Chintoh Araba F, Mann Steve W, Lam Loretta, Lam Carol, Cohn Tony A, Fletcher Paul J, Nobrega Jose N, Giacca Adria, Remington Gary
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
J Clin Psychopharmacol. 2008 Oct;28(5):494-9. doi: 10.1097/JCP.0b013e318184b4c5.
The newer atypical antipsychotics, as a class, have been associated with an increased risk of weight gain and metabolic abnormalities. The mechanisms underlying this phenomenon are currently unclear, but there are data to suggest the possibility of an immediate (as opposed to chronic) effect of these drugs. The aim of the present study was to assess the acute effects of olanzapine on specific measures of insulin sensitivity and secretion. Healthy animals were tested in either the hyperinsulinemic-euglycemic or the hyperglycemic clamp. After reaching steady state in the hyperinsulinemic-euglycemic clamp, rats were injected with olanzapine (3 mg/kg sc) and monitored for an additional 130 minutes. In the hyperglycemic clamp, olanzapine was injected approximately 90 minutes before receiving a glucose bolus, and hyperglycemia was maintained via exogenous glucose infusion for an additional 90 minutes. Insulin and C-peptide levels were monitored throughout this clamp.Acute administration of olanzapine significantly lowered the glucose infusion rate due to an increase in hepatic glucose production and a decrease in glucose utilization. Olanzapine pretreatment induced hyperglycemia and markedly decreased plasma insulin and C-peptide in response to the glucose challenge. These findings indicate that olanzapine can directly induce metabolic changes that occur rapidly and well in advance of the changes that might be anticipated as a result of its weight-gain liability. We present novel findings highlighting an olanzapine-induced deficit in beta-cell functioning.
作为一个类别，新型非典型抗精神病药物与体重增加和代谢异常风险的增加有关。目前尚不清楚这一现象背后的机制，但有数据表明这些药物可能会产生即时（而非慢性）效应。本研究的目的是评估奥氮平对胰岛素敏感性和分泌的特定指标的急性影响。健康动物在高胰岛素正常血糖钳夹试验或高血糖钳夹试验中接受测试。在高胰岛素正常血糖钳夹试验达到稳态后，给大鼠注射奥氮平（3mg/kg皮下注射），并额外监测130分钟。在高血糖钳夹试验中，在给予葡萄糖推注前约90分钟注射奥氮平，并通过外源性葡萄糖输注维持高血糖状态90分钟。在整个钳夹试验过程中监测胰岛素和C肽水平。奥氮平的急性给药由于肝葡萄糖生成增加和葡萄糖利用减少而显著降低了葡萄糖输注率。奥氮平预处理在葡萄糖激发试验中诱导了高血糖，并显著降低了血浆胰岛素和C肽水平。这些发现表明，奥氮平可直接诱导代谢变化，这些变化迅速发生，且远早于因其导致体重增加而可能预期的变化。我们提出了新的发现，突出了奥氮平诱导的β细胞功能缺陷。
