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 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 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-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 α-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.

Keywords:
Clozapine-induced alteration, Glucose homeostasis, Hypothalamic-pituitary-adrenal axis activation, Antipsychotic drugs, Clozapine, 11-β-HSD-1 and PEPCK expression
1.
Melkersson K, Dahl ML, Hulting AL: Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose-insulin homeostasis and lipid metabolism. Psychopharmacology 2004;175:1–6.
2.
Melkersson K, Dahl ML: Adverse metabolic effects associated with atypical antipsychotics. Drugs 2004;64:701–723.
3.
Mir S, Taylor D: Atypical antipsychotics and hyperglycemia. International Clinical Psychopharmacology 2001;16:63–73.
4.
Muench J, Carey M: Diabetes mellitus associated with atypical antipsychotic medications: new case report and review of the literature. J Am Board Fam Pract 2001;14:278–282.
5.
Henderson DC: Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16:77–89.
6.
Melkersson K, Hulting AL, Brismar KE: Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry 1999;60:783–791.
7.
Ryan MCM, Collins P, Thakore JH: Impaired fasting glucose tolerance in first-episode, drug-naïve patients with schizophrenia. Am J Psychiatry 2003;160:284–288.
8.
Holt RIG, Peveler RC, Byrne CD: Schizophrenia, the metabolic syndrome and diabetes. Diabet Med 2004;21:515–523.
9.
Baptista T, Parada MA, Hernandez L: Long-term administration of some antipsychotics drugs increases body weight and feeding in rats: are D2 dopamine receptors involved? Pharmacol Biochem Behav 1987;27:399–405.
10.
Baptista T, Mata A, Teneud L, et al: Effects of long-term administration of clozapine on body weight and food intake in rats. Pharmacol Biochem Behav 1993;45:51–54.
11.
Fadel J, Bubser M, Deutch AY: Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 2002;22:6742–6746.
12.
Kaur G, Kulkarni SK: Studies on modulation of feeding behavior by atypical antipsychotics in female mice. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:277–285.
13.
Lee MD, Clifton PG: Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol. Pharmacol Biochem Behav 2002;71:147–154.
14.
Pouzet B, Mow T, Kreilgaard M, Velschow S: Chronic treatment with antipsychotics in rats as a model for antipsychotic-induced weight gain in human. Pharmacol Biochem Behav 2003;75:133–140.
15.
Arjona AA, Zhang SX, Adamson B, et al: An animal model of antipsychotic-induced weight gain. Behav Brain Res 2004;152:121–127.
16.
Albaugh VL, Henry CR, Bello NT, et al: Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity 2006;14:36–51.
17.
Casey DE, Zorn SH: The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 2001;62(suppl 7):4–10.
18.
Kapur S, Vandespek SC, Brownlee BA, et al: Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J Pharmacol Exp Ther 2003;305:625–631.
19.
Melkersson K: Clozapine and olanzapine, but not conventional antipsychotics, increase insulin release in vitro. Eur Neuropsychopharmacol 2004;14:115–119.
20.
Johnson DE, Yamazaki H, Ward KM, et al: Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perifused rat islets. Diabetes 2005;54:1552–1558.
21.
Dwyer DS, Donohoe D: Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol Biochem Behav 2003;75:255–260.
22.
Levy AD, Van der Kar L: Endocrine and receptor pharmacology of serotoninergic anxiolytics, antipsychotics and antidepressants. Life Sci 1992;51:83–94.
23.
Barbaccia ML, Affricano D, Purdy RH, et al: Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat. Neuropsychopharmacology 2001;25:490–497.
24.
Marx CE, VanDoren MJ, Duncan GE, et al: Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnenolone in rodents. Neuropsychopharmacology 2003;28:1–13.
25.
Seckl JR, Walker BR: Minireview: 11β-hydroxysteroid dehydrogenase type 1 – a tissue-specific amplifier of glucocorticoid action. Endocrinology 2001;142:1371–1375.
26.
Putignano P, Pecori Giraldi F, Cavagnini F: Tissue-specific dysregulation of 11β-hydroxysteroid dehydrogenase type 1 and pathogenesis of the metabolic syndrome. J Endocrinol Invest 2004;27:969–974.
27.
Paterson JM, Morton NM, Fievet C, et al: Metabolic syndrome without obesity: hepatic overexpression of 11β-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci USA 2004;101:7089–7093.
28.
Boot E, de Haan L: Massive increase in serum creatine kinase during olanzapine and quietapine treatment, not during treatment with clozapine. Psychopharmacology 2000;150:347–348.
29.
Meltzer HY: Massive serum creatine kinase increases with atypical antipsychotic drug: what is the mechanism and the message? Psychopharmacology 2000;150:349–350.
30.
Devarajan S, Dursun SM: Antipsychotic drugs, serum creatine kinase and possible mechanisms. Psychopharmacology 2000;152:122.
31.
Furuya DT, Binsack R, Onishi ME, et al: Low ethanol consumption induces enhancement of insulin sensitivity in liver of normal rats. Life Sci 2005;77:1813–1824.
32.
Liu Y, Nakagawa Y, Wang Y, et al: Increased glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice. Diabetes 2005;54:32–39.
33.
Swerdlow NR, Bakshi V, Geyer MA: Seroquel restores sensorimotor gating in phencyclidine-treated rats. J Pharmacol Exp Ther 1996;279:1290–1299.
34.
Ardizzone TD, Bradley RJ, Freeman AM, et al: Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drug risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82–90.
35.
Hajduch E, Rencurel F, Balendran A, et al: Serotonin (5-hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle. J Biol Chem 1999;274:13563–13568.
36.
Yamada J, Sugimoto Y, Yoshikawa T, Horisaka K: Hyperglycemia induced by the 5-HT receptor agonist, 5-methoxytryptamine, in rats: involvement of the peripheral 5-HT2A receptor. Eur J Pharmacol 1997;323:235–240.
37.
Muller EE, Locatelli V, Cocchi D: Neuroendocrine control of growth hormone secretion. Physiol Rev 1999;79:511–607.
38.
O’Connel T, Clemmons DR: IGF-I/IGF-binding protein-3 combination improves insulin resistance by GH-dependent and independent mechanisms. J Clin Endocrinol Metab 2002;87:4356–4360.
39.
Korpi ER, Wong G, Luddens H: Subtype specificity of γ-aminobutyric acid type A receptor antagonism by clozapine. Naunyn Schmiedebergs Arch Pharmacol 1995;352:365–373.
40.
Calogero AE, Gallucci WT, Chrousos GP, et al: Interaction between GABAergic neurotransmission and rat hypothalamic corticotropin-releasing hormone secretion in vitro. Brain Res 1988;463:28–36.
41.
Low SC, Seckl JR: Sexual dimorphism of hepatic 11β-hydroxysteroid dehydrogenase in the rat. J Endocrinol 1994;143:541–548.
42.
Wake DJ, Rask E, Livingstone DE, et al: Local and systemic impact of transcriptional upregulation of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity. J Clin Endocrinol Metab 2003;88:3988–3989.
43.
Lavery GG, Walker EA, Draper N, et al: Hexose-6-phosphate dehydrogenase knockout mice lack 11β-hydroxysteroid dehydrogenase type-1-mediated glucocorticoid generation. J Biol Chem 2006;281:6546–6551.
44.
Jamieson PM, Chapman KE, Seckl JR: Tissue- and temporal-specific regulation of 11β-hydroxysteroid dehydrogenase type 1 by glucocorticoids in vivo. J Steroid Biochem Mol Biol 1999;68:245–250.
45.
Hermanowski-Vosatka, Balkovec JM, Cheng K, et al: 11β-HSD-1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 2005;202:517–527.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.