Grajales Diana, Vázquez Patricia, Alén Rosa, Hitos Ana B, Valverde Ángela M
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), 28029 Madrid, Spain.
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Metabolites. 2022 May 16;12(5):443. doi: 10.3390/metabo12050443.
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.
第二代抗精神病药物（SGAs），尤其是奥氮平和氯氮平，与精神分裂症患者发生2型糖尿病（T2D）和代谢综合征有关。在这种情况下，β细胞功能障碍是SGAs导致T2D的一种合理机制。在此，我们分析了具有致糖尿病特性的常用SGA奥氮平对INS-1（821/13）β细胞系和分离的胰岛的直接作用。用无毒浓度的奥氮平（3-6 μM）处理INS-1 β细胞4小时，通过增加PERK/eIF2α磷酸化、IRE-1磷酸化和XBP-1剪接激活内质网（ER）应激介导的信号传导。此外，当奥氮平存在16小时时，葡萄糖刺激的胰岛素分泌（GSIS）受到抑制。用牛磺熊去氧胆酸（TUDCA）抑制奥氮平诱导的ER应激可恢复INS-1细胞的胰岛素分泌功能。在雌性小鼠的胰岛中也发现了奥氮平无论有无TUDCA对ER应激介导的信号传导和GSIS的类似作用。我们的结果表明，胰腺β细胞中ER应激的早期激活是奥氮平诱导的葡萄糖稳态改变背后的潜在机制。
