Acute Peripheral but Not Central Administration of Olanzapine Induces Hyperglycemia Associated with Hepatic and Extra-Hepatic Insulin Resistance
Acute Peripheral but Not Central Administration of Olanzapine Induces Hyperglycemia Associated with Hepatic and Extra-Hepatic Insulin Resistance
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DOI：
10.1371/journal.pone.0043244
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发表时间：
2012-08-14
期刊：
影响因子：
3.7
通讯作者：
Kalsbeek, Andries
中科院分区：
文献类型：
--
作者：
Girault, Elodie M.;Alkemade, Anneke;Kalsbeek, Andries
非典型抗精神病药物，如奥氮平，会导致体重增加和与2型糖尿病发展相关的代谢变化。这些中枢作用药物的代谢副作用的潜在机制在很大程度上仍不清楚。我们用稳定同位素稀释法(实验1)结合高胰岛素-正常血糖钳夹(实验2和实验3)比较了外周(灌胃；3 mg/kg/h)和中枢(脑室内；30 mg/kg/h)给予奥氮平对成年雄性Wistar大鼠肝脏和肝外胰岛素敏感性的影响。测定血糖、血浆皮质酮和胰岛素水平，同时测定内源性葡萄糖生成和葡萄糖消失情况。取肝脏测定肝糖原含量。在基础条件下，外周给药奥氮平可引起明显的高血糖，但不会显着增加肝脏葡萄糖的产生(实验1)。钳夹实验显示肝脏(实验2)和肝外水平(实验3)均存在明显的胰岛素抵抗。实验2和实验3中诱导的胰岛素抵抗得到了奥氮平治疗的大鼠肝糖原储存减少的支持。然而，中央给药奥氮平没有导致血糖、血浆胰岛素或皮质酮浓度或葡萄糖产生的任何显著变化。总之，急性灌胃给予奥氮平会导致雄性大鼠高血糖和胰岛素抵抗。奥氮平的代谢副作用似乎主要是通过外周机制调节的，而不是中枢性来源。
Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying the metabolic side-effects of these centrally acting drugs are still unknown to a large extent. We compared the effects of peripheral (intragastric; 3 mg/kg/h) versus central (intracerebroventricular; 30 mg/kg/h) administration of Olanzapine on glucose metabolism using the stable isotope dilution technique (Experiment 1) in combination with low and high hyperinsulinemic-euglycemic clamps (Experiments 2 and 3), in order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance. Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine induced pronounced hyperglycemia without a significant increase in hepatic glucose production (Experiment 1). The clamp experiments revealed a clear insulin resistance both at hepatic (Experiment 2) and extra-hepatic levels (Experiment 3). The induction of insulin resistance in Experiments 2 and 3 was supported by decreased hepatic glycogen stores in Olanzapine-treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose, plasma insulin or corticosterone concentrations nor in glucose production. In conclusion, acute intragastric administration of Olanzapine leads to hyperglycemia and insulin resistance in male rats. The metabolic side-effects of Olanzapine appear to be mediated primarily via a peripheral mechanism, and not to have a central origin.