Burghardt Kyle J, Seyoum Berhane, Dass Sabrina E, Sanders Elani, Mallisho Abdullah, Yi Zhengping
Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.
Division of Endocrinology, Wayne State University School of Medicine, Detroit, Michigan.
Pharmacotherapy. 2018 Apr;38(4):428-435. doi: 10.1002/phar.2097. Epub 2018 Mar 26.
Atypical antipsychotics cause insulin resistance that leads to an increased risk of diabetes mellitus and cardiovascular disease. Skeletal muscle is the primary tissue for uptake of glucose, and its dysfunction is considered one of the primary defects in the development of insulin resistance. Protein kinase B (AKT) plays an important role in overall skeletal muscle health and glucose uptake into the muscle. The objective of this study was to measure AKT isoform-specific gene methylation differences in the skeletal muscle of patients with bipolar disorder treated with atypical antipsychotic or mood stabilizer maintenance therapy.
Cross-sectional observational study.
Clinical research services center at an academic center.
Thirty patients with a confirmed diagnosis of bipolar disorder who were treated with either an atypical antipsychotic (16 patients) or mood stabilizer (14 patients) at a consistent dose for at least 3 months.
A fasting skeletal muscle biopsy was performed in the vastus lateralis in each patient. Patients also underwent fasting blood sample collection and a standard 75-g oral glucose tolerance test.
Skeletal muscle DNA methylation near the promoter region for three genes, AKT1, AKT2, and AKT3, was measured by methylation-sensitive high-resolution melting. Gene methylation was analyzed based on atypical antipsychotic versus mood stabilizer maintenance therapy. Associations between gene methylation, insulin resistance, and glucose tolerance were also analyzed. In patients treated with atypical antipsychotics, AKT1 and AKT2 methylation was increased compared with patients treated with mood stabilizers (p=0.03 and p=0.02, respectively). In addition, for patients receiving atypical antipsychotics, a positive trend for AKT2 hypermethylation with increasing insulin resistance was observed, whereas for patients receiving mood stabilizers, a trend for decreased AKT2 methylation with increasing insulin resistance was observed.
Overall, our findings suggest that the AKT gene is differentially methylated in the skeletal muscle of patients taking atypical antipsychotics or mood stabilizer maintenance therapy. These results may direct future approaches to reduce the harmful adverse effects of atypical antipsychotic treatment.
非典型抗精神病药物会导致胰岛素抵抗，进而增加患糖尿病和心血管疾病的风险。骨骼肌是摄取葡萄糖的主要组织，其功能障碍被认为是胰岛素抵抗发生发展的主要缺陷之一。蛋白激酶B（AKT）在骨骼肌整体健康及肌肉对葡萄糖的摄取过程中发挥着重要作用。本研究的目的是测量接受非典型抗精神病药物或心境稳定剂维持治疗的双相情感障碍患者骨骼肌中AKT亚型特异性基因甲基化差异。
横断面观察性研究。
一所学术中心的临床研究服务中心。
30例确诊为双相情感障碍的患者，其中16例接受非典型抗精神病药物治疗，14例接受心境稳定剂治疗，均持续至少3个月且剂量一致。
对每位患者的股外侧肌进行空腹骨骼肌活检。患者还需进行空腹血样采集及标准的75克口服葡萄糖耐量试验。
采用甲基化敏感高分辨率熔解曲线法测量三个基因（AKT1、AKT2和AKT3）启动子区域附近的骨骼肌DNA甲基化情况。根据非典型抗精神病药物与心境稳定剂维持治疗对基因甲基化进行分析。同时分析基因甲基化、胰岛素抵抗和葡萄糖耐量之间的关联。与接受心境稳定剂治疗的患者相比，接受非典型抗精神病药物治疗的患者中，AKT1和AKT2甲基化增加（分别为p = 0.03和p = 0.02）。此外，对于接受非典型抗精神病药物治疗的患者，观察到AKT2高甲基化与胰岛素抵抗增加呈正相关趋势；而对于接受心境稳定剂治疗的患者，观察到AKT2甲基化随胰岛素抵抗增加呈下降趋势。
总体而言，我们的研究结果表明，在接受非典型抗精神病药物或心境稳定剂维持治疗的患者骨骼肌中，AKT基因存在差异甲基化。这些结果可能为未来减少非典型抗精神病药物治疗有害副作用的方法提供指导。
