loss of CDKs is associated with impaired insulin secretion and beta cell survival; however, the function of CDK8 in beta cells remains elusive. Here, we report that genetic ablation of Cdk8 improves glucose tolerance by increasing insulin secretion. We identify OSBPL3 as a CDK8-dependent phosphoprotein, which acts as a negative regulator of insulin secretion in response to glucose. We also show that embryonic gene silencing of neuropeptide Y in beta cells is compromised in Cdk8-null mice, leading to continued expression into adulthood. Cdk8 ablation in beta cells aggravates apoptosis and induces de novo expression of neuropeptides upon oxidative stress. Moreover, pancreatic islets exposed to stress display augmented apoptosis in the presence of these same neuropeptides. Our results reveal critical roles for CDK8 in beta cell function and survival during metabolic stress that are in part mediated through de novo expression of neuropeptides.