Effects of the Second Generation Antipsychotics olanzapine and aripiprazole in beta cell functionality and pancreatic islet plasticity

Abstract

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