LAUSR

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. Increases in glucagon are central to the metabolic side effects of olanzapine. Amylin receptor activation has been shown to reduce circulating glucagon but it is unclear if targeting amylin signaling would be an effective approach to lessen olanzapine-induced hyperglycemia alone or as an adjunct with other glucose lowering medications such as glucagon-like peptide-1 (GLP1) receptor agonist liraglutide. The purpose of this study was to 1) determine if treatment with recombinant amylin or the amylin receptor agonist pramlintide is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis and 2) if there are synergistic effects of combining pramlintide and liraglutide. We hypothesized that amylin and pramlintide would confer protection against olanzapine-induced perturbations in glucose homeostasis and that these effects would be additive with liraglutide. We found that pramlintide co-treatment lowered olanzapine-induced increases in glucagon:insulin. There was an additive effect of pramlintide and liraglutide in protecting against olanzapine-induced hyperglycemia and a synergistic effect on markers of dyslipidemia. Our findings provide evidence that pramlintide, while moderately protective against some aspects of olanzapine-induced metabolic dysfunction, can be used to enhance other interventions which protect against olanzapine-induced hyperglycemia. This research was supported by a Project Grant (PJT 159538) from the Canadian Institutes of Health Research to DCW. KDM was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council (NSERC) of Canada. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.