Olanzapine increases hepatic glucose production through the activation of hypothalamic adenosine 5′‐monophosphate‐activated protein kinase

Abstract

Our results indicate that olanzapine activates AMPK in the hypothalamus, which increases hepatic glucose production via the sympathetic nervous system.

In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact

“…Furthermore, acute central olanzapine administration in rodents was found to induce hyperglycemia only in a postprandial state (where one would expect elevated physiologic levels of insulin or glucose that reach the brain) in association with increases in key gluconeogenic enzymes in the liver. 28 This effect was not observed in fasted rodents receiving a central olanzapine infusion. 28 Our data, taken together with the aforementioned evidence, suggest that a central insulin …”

“…28 This effect was not observed in fasted rodents receiving a central olanzapine infusion. 28 Our data, taken together with the aforementioned evidence, suggest that a central insulin …”

“…12,[27][28][29] Notably, most studies examining acute glucose dysregulation by these agents have used hyperinsulinemiceuglycemic clamps. 10,11,14,30 This clamp design uses an elevated level (hyperinsulinemic) of continuous intravenous insulin, which crosses into the brain, exerting both peripheral and central effects.…”

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine

“…36) Thus, the serum concentrations of olanzapine in the present study were higher than those at clinical doses of olanzapine. Though acute hyperglycemias were reported in patients treated with 2.5-10 mg/d of olanzapine, 6,7) it is still unknown about the concentrations of olanzapine at the onset of acute hyperglycemia in clinical setting. Therefore, the concentration-effect relationship of olanzapine-induced acute hyperglycemia in humans remains to be solved.…”

“…Mizukami et al described a 22-year-old woman without diabetes who developed hyperglycemia (her glucose concentration exceeded the detection limits) 4 h after the first administration of olanzapine. 7) Regarding the mechanism responsible for the induction of acute hyperglycemia by olanzapine, Ikegami et al recently showed that olanzapine activates adenosine 5′-monophosphate-activated protein kinase (AMPK) in the hypothalamus, which increases the hepatic production of glucose via the sympathetic nervous system. 8) They also suggested that olanzapine activates hypothalamic AMPK by antagonizing histamine H 1 , dopamine D 2 , and α 1 -adrenergic receptors.…”