PKCζ Is Essential for Pancreatic β-Cell Replication During Insulin Resistance by Regulating mTOR and Cyclin-D2

Diabetes. 2016 May;65(5):1283-96. doi: 10.2337/db15-1398. Epub 2016 Feb 11.


Adaptive β-cell replication occurs in response to increased metabolic demand during insulin resistance. The intracellular mediators of this compensatory response are poorly defined and their identification could provide significant targets for β-cell regeneration therapies. Here we show that glucose and insulin in vitro and insulin resistance in vivo activate protein kinase C ζ (PKCζ) in pancreatic islets and β-cells. PKCζ is required for glucose- and glucokinase activator-induced proliferation of rodent and human β-cells in vitro. Furthermore, either kinase-dead PKCζ expression (KD-PKCζ) or disruption of PKCζ in mouse β-cells blocks compensatory β-cell replication when acute hyperglycemia/hyperinsulinemia is induced. Importantly, KD-PKCζ inhibits insulin resistance-mediated mammalian target of rapamycin (mTOR) activation and cyclin-D2 upregulation independent of Akt activation. In summary, PKCζ activation is key for early compensatory β-cell replication in insulin resistance by regulating the downstream signals mTOR and cyclin-D2. This suggests that alterations in PKCζ expression or activity might contribute to inadequate β-cell mass expansion and β-cell failure leading to type 2 diabetes.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Cyclin D2 / metabolism*
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Enzyme Activation
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Overweight / metabolism*
  • Overweight / pathology
  • Overweight / physiopathology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / chemistry
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • RNA Interference
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Tissue Banks


  • Ccnd2 protein, mouse
  • Cyclin D2
  • Insulin
  • Recombinant Proteins
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • protein kinase C zeta
  • Protein Kinase C
  • Glucose