AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis
The purpose of this thesis was to examine whether the 5’AMP-activated protein kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) could prevent acute olanzapine (OLZ)-induced metabolic disturbances in mice. Experiments were performed using male C57BL6/J mice separated into four treatment groups: A) Vehicle; B) Vehicle + OLZ (5mg/kg; IP); C) Vehicle + AICAR (250mg/kg; IP); or D) AICAR + OLZ. OLZ rapidly increased blood glucose, reduced the insulin response and increased pyruvate intolerance, all of which were prevented with AICAR. These results were reproduced in high-fat diet-induced obese mice. While OLZ significantly reduced the respiratory exchange ratio (RER), VO2, activity and heat production, AICAR had no effect on these parameters. Peripheral injection of AICAR, but not OLZ, activated AMPK signalling in the hypothalamus. Despite increasing hypothalamic AMPK signalling, this study provides evidence that AICAR prevents OLZ-induced hyperglycemia perhaps by preventing the development of insulin resistance and by reducing liver glucose production.