Department of Food and Nutrition, Diabetes/Obesity Center, College of Natural Science, Hoseo University, Asan, South Korea. smpark @ hoseo.edu
Neuropsychobiology. 2010;61(3):148-61. doi: 10.1159/000285780. Epub 2010 Feb 18.
We investigated whether estrogen replacement modulated energy and glucose metabolic changes induced by olanzapine (OZP) and risperidone (RPD) in 90% pancreatectomized diabetic rats, some of whom had also been ovariectomized (OVX) and some of whom had not (sham).
OVX diabetic rats were subcutaneously injected with estrogen replacement (17beta-estradiol, 30 microg/kg/day) or a vehicle. Each group was divided into 3 subgroups, and each subgroup was orally either given a placebo, RPD (0.5 mg/kg body weight/day) or OZP (2 mg/kg body weight/day) for 8 weeks. Sham rats were also divided into 3 subgroups and given drugs in the same manner as the OVX rats were. All rats were fed high-fat diets.
OZP increased body weight and epididymal fat pads more than the control (vehicle) in sham and OVX rats. Increased body weight in OZP-treated sham and OVX rats was due to the increment in food intake, which was associated with potentiating the phosphorylation of hypothalamic adenosine-monophosphate-activated protein kinase. At euglycemic hyperinsulinemic clamping, OZP decreased glucose infusion rates and increased hepatic glucose output in OVX diabetic rats. In sham rats, OZP increased hepatic glucose output but not as much as in OVX rats. Hepatic insulin signaling and glucose sensing were attenuated in OZP-treated OVX rats, and the attenuation increased hepatic phosphoenolpyruvate carboxykinase expression to induce gluconeogenesis. These negative and harmful effects noted among OZP-treated OVX rats were reversed by estrogen replacement treatment. However, RPD did not alter body weight and peripheral insulin sensitivity in sham and OVX rats.
OZP treatment should be avoided when treating diabetic and schizophrenic women, especially those in their postmenopausal period.
我们研究了雌激素替代疗法是否能调节奥氮平（OZP）和利培酮（RPD）对 90%胰腺切除糖尿病大鼠引起的能量和葡萄糖代谢变化，其中一些大鼠还进行了卵巢切除术（OVX），而另一些则没有（假手术）。
OVX 糖尿病大鼠皮下注射雌激素替代物（17β-雌二醇，30μg/kg/天）或载体。每个组分为 3 个亚组，每个亚组分别口服安慰剂、RPD（0.5mg/kg 体重/天）或 OZP（2mg/kg 体重/天）8 周。假手术大鼠也分为 3 个亚组，并以与 OVX 大鼠相同的方式给予药物。所有大鼠均喂食高脂肪饮食。
OZP 比对照组（载体）更能增加 sham 和 OVX 大鼠的体重和附睾脂肪垫。OZP 处理的 sham 和 OVX 大鼠体重增加是由于食物摄入量增加所致，这与增强下丘脑腺苷一磷酸激活蛋白激酶的磷酸化有关。在血糖正常高胰岛素钳夹试验中，OZP 降低了 OVX 糖尿病大鼠的葡萄糖输注率并增加了肝葡萄糖输出。在 sham 大鼠中，OZP 增加了肝葡萄糖输出，但不如 OVX 大鼠多。OZP 处理的 OVX 大鼠的肝胰岛素信号和葡萄糖感知减弱，这种减弱增加了肝磷酸烯醇丙酮酸羧激酶的表达，从而诱导糖异生。这些在 OZP 处理的 OVX 大鼠中观察到的负面和有害影响，通过雌激素替代治疗得到了逆转。然而，RPD 并未改变 sham 和 OVX 大鼠的体重和外周胰岛素敏感性。
在治疗糖尿病和精神分裂症女性，特别是处于绝经后阶段的女性时，应避免使用 OZP 治疗。
