Murashita Mari, Kusumi Ichiro, Hosoda Hiroshi, Kangawa Kenji, Koyama Tsukasa
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.
Psychoneuroendocrinology. 2007 Aug;32(7):777-84. doi: 10.1016/j.psyneuen.2007.05.007. Epub 2007 Jul 12.
Among antipsychotics, clozapine ranks highest in terms of the risk for weight gain and developing diabetes. However, the mechanism by which clozapine induces weight gain and diabetes remains unclear. The aim of this study was to determine the mechanism of clozapine-induced weight gain and hyperglycemia, and to clarify whether clozapine-induced hyperglycemia results from impairment of the system regulating appetite.
Circulatory glucose, insulin, leptin and ghrelin levels were analyzed after acute administration of clozapine in rats. Clozapine (10 mg/kg) or a vehicle was injected intraperitoneally and blood samples were collected at 0, 15, 30, and 60 min after the injection. Clozapine (5, 10 or 20 mg/kg) or the vehicle was given, and blood samples were collected at 30 min after the injection. Since clozapine has receptor affinity for multiple neurotransmitters, selective antagonists of it, including dopamine, serotonin, alpha-adrenergic, muscarine and histamine were administered to clarify the pathway of clozapine-induced blood glucose and changes in plasma ghrelin.
Clozapine administration increased the blood glucose level at all time points (p<0.05) compared to controls. Plasma ghrelin was elevated at 30 min (p=0.0124) and 60 min (p=0.00152). Blood glucose was increased in rats given 5 (p=0.0344), 10 (p<0.0001), or 20 mg/kg (p<0.0001) clozapine, while plasma ghrelin was increased in rats treated with 10 mg/kg (p=0.0009) or 20 mg/kg (p=0.0059) clozapine. Blood glucose was increased in rats treated with a selective alpha1-adrenergic receptor antagonist (p<0.0001), while plasma ghrelin was significantly increased in rats given a selective alpha1- (p=0.025) or alpha2-adrenergic receptor antagonist (p=0.0003).
Clozapine impairs glucose metabolism and the appetite-regulation system. Clozapine increases blood glucose independent of insulin. The antagonistic action of alpha-adrenergic receptors is one of the mechanisms that induces both hyperglycemia and elevation of ghrelin.
在抗精神病药物中，氯氮平在体重增加和患糖尿病风险方面排名最高。然而，氯氮平导致体重增加和糖尿病的机制仍不清楚。本研究的目的是确定氯氮平诱导体重增加和高血糖的机制，并阐明氯氮平诱导的高血糖是否源于食欲调节系统受损。
在大鼠急性给予氯氮平后，分析循环中的葡萄糖、胰岛素、瘦素和胃饥饿素水平。腹腔注射氯氮平（10mg/kg）或赋形剂，并在注射后0、15、30和60分钟采集血样。给予氯氮平（5、10或20mg/kg）或赋形剂，并在注射后30分钟采集血样。由于氯氮平对多种神经递质具有受体亲和力，因此给予其选择性拮抗剂，包括多巴胺、5-羟色胺、α-肾上腺素能、毒蕈碱和组胺拮抗剂，以阐明氯氮平诱导血糖升高和血浆胃饥饿素变化的途径。
与对照组相比，给予氯氮平后所有时间点的血糖水平均升高（p<0.05）。血浆胃饥饿素在30分钟（p=0.0124）和60分钟（p=0.00152）时升高。给予5mg/kg（p=0.0344）、10mg/kg（p<0.0001）或20mg/kg（p<0.0001）氯氮平的大鼠血糖升高，而给予10mg/kg（p=0.0009）或20mg/kg（p=0.0059）氯氮平的大鼠血浆胃饥饿素升高。给予选择性α1-肾上腺素能受体拮抗剂的大鼠血糖升高（p<0.0001），而给予选择性α1-（p=0.025）或α2-肾上腺素能受体拮抗剂的大鼠血浆胃饥饿素显著升高（p=0.0003）。
氯氮平损害葡萄糖代谢和食欲调节系统。氯氮平增加血糖，与胰岛素无关。α-肾上腺素能受体的拮抗作用是诱导高血糖和胃饥饿素升高的机制之一。
