Clozapine-induced alteration of glucose homeostasis in the rat: the contribution of hypothalamic-pituitary-adrenal axis activation.
OBJECTIVE
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 subchronic 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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-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.


CONCLUSIONS
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-HT(2A) receptors to the observed metabolic alterations.
Tulipano
Giovanni
G
Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
Rizzetti
Cristina
C
Bianchi
Irene
I
Fanzani
Alessandro
A
Spano
PierFranco
P
Cocchi
Daniela
D
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003024:Clozapine / Q000008:administration & dosage / Q000633:toxicity*; D003345:Corticosterone / Q000097:blood; D004435:Eating / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006220:Haloperidol / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D014150:Antipsychotic Agents; D001786:Blood Glucose; D005947:Glucose; D003024:Clozapine; D006220:Haloperidol; D003345:Corticosterone