Clozapine-induced alteration of glucose homeostasis in the rat: The contribution of hypothalamic-pituitary-adrenal axis activation

Background/Aims: To our knowledge, a suitable animal model to investigate how atypical antipsychotics may induce diabetes in patients has not received much attention. Methods: We investigated the effects of acute as well as sub-chronic administration of clozapine on food intake, body weight gain, glucose tolerance and insulin secretion in response to glucose in Sprague-Dawley rats. We then evaluated the effects of clozapine on corticosterone secretion and 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) and phosphoenolpyruvate carboxykinase ( PEPCK) expression in the liver. We investigated the in vitro effects of clozapine on glucose uptake and development of differentiated myotubes in skeletal muscle cell ( C2C12) cultures. Results: Clozapine administration caused hyperglycemia ( p < 0.05) in female rats. In male rats, the increase of plasma glucose levels after clozapine injection was not statistically significant. The increase of plasma insulin concentrations and the intraperitoneal glucose tolerance test results proved that clozapine reduced insulin sensitivity in female rats. These endocrine and metabolic effects of clozapine were not related to changes in feeding behavior of fat accumulation. We observed a stimulatory effect of clozapine on corticosterone ( p < 0.01) secretion in both female and male rats. Chronic clozapine administration upregulated PEPCK and 11 beta-HSD-1 expression in rat liver. Clozapine did not inhibit basal and insulin-induced glucose transport in murine myotubes but it was able to antagonize the stimulatory effect of alpha-methyl-5- hydroxytryptamine on glucose uptake. Conclusion: Clozapine induces sex-related alterations of glucose homeostasis and insulin sensitivity in rodents. We discussed the possible contribution of clozapine-induced activation of HPA and clozapine antagonistic activity at peripheral 5-HT2A receptors to the observed metabolic alterations. Copyright (C) 2007 S. Karger AG, Basel.