Deletion of Ia-2 and/or Ia-2β in mice decreases insulin secretion by reducing the number of dense core vesicles

Diabetologia. 2011 Sep;54(9):2347-57. doi: 10.1007/s00125-011-2221-6. Epub 2011 Jul 6.


Aims/hypothesis: Islet antigen 2 (IA-2) and IA-2β are dense core vesicle (DCV) transmembrane proteins and major autoantigens in type 1 diabetes. The present experiments were initiated to test the hypothesis that the knockout of the genes encoding these proteins impairs the secretion of insulin by reducing the number of DCV.

Methods: Insulin secretion, content and DCV number were evaluated in islets from single knockout (Ia-2 [also known as Ptprn] KO, Ia-2β [also known as Ptprn2] KO) and double knockout (DKO) mice by a variety of techniques including electron and two-photon microscopy, membrane capacitance, Ca(2+) currents, DCV half-life, lysosome number and size and autophagy.

Results: Islets from single and DKO mice all showed a significant decrease in insulin content, insulin secretion and the number and half-life of DCV (p < 0.05 to 0.001). Exocytosis as evaluated by two-photon microscopy, membrane capacitance and Ca(2+) currents supports these findings. Electron microscopy of islets from KO mice revealed a marked increase (p < 0.05 to 0.001) in the number and size of lysosomes and enzymatic studies showed an increase in cathepsin D activity (p < 0.01). LC3 protein, an indicator of autophagy, also was increased in islets of KO compared with wild-type mice (p < 0.05 to 0.01) suggesting that autophagy might be involved in the deletion of DCV.

Conclusions/interpretation: We conclude that the decrease in insulin content and secretion, resulting from the deletion of Ia-2 and/or Ia-2β, is due to a decrease in the number of DCV.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Autophagy / physiology
  • Calcium / metabolism
  • Cathepsin D / metabolism
  • Exocytosis / physiology
  • Female
  • Gene Deletion*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Islets of Langerhans / ultrastructure
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Microtubule-Associated Proteins / metabolism
  • Models, Animal
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / deficiency
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / genetics*
  • Secretory Vesicles / pathology*
  • Secretory Vesicles / ultrastructure


  • Insulin
  • MAP1LC3 protein, mouse
  • Microtubule-Associated Proteins
  • Ptprn protein, mouse
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • Cathepsin D
  • Calcium