F23. OLANZAPINE-INDUCED PERTURBATIONS OF WHOLE-BODY INSULIN SENSITIVITY MAY OCCUR VIA INACTIVATION OF CENTRAL K-ATP CHANNELS

• Published in: Schizophrenia bulletin Vol. 45; no. Supplement_2; p. S263
• Main Authors: Kowalchuk, Chantel, Castellani, Laura, McIntyre, William Brett, Hahn, Margaret
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 09.04.2019
• Subjects: Poster Session II
• ISSN: 0586-7614; 1745-1701
• DOI: 10.1093/schbul/sbz018.435

Abstract Background Antipsychotics are the cornerstone of treatment for schizophrenia and are widely prescribed on- and off- label for other mental illnesses. However, antipsychotic use is associated with excessive weight gain (over 75% of youth will gain >7% body weight) and increased risk of type 2 diabetes. Recent work suggests that antipsychotics can immediately and independently of weight gain induce insulin resistance, and that this may occur via the central nervous system (CNS). To this point, we recently published data demonstrating that olanzapine, a highly effective and widely prescribed antipsychotic, abolishes the ability of a CNS insulin infusion to restrain glucose production by the liver in rodents. These data demonstrate that olanzapine inhibits CNS insulin action, but the mechanism is unknown. The ATP-sensitive potassium (KATP) channel is a key metabolic sensor downstream of CNS insulin signaling in the hypothalamus, which is involved the maintenance of energy and glucose homeostasis. In the present study, we set out to determine whether olanzapine in rodents inhibits CNS KATP channel activation to disrupt peripheral glucose metabolism. Methods Sprague Dawley rats underwent intracerebroventricular (ICV) cannulae implantation into the 3rd ventricle, and following a 1-week recovery, underwent jugular and carotid cannulation surgeries. Gold-standard pancreatic euglycemic clamps were then used to measure glucose kinetics. During the clamp procedure, endogenous insulin secretion is inhibited by a somatostatin infusion, and insulin is replaced at basal levels. Glucose is infused at a variable rate to maintain euglycemia, and the glucose infusion rate is a measure of whole-body insulin sensitivity. Additionally, a continuous infusion of a radioactive glucose tracer allows the measurement of glucose uptake and production. Prior to the clamp, rats were also pre-treated with an acute subcutaneous injection of olanzapine (OLA) or vehicle (VEH). A primed, continuous ICV infusion of the KATP channel activator Diazoxide (DIAZ) or vehicle (VEH) was administered throughout the clamp procedure. Groups included (central-peripheral): VEH-VEH (n=6), VEH-OLA (n=4), DIAZ-VEH (n=9), DIAZ-OLA (n=11). Results The glucose infusion rate needed to maintain euglycemia during the clamp was significantly higher in DIAZ-VEH rats compared to VEH-VEH or VEH-OLA controls, while DIAZ-OLA rats had a significantly decreased glucose infusion rate compared to DIAZ-VEH, indicative of impaired whole-body insulin sensitivity. We replicated previous findings that ICV DIAZ treatment significantly suppresses glucose production, and interestingly this suppression was undisturbed by OLA co-treatment (DIAZ-OLA). Glucose uptake was significantly increased by ICV DIAZ, and this effect was abolished by OLA co-administration (DIAZ-OLA). Discussion These data suggest that olanzapine can inhibit central KATP channel activation to perturb whole body insulin sensitivity, via inhibition of glucose uptake. Combining this with our previous findings that olanzapine impairs central insulin-mediated glucose production, olanzapine may act through potential divergent CNS pathways to regulate glucose production and uptake. Regardless, inactivation of KATP channels (a key central metabolic sensor) is a novel mechanism by which antipsychotics could induce diabetes and disrupt energy homeostasis. Given that KATP channels are also involved in CNS interactions of neurotransmitter systems (i.e. dopamine, glutamate), our findings may also have future implications beyond metabolic side-effects of these drugs to effects on psychopathology.