Olanzapine-induced hyperglycemia: possible involvement of histaminergic, dopaminergic and adrenergic functions in the central nervous system.

BACKGROUND/AIMS: Atypical antipsychotic drugs such as olanzapine are known to induce metabolic disturbance. We have already shown that olanzapine induces hepatic glucose production through the activation of hypothalamic adenosine 5'-monophosphate-activated protein kinase (AMPK). However, it is unclear how olanzapine activates hypothalamic AMPK. Since olanzapine is known to antagonize several receptors, including histaminergic, muscarinic, serotonergic, dopaminergic and adrenergic receptors, we examined the effect of each receptor antagonist on blood glucose levels in mice. Moreover, we also investigated whether these antagonists activate hypothalamic AMPK. METHODS: Male 6-week-old ICR mice were used. Blood glucose levels were determined by the glucose oxidase method. AMPK expression was measured by Western blotting. RESULTS: Central administration of olanzapine (5-15 nmol i.c.v.) dose-dependently increased blood glucose levels in mice, whereas olanzapine did not change blood insulin levels. Histamine H1 receptor antagonist chlorpheniramine (1-10 µg i.c.v.), dopamine D2 receptor antagonist L-sulpiride (1-10 µg i.c.v.) and α1-adrenoceptor antagonist prazosin (0.3-3 µg i.c.v.) also significantly increased blood glucose levels in mice. In contrast, the blood glucose levels were not affected by muscarinic M1 receptor antagonist dicyclomine (1-10 µg i.c.v.) or serotonin 5-HT2A receptor antagonist M100907 (1-10 ng i.c.v.). Olanzapine-induced hyperglycemia was inhibited by the AMPK inhibitor compound C, and AMPK activator AICAR (10 ng to 1 µg i.c.v.) significantly increased blood glucose levels. Olanzapine (15 nmol), chlorpheniramine (10 µg), L-sulpiride (10 µg) and prazosin (3 µg) significantly increased phosphorylated AMPK in the hypothalamus of mice. CONCLUSION: These results suggest that olanzapine activates hypothalamic AMPK by antagonizing histamine H1 receptors, dopamine D2 receptors and α1-adrenoceptors, which induces hyperglycemia.

Olanzapine induces glucose intolerance through the activation of AMPK in the mouse hypothalamus.

Treatment with atypical antipsychotic drugs is known to increase the risk of glucose intolerance and diabetes. However, the mechanism of this effect is unclear. Since central adenosine 5'-monophosphate-activated protein kinase (AMPK) plays an important role in regulating nutrient homeostasis, the present study was performed to examine the involvement of central AMPK in the glucose intolerance induced by olanzapine, an atypical antipsychotic drug, in mice. Acute intraperitoneal treatment with olanzapine dose-dependently increased blood glucose levels in the glucose tolerance test. Intracerebroventricular administration of olanzapine also increased blood glucose levels in the glucose tolerance test. The glucose intolerance induced by both intraperitoneal and intracerebroventricular treatment with olanzapine was significantly attenuated by intracerebroventricular pretreatment with the AMPK inhibitor compound C. Intracerebroventricular treatment with the AMPK activator AICAR increased blood glucose levels in the glucose tolerance test, and this increase was inhibited by compound C. Moreover, the hypothalamic level of phosphorylated AMPK after glucose injection was significantly increased by intracerebroventricular pretreatment with olanzapine. Olanzapine did not affect plasma glucagon and insulin levels. Our results indicate that acute treatment with olanzapine causes glucose intolerance through the activation of hypothalamic AMPK. The present study suggests that the inhibition of central AMPK activity may have a therapeutic effect on the metabolic disturbance induced by atypical antipsychotic drugs.