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Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells

Molecular Psychiatry volume 10, pages 1089–1096 (2005)Cite this article

Abstract

Second-generation antipsychotic agents (SGAs) are increasingly replacing first-generation antipsychotic agents due to their superior activity against the negative symptoms of schizophrenia, decreased extrapyramidal symptoms and better tolerability. However, some SGAs are associated with adverse metabolic effects as significant weight gain, lipid disorders and diabetes mellitus. The pathogenesis of SGA-induced disturbances of glucose homeostasis is unclear. In vivo studies suggest a direct influence of SGAs on peripheral insulin resistance. To this end, we analyzed whether olanzapine might alter glycogen synthesis and the insulin-signaling cascade in L6 myotubes. Glycogen content was diminished in a dose- and time-dependent manner. Within the insulin-signaling cascade IRS-1 tyrosine phosphorylation was induced several fold by insulin and was diminished by preincubation with olanzapine. IRS-1-associated PI3K activity was stimulated by insulin three-fold in L6 myotubes. Olanzapine inhibited insulin-stimulated IRS-1-associated PI3K activity in a dose-dependent manner. Protein mass of AKT, GSK-3 and GS was unaltered, whereas phosphorylation of AKT and GSK-3 was diminished, and pGS was increased. Finally, we compared olanzapine with amisulpride, an SGA clinically not associated with the induction of diabetes mellitus. Glycogen content was diminished in olanzapine-preincubated L6 cells, whereas this effect was not observed under the amisulpride conditions. We conclude that olanzapine impairs glycogen synthesis via inhibition of the classical insulin-signaling cascade and that this inhibitory effect may lead to the induction of insulin resistance in olanzapine-treated patients.

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Acknowledgements

This study was supported by the OeNB (Grant 11172) and the MFF Tirol (Grant 90). We thank K Salzmann for expert technical assistance.

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Authors and Affiliations

  1. Clinical Department of Internal Medicine, Clinical Division of General Internal Medicine, Innsbruck, Austria

    J Engl, M Laimer, A Niederwanger, M Kranebitter, M Starzinger, M T Pedrini, J R Patsch & C F Ebenbichler

  2. Department of Biological Psychiatry, Medical University Innsbruck, Innsbruck, Austria

    W W Fleischhacker

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  1. J Engl
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  2. M Laimer
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Correspondence to C F Ebenbichler.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Engl, J., Laimer, M., Niederwanger, A. et al. Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 10, 1089–1096 (2005). https://doi.org/10.1038/sj.mp.4001729

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