CLOZAPINE AND HALOPERIDOL INCREASE THE EXPRESSION OF PED/PEA-15: A PUTATIVE NOVEL MECHANISM FOR ANTIPSYCHOTIC-RELATED DIABETES

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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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.

Tipologia di documento:Tesi di dottorato
Parole chiave:Antipsychotics, Diabetes, Ped/Pea-15
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/25 PSCHIATRIA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Annunziato, Lucio
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
de Bartolomeis, Andrea
Stato del full text:Accessibile
Data:27 Dicembre 2008
Numero di pagine:57
Istituzione:Università degli Studi di Napoli "Federico II"
Dipartimento o Struttura:Neuroscienze
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Scuola di dottorato:Scuola di Medicina Molecolare
Denominazione del dottorato:Neuroscienze
Ciclo di dottorato:XXI
Numero di sistema:3304
Depositato il:13 Novembre 2009 12:48
Ultima modifica:13 Novembre 2009 12:48

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