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

Cell Rep. 2019 Sep 10;28(11):2892-2904.e7. doi: 10.1016/j.celrep.2019.08.025.

Abstract

Cyclin-dependent kinases (CDKs) contribute to vital cellular processes including cell cycle regulation. Loss of CDKs is associated with impaired insulin secretion and β cell survival; however, the function of CDK8 in β 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 β cells is compromised in Cdk8-null mice, leading to continued expression into adulthood. Cdk8 ablation in β 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 β cell function and survival during metabolic stress that are in part mediated through de novo expression of neuropeptides.

Keywords: CDK8; Osbpl3; apoptosis; insulin secretion; neuropeptide; pancreatic β cell; phosphoproteomic analysis.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Cell Line
  • Cyclin-Dependent Kinase 8 / genetics
  • Cyclin-Dependent Kinase 8 / metabolism*
  • Gene Silencing
  • Glucose / metabolism*
  • Humans
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Secretion / genetics*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / embryology
  • Islets of Langerhans / growth & development
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuropeptide Y / metabolism*
  • Oxidative Stress / genetics
  • RNA-Seq
  • Streptozocin / toxicity
  • Tandem Mass Spectrometry

Substances

  • Insulin
  • Neuropeptide Y
  • Streptozocin
  • Cdk8 protein, mouse
  • Cyclin-Dependent Kinase 8
  • Glucose