Objective: 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.
Methods: 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.
Results: 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).
Conclusions: 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.