Panariello, Fabio (2008) CLOZAPINE AND HALOPERIDOL INCREASE THE EXPRESSION OF PED/PEA-15: A PUTATIVE NOVEL MECHANISM FOR ANTIPSYCHOTIC-RELATED DIABETES. [Tesi di dottorato] (Inedito)

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: CLOZAPINE AND HALOPERIDOL INCREASE THE EXPRESSION OF PED/PEA-15: A PUTATIVE NOVEL MECHANISM FOR ANTIPSYCHOTIC-RELATED DIABETES
Autori:
AutoreEmail
Panariello, Fabiofabiomdphd@gmail.com
Data: 27 Dicembre 2008
Numero di pagine: 57
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Neuroscienze
Scuola di dottorato: Medicina molecolare
Dottorato: Neuroscienze
Ciclo di dottorato: 21
Coordinatore del Corso di dottorato:
nomeemail
Annunziato, Lucio[non definito]
Tutor:
nomeemail
De Bartolomeis, Andrea[non definito]
Data: 27 Dicembre 2008
Numero di pagine: 57
Parole chiave: Antipsychotics, Diabetes, Ped/Pea-15
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/25 - Pschiatria
Depositato il: 13 Nov 2009 11:48
Ultima modifica: 30 Apr 2014 19:36
URI: http://www.fedoa.unina.it/id/eprint/3304
DOI: 10.6092/UNINA/FEDOA/3304

Abstract

Schizophrenia is a serious disorder that affects 1% of the population in the United States and Europe, and is associated with a significant reduction in life expectancy that approaches 20% compared with that of the general population. Current management of patients with schizophrenia involves the increasing use of atypical antipsychotic agents, such as risperidone, quetiapine, olanzapine, and clozapine. The use of these agents has been associated with increased morbidity from obesity,hyperlipidemia, development of new-onset diabetes, and, in rare instances, development of diabetic ketoacidosis. The precise mechanism for the abnormalities in carbohydrate and lipid metabolism is incompletely understood. We investigated whether haloperidol and clozapine, respectively a typical and an atypical antipsychotics, directly affect insulin action in cultured cell models and in vivo. In our experimental paradigms, both haloperidol and clozapine reduced insulin-stimulated glucose uptake in a time- and concentration dependent manner, although with a different efficacy. Indeed, pre-treatment with clozapine, but not with haloperidol, prevented insulin effect on insulin receptor (IR) and IR substrate-1/2 (IRS-1/2) tyrosine phosphorylation. Moreover, both drugs reduced insulin-dependent phosphorylation of protein kinase C-ζ (PKC- ζ), and induced an insulin- independent increase of phosphorylated Akt. These effects were paralleled by increased expression of Ped/Pea-15, an Akt substrate and inducer of insulin resistance. Similar changes of these signalling proteins were detected in caudate-putamen and in skeletal muscle of mice treated with either haloperidol or clozapine. Thus, antipsychotics may impair insulin action, at least in part, by upregulating Ped/Pea-15 and inhibiting activation of PKC- ζ.

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