Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Pathology Department, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia.
Basic Clin Pharmacol Toxicol. 2021 Jan;128(1):154-168. doi: 10.1111/bcpt.13484. Epub 2020 Sep 11.
Antipsychotics (APs) are widely used medications with reported diabetogenic side effects. This study investigated the effect of commonly used APs, namely chlorpromazine (CPZ), haloperidol (HAL) and clozapine, on the bioenergetics of male CD1 mice isolated pancreatic beta cells as an underlying mechanism of their diabetogenic effects. The effect of APs on Alamar blue reduction, adenosine triphosphate (ATP) production and glucose-stimulated insulin secretion (GSIS) of isolated beta cells was evaluated. Then, the effects of APs on the activities of mitochondrial complexes and their common coding genes expression, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and lactate production were investigated. The effects of APs on the mitochondrial membrane fluidity (MMF) and mitochondrial membrane fatty acid composition were also examined. Results showed that the tested APs significantly decreased cellular ATP production and GSIS of the beta cells. The APs significantly inhibited the activities of mitochondrial complexes and their coding gene expression, MMP and OCR of the treated cells, with a parallel increase in lactate production to different extents with the different APs. CPZ and HAL showed increased MMF and mitochondrial membrane polyunsaturated fatty acid content. In conclusion, the tested APs-induced mitochondrial disruption can play a role in their diabetogenic side effect.
抗精神病药物（APs）是广泛使用的药物，具有报道的致糖尿病副作用。本研究旨在探讨常用的 APs，即氯丙嗪（CPZ）、氟哌啶醇（HAL）和氯氮平，对 CD1 雄性小鼠分离的胰岛β细胞生物能量的影响，作为其致糖尿病作用的潜在机制。评估了 APs 对分离的β细胞中 Alamar blue 还原、三磷酸腺苷（ATP）产生和葡萄糖刺激胰岛素分泌（GSIS）的影响。然后，研究了 APs 对线粒体复合物活性及其共同编码基因表达、耗氧量（OCR）、线粒体膜电位（MMP）和乳酸产生的影响。还检查了 APs 对线粒体膜流动性（MMF）和线粒体膜脂肪酸组成的影响。结果表明，测试的 APs 显著降低了β细胞的细胞内 ATP 产生和 GSIS。这些 APs 显著抑制了线粒体复合物及其编码基因表达、MMP 和 OCR 的活性，不同的 APs 导致乳酸产生的程度不同。CPZ 和 HAL 显示出增加的 MMF 和线粒体膜多不饱和脂肪酸含量。总之，测试的 APs 诱导的线粒体破坏可能在其致糖尿病副作用中发挥作用。
