Female mice are protected against acute olanzapine-induced hyperglycemia

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 believed to be mediated by increases in liver glucose output, skeletal muscle insulin resistance, and beta cell dysfunction. Further, the acute lipidemic response to olanzapine has been largely unexplored. While females have been reported to be more susceptible to olanzapine-induced weight gain, there is little known about the impact of sex on the acute response to SGAs. The purpose of this study was to determine if the acute effects of SGAs on glucose and lipid metabolism display a sexually dimorphic response in C57BL/6 J mice and examine potential mechanisms mediating this effect. Age matched male and female C57BL/6 J mice were treated with olanzapine (5 mg/ kg, IP) or vehicle control and blood glucose was measured at baseline, 15, 30, 60, 90, and 120 min post-treatment and tissues and serum harvested. These experiments were repeated, and mice underwent an insulin (0.5 IU/kg) or pyruvate tolerance test (2 g/kg) following 60 min of olanzapine treatment. Females were protected against olanzapine-induced increases in blood glucose and pyruvate intolerance compared to male mice, and this occurred despite the development of severe insulin resistance. In male mice olanzapine increased the glucagon:insulin ratio whereas in females this ratio was reduced. When challenged with exogenous glucagon (1 mg/kg IP), females were less responsive than males. Male and female mice displayed similar increases in whole body fatty acid oxidation, serum fatty acids and liver triglyceride accumulation. Our findings provide evidence that while there are no apparent sex differences in the lipid metabolism response to olanzapine, that females are protected from acute olanzapine-induced excursions in blood glucose. This is likely due in part to reductions in the glucagon:insulin ratio and glucagon responsiveness which could impact olanzapine induced increases in liver glucose production.