Korean J Biol Psychiatry.  2012 Nov;19(4):187-192.

The Effect of Clozapine on Central Insulin Response in Rats

• Kim SH
• Yu HS
• Park SY
• Kim MK
• Park HG
• Kim YS

Abstract

OBJECTIVES
Although antipsychotic drug clozapine has superior efficacy, this is hampered by metabolic side effects such as weight gain and diabetes. Recent studies demonstrate that clozapine induces insulin resistance. However, the identity and location of insulin resistance induced by clozapine has not been clarified. In this study, the effect of clozapine on central insulin response was investigated in rats.
METHODS
Male Sprague-Dawley rats received intraperitoneal injection of clozapine or vehicle, which was followed by intracerebroventricular injection of insulin or its vehicle. The effects of clozapine on insulin-induced changes in blood glucose level and Akt phosphorylation in hypothalamus were investigated.
RESULTS
Intraperitoneal injection of clozapine (20 mg/kg) increased blood glucose in rats. Intracerebroventricular injection of insulin reduced blood glucose in rats, which was blunted by pretreatment of clozapine. Accompanied with the antagonistic effect of clozapine to central insulin action in terms of blood glucose, clozapine inhibited the insulin-induced phosphorylation of Akt at Ser473 in rat hypothalamus.
CONCLUSION
Administration of clozapine inhibited the central insulin-induced changes in blood glucose and Akt phosphorylation in rat hypothalamus. These findings suggest that hypothalamus could be the site of action for the clozapine-induced insulin resistance.

Keyword

Atypical antipsychotics; Insulin resistance; Blood glucose; Hypothalamus; Akt

MeSH Terms

Animals
Blood Glucose
Clozapine
Humans
Hypothalamus
Injections, Intraperitoneal
Insulin
Insulin Resistance
Male
Phosphorylation
Rats
Rats, Sprague-Dawley
Weight Gain
Blood Glucose
Clozapine
Insulin