Estrogen Protects Against Olanzapine‐induced Hyperglycemia

Abstract

Olanzapine is a second‐generation antipsychotic (SGA) used frequently in the treatment of schizophrenia and a growing list of off‐label conditions. Though effective in reducing psychoses, acute olanzapine treatment causes rapid increases in blood glucose that are mediated by increases in liver glucose output, skeletal muscle insulin resistance, and beta cell dysfunction. We recently reported that female, compared to male, mice are protected against acute olanzapine‐induced hyperglycemia. To date the mechanism by which female sex confers protection against olanzapine‐induced excursions in blood glucose have not been identified. The purpose of this study was to determine if the protective effects of the female sex against acute olanzapine‐induced hyperglycemia are due, in part, to female sex hormones and if this is mediated by GLP1 signalling. Ovariectomized (OVX) C57BL/6J mice or sham‐operated female controls were treated with olanzapine (5 mg/ kg, IP) or vehicle and blood glucose was measured at baseline, 15, 30, 60, 90, and 120 minutes post‐treatment. These experiments were repeated in female OVX mice following 2‐days of estradiol (E2) treatment (80 ug/kg/day; I.P.) compared to OVX or SHAM mice treated with vehicle. OVX exacerbated the effects of olanzapine on blood glucose, while the add back of E2 rescued olanzapine‐induced impairments in glucose homeostasis in OVX mice. Serum GLP1 concentrations were increased in female compared to male mice and thus, we wanted to determine if GLP1 signaling could be involved in the protective effects of female sex. Female mice were co‐treated with olanzapine and the GLP1 antagonist Exendin 9–39 (25 nmol/kg BW). GLP1 antagonism in female mice exacerbated olanzapine‐induced hyperglycemia. Given the evidence of E2 and GLP1 conferring a protective effect against olanzapine induced hyperglycemia in female mice, we co‐treated male mice with the GLP1 receptor agonist liraglutide (0.4 mg/kg BW) and olanzapine (5 mg/kg, IP). GLP1 agonism protected male mice from olanzapine‐induced hyperglycemia. Taken together, we provide evidence that the protection conferred by female sex on the hyperglycemic effects of olanzapine is due, at least in part, to E2 and GLP1 and that the protective effects of female sex can be recapitulated in male mice treated with liraglutide. Future work will be needed to determine if the protection afforded by female sex hormones on olanzapine‐induced hyperglycemia are dependent on GLP1 and the importance of this proposed mechanism in humans to provide insight into new adjunct treatments to offset the metabolic side effects of SGA treatment.