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.