Antipsychotic use is associated with an increased risk of type 2 diabetes. Recent work suggests antipsychotics can induce insulin resistance immediately and independently of weight gain, and that this may occur via the central nervous system (CNS). We have previously shown that the highly effective and widely prescribed antipsychotic, olanzapine inhibits CNS insulin-mediated suppression of hepatic glucose production, but the mechanisms remain unknown. The ATP-sensitive potassium (K) channel is a key metabolic sensor downstream of hypothalamic insulin signalling, involved in the maintenance of glucose homeostasis. Thus, the possibility arises that olanzapine inhibits central K channel activation to disrupt glucose metabolism. We replicate that intracerebroventricular (ICV) administration of the K channel activator, diazoxide, suppresses hepatic glucose production and additionally demonstrate stimulation of peripheral glucose utilization. We report that olanzapine inhibits the effects of central K channel activation resulting in perturbation of whole body insulin sensitivity, specifically via inhibition of glucose utilization, while leaving central K channel-mediated suppression of glucose production intact. Perturbation of K channel action in the CNS could represent a novel mechanism of antipsychotic-induced diabetes.Copyright © 2020 Elsevier B.V. All rights reserved.