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

ABSTRACT: AIMS/HYPOTHESIS:Islet antigen 2 (IA-2) and IA-2? 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-2? [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-2?, is due to a decrease in the number of DCV.

SUBMITTER: Cai T 

PROVIDER: S-EPMC3168514 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature