Association of Protein Kinase B (AKT) DNA Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder.
Association of Protein Kinase B (AKT) DNA Hypermethylation with Maintenance Atypical Antipsychotic Treatment in Patients with Bipolar Disorder.
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DOI：
10.1002/phar.2097
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发表时间：
2018-04
期刊：
影响因子：
4.1
通讯作者：
Yi Z
中科院分区：
文献类型：
--
作者：
Burghardt KJ;Seyoum B;Dass SE;Sanders E;Mallisho A;Yi Z
非典型抗精神病药物会导致胰岛素抵抗，从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展中的主要缺陷之一。蛋白激酶B（AKT）在骨骼肌整体健康和葡萄糖摄取到肌肉中起重要作用。本研究的目的是测量接受非典型抗精神病药物或情绪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。临床研究服务中心在一个学术中心。30例确诊为双相情感障碍的患者，接受非典型抗精神病药（16例患者）或情绪稳定剂（14例患者）以一致剂量治疗至少3个月。在每例患者的股外侧肌进行空腹骨骼肌活检。患者还接受了空腹血液样本采集和标准的75克口服葡萄糖耐量试验。通过甲基化敏感的高分辨率熔解，测量了三个基因AKT1，AKT2和AKT3的启动子区域附近的骨骼肌DNA甲基化。基于非典型抗精神病药与情绪稳定剂维持治疗分析基因甲基化。基因甲基化、胰岛素抵抗和葡萄糖耐量之间的关系也进行了分析。在接受非典型抗精神病药物治疗的患者中，与接受情绪稳定剂治疗的患者相比，AKT1和AKT2甲基化水平升高（p=0.03和p= 0.05）。0.02）。此外，对于接受非典型抗精神病药物的患者，观察到AKT2高甲基化与胰岛素抵抗增加的积极趋势，而对于接受情绪稳定剂的患者，观察到AKT2甲基化降低与胰岛素抵抗增加的趋势。总的来说，我们的研究结果表明，AKT基因在服用非典型抗精神病药物或情绪稳定剂维持治疗的患者骨骼肌中甲基化程度不同。这些结果可能指导未来的方法，以减少非典型抗精神病药物治疗的有害副作用。
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. 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.
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