Stapel Britta, Kotsiari Alexandra, Scherr Michaela, Hilfiker-Kleiner Denise, Bleich Stefan, Frieling Helge, Kahl Kai G
Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Department of Cardiology and Angiology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
J Psychiatr Res. 2017 May;88:18-27. doi: 10.1016/j.jpsychires.2016.12.012. Epub 2016 Dec 22.
The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only. Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients.
使用抗精神病药物存在代谢副作用的风险，如体重增加和新发2型糖尿病。所观察到的代谢改变的机制尚未完全明确。我们比较了两种非典型抗精神病药物对葡萄糖代谢的影响，一种已知易导致体重增加（奥氮平），另一种则不然（阿立哌唑）。分离出原代人外周血单核细胞（PBMC），并用奥氮平或阿立哌唑刺激72小时。通过18F-FDG摄取在体外分析细胞葡萄糖摄取。进一步的测量包括葡萄糖转运蛋白（GLUT）1和3的mRNA表达、GLUT1蛋白表达、GLUT1启动子区域的DNA甲基化以及参与下游糖代谢过程的蛋白质。我们观察到用阿立哌唑刺激后葡萄糖摄取增加了2倍。相比之下，奥氮平刺激使葡萄糖摄取降低了40%，同时细胞能量传感器AMP激活蛋白激酶（AMPK）下调。两种抗精神病药物都使GLUT1蛋白表达增加、GLUT1 mRNA表达降低以及GLUT1启动子高甲基化。仅奥氮平使丙酮酸脱氢酶（PDH）复合物活性降低。我们的研究结果表明，非典型抗精神病药物奥氮平和阿立哌唑对PBMC中的能量代谢有不同影响。在奥氮平刺激的PBMC中观察到的葡萄糖摄取减少，同时PDH降低，表明细胞能量代谢恶化，未通过AMKP上调得到补偿。相比之下，阿立哌唑刺激导致葡萄糖摄取增加，同时不影响PDH复合物表达。观察到的差异可能与阿立哌唑和奥氮平治疗患者中观察到的不同代谢特征有关。
