Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance.
Bottom Line: 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%.
Affiliation: Dipartimento di Neuroscienze, Sezione di Psichiatria, Laboratorio di Psichiatria Molecolare, University of Napoli Federico II, Napoli, Italy.Show MeSH
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Mentions: In order to investigate at what level insulin action was impaired, L6 cells have been incubated with 1.5 µM clozapine for 24 h and with 100 nM insulin for additional 30 min. Concentration and time were chosen according to the maximal effect obtained in previous experiments. No significant change of the cellular content of the insulin receptor (IR) and of the IRS1 was detected by Western blot with specific antibodies. However, clozapine-treated cells displayed a reduction of insulin-stimulated IR (Fig. 2A,B) and IRS1 (Fig. 2A,C) tyrosine phosphorylation of about 40% and 60%, respectively. Comparable results were obtained by stimulating PC12 cells with insulin (Fig. 3).
Affiliation: Dipartimento di Neuroscienze, Sezione di Psichiatria, Laboratorio di Psichiatria Molecolare, University of Napoli Federico II, Napoli, Italy.