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 [Tesi di dottorato] (Unpublished)

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Item Type: Tesi di dottorato
Language: English
Title: CLOZAPINE AND HALOPERIDOL INCREASE THE EXPRESSION OF PED/PEA-15: A PUTATIVE NOVEL MECHANISM FOR ANTIPSYCHOTIC-RELATED DIABETES
Creators:
CreatorsEmail
Panariello, Fabiofabiomdphd@gmail.com
Date: 27 December 2008
Number of Pages: 57
Institution: Università degli Studi di Napoli Federico II
Department: Neuroscienze
Doctoral School: Medicina molecolare
PHD name: Neuroscienze
PHD cycle: 21
PHD Coordinator:
nameemail
Annunziato, LucioUNSPECIFIED
Tutor:
nameemail
De Bartolomeis, AndreaUNSPECIFIED
Date: 27 December 2008
Number of Pages: 57
Uncontrolled Keywords: Antipsychotics, Diabetes, Ped/Pea-15
MIUR S.S.D.: Area 06 - Scienze mediche > MED/25 - Pschiatria
Date Deposited: 13 Nov 2009 11:48
Last Modified: 30 Apr 2014 19:36
URI: http://www.fedoa.unina.it/id/eprint/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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