BUSCADOR RECOLECTA

Digital.CSIC. Repositorio Institucional del CSIC

oai:digital.csic.es:10261/245528

Folder 1. Analysis of in vivo chronic dietary treatment with both olanzapine and aripiprazole (5.5-6 mg/kg/d) for 6 months in WT females to assess disturbances in glucose metabolism as well as beta-cell dysfunction. Metabolic tests have been done before sacrifice: glucose tolerance test (GTT), insulin tolerance test (ITT), and glucose-stimulated insulin secretion (GSIS). The xls file shows the statistics analysis and raw data analysis of the parameters measured. The immunofluorescence and immunohistochemistry analysis are also included in xls file. The pzfx files can be opened with GraphPad Prism 8 XML Project show the relationships between some of the parameters showed in xls files. Folder 2. In vitro data in INS-1 cells. The xls files showed the quantification of the short-term impact of olanzapine (1-6 µM) and the long-term impact of both olanzapine and aripiprazole (1-6 µM) in glucose-stimulated insulin secretion (GSIS) and the western blot quantification of the molecular machinery associated with ER stress activation (mainly PERK/eIF2a and IRE1-alpha) in INS-1 cells after olanzapine/aripiprazole treatment with different concentrations (1-6 µM) for 4h. The pzfx files can be opened with GraphPad Prism 8 XML Project and show the relationships between some of the parameters showed in xls files., The incidence of Type 2 Diabetes Mellitus (T2DM) is reaching epidemic proportions. Recent investigations have demonstrated that long-term treatment with Second Generation Antipsychotics (SGAs), the main-line treatment for schizophrenia, can induce T2DM. Beta cell dysfunction is proposed as a plausible mechanism by which SGAs cause T2DM, but the process remains largely unknown. In this Thesis, we have investigated whether two unrelated SGAs, olanzapine, a common prescribed SGA with diabetogenic properties, and aripiprazole, a more recently developed SGA with less explored metabolic-side effects, can impact on beta cells. We analyzed beta cell functionality and pancreatic islet plasticity in two in vivo studies: female mice treated with olanzapine for 6 weeks via intraperitoneal and female mice fed an olanzapine- or aripiprazole-supplemented diet for 6 months. Additionally, we conducted gene expression analysis in islets of mice receiving the medicated diet and in vitro studies to evaluate beta cell functionality and the molecular mechanisms associated to the treatments. Our results evidenced that long-term treatment with olanzapine or aripiprazole induced weight gain, glucose intolerance and beta cell dysfunction, but the mechanisms behind these alterations are specific for each SGA. Whereas olanzapine effects in the pancreas in female mice seem to be dependent on an obesogenic-like phenotype, it activated endoplasmic reticulum (ER) stress in both INS-1 cells and pancreatic islets. Alleviation of olanzapine-induced ER stress with Tauroursodeoxycholic acid (TUDCA) recovered insulin secretion, suggesting that inhibition of insulin secretion by olanzapine is dependent on ER stress activation. On the other hand, aripiprazole treatment during 6 months induced serotonin production through tryptophan hydroxylase 1 (TPH1) activation in pancreatic islets. Moreover, beta cell hypertrophy and higher beta cell mass were found in aripiprazole-treated mice concomitantly to the activation of mTORC1/S6. Additionally, ex vivo experiments using pancreatic islets revealed that aripiprazole inhibition of insulin secretion was due to a reduction in calcium entry into the beta cell. Until now, regulation of the serotonergic system in islets has been associated to beta cell compensation in pregnancy and postnatal growth. Thus, in this Thesis, we have described for the first time the modulation of the serotonergic system in pancreatic islets by pharmacological treatment with aripiprazole, showing that serotonin production induced by this SGA plays a critical role in intra-islet functionality and beta cell mass and it might also explain other metabolic disturbances associated with aripiprazole treatment, European Comission ITN Treatment H2020-MSCA-ITN-721236, Peer reviewed