Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance

Fabio Panariello, Giuseppe Perruolo, Angela Cassese, Ferdinando Giacco, Ginevra Botta, Alessia P.M. Barbagallo, Giovanni Muscettola, Francesco Beguinot, Pietro Formisano, Andrea de Bartolomeis

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Clinical and experimental evidence indicates that atypical antipsychotics impair glucose metabolism. We investigated whether clozapine may directly affect insulin action by analyzing insulin signaling in vitro and in vivo. Clozapine reduced insulin-stimulated glucose uptake in PC12 and in L6 cells, representative models of neuron and skeletal muscle, respectively. Consistently, clozapine reduced insulin effect on insulin receptor (IR) by 40% and on IR substrate-1 (IRS1) tyrosine phosphorylation by 60%. Insulin-stimulated Akt phosphorylation was also reduced by about 40%. Moreover, insulin-dependent phosphorylation of protein kinase C-ζ (PKC-ζ) was completely blunted in clozapine-treated cells. Interestingly, clozapine treatment was accompanied by an insulin-independent increase of Akt phosphorylation, with no change of IR, IRS1, and PKC-ζ basal phosphorylation. The cellular abundance of Ped/Pea-15, an Akt substrate and inducer of insulin resistance, was also increased following clozapine exposure, both in the absence and in the presence of cyclohexymide, a protein synthesis inhibitor. Similar as in cellular models, in the caudate-putamen and in the tibialis muscle of clozapine-treated C57/BL/KsJ mice, Akt phosphorylation and Ped/Pea-15 protein levels were increased and PKC-ζ phosphorylation was decreased. Thus, in these experimental models, clozapine deranged Akt function and up-regulated Ped/Pea-15, thereby inhibiting insulin stimulation of PKC-ζ and of glucose uptake.

Original languageEnglish (US)
Pages (from-to)1485-1492
Number of pages8
JournalJournal of Cellular Physiology
Volume227
Issue number4
DOIs
Publication statusPublished - Apr 1 2012

    Fingerprint

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Panariello, F., Perruolo, G., Cassese, A., Giacco, F., Botta, G., Barbagallo, A. P. M., ... de Bartolomeis, A. (2012). Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance. Journal of Cellular Physiology, 227(4), 1485-1492. https://doi.org/10.1002/jcp.22864