Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells

Metabolites

Patricia Vázquez¹  Rosa Alén¹  Ángela M. Valverde¹  Diana Grajales¹  Ana B. Hitos¹ 

[1] Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), 28029 Madrid, Spain;

关键词: olanzapine;    ER stress;    beta cell;    second-generation antipsychotics;    schizophrenia;    type 2 diabetes;   

DOI  :  10.3390/metabo12050443

来源: DOAJ

【 摘 要 】

Second-generation antipsychotics (SGAs), in particular, olanzapine and clozapine, have been associated with the development of type 2 diabetes mellitus (T2D) and metabolic syndrome in individuals with schizophrenia. In this context, beta cell dysfunction is a plausible mechanism by which SGAs cause T2D. Herein, we analyzed the direct effects of olanzapine, a commonly prescribed SGA with diabetogenic properties, on the INS-1 (821/13) beta cell line and isolated pancreatic islets. Treatment of INS-1 beta cells with non-toxic concentrations of olanzapine (3–6 μM) during 4 h activated endoplasmic reticulum (ER) stress-mediated signaling by increasing PERK/eIF2α phosphorylation, IRE-1 phosphorylation and XBP-1 splicing. Moreover, glucose-stimulated insulin secretion (GSIS) was inhibited when olanzapine was present for 16 h. The insulin secretory function of INS-1 cells was restored by inhibiting olanzapine-induced ER stress with tauroursodeoxycholic acid (TUDCA). Similar effects of olanzapine with or without TUDCA on ER-stress-mediated signaling and GSIS were found in pancreatic islets from female mice. Our results indicate that early activation of ER stress in pancreatic beta cells is a potential mechanism behind the alterations in glucose homeostasis induced by olanzapine.

【 授权许可】

Unknown