Clozapine-induced alteration of glucose homeostasis in the rat

The contribution of hypothalamic-pituitary-adrenal axis activation

Giovanni Tulipano, Cristina Rizzetti, Irene Bianchi, Alessandro Fanzani, PierFranco Spano, Daniela Cocchi

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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-HT 2A receptors to the observed metabolic alterations.

Original languageEnglish
Pages (from-to)61-70
Number of pages10
JournalNeuroendocrinology
Volume85
Issue number2
DOIs
Publication statusPublished - May 2007

Fingerprint

Clozapine
Homeostasis
Glucose
11-beta-Hydroxysteroid Dehydrogenases
Phosphoenolpyruvate
Skeletal Muscle Fibers
Insulin
Corticosterone
Insulin Resistance
Receptor, Serotonin, 5-HT2A
Liver
Feeding Behavior
Glucose Tolerance Test
Hyperglycemia
Muscle Cells
Antipsychotic Agents
Weight Gain
Sprague Dawley Rats
Rodentia
Serotonin

Keywords

  • 11-β-HSD-1 and PEPCK expression
  • Antipsychotic drugs
  • Clozapine
  • Clozapine-induced alteration
  • Glucose homeostasis
  • Hypothalamic-pituitary- adrenal axis activation

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)

Cite this

Clozapine-induced alteration of glucose homeostasis in the rat : The contribution of hypothalamic-pituitary-adrenal axis activation. / Tulipano, Giovanni; Rizzetti, Cristina; Bianchi, Irene; Fanzani, Alessandro; Spano, PierFranco; Cocchi, Daniela.

In: Neuroendocrinology, Vol. 85, No. 2, 05.2007, p. 61-70.

Research output: Contribution to journalArticle

Tulipano, Giovanni ; Rizzetti, Cristina ; Bianchi, Irene ; Fanzani, Alessandro ; Spano, PierFranco ; Cocchi, Daniela. / Clozapine-induced alteration of glucose homeostasis in the rat : The contribution of hypothalamic-pituitary-adrenal axis activation. In: Neuroendocrinology. 2007 ; Vol. 85, No. 2. pp. 61-70.
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