flumethasone br Conflict of interest br Acknowledgements

Conflict of interest
Acknowledgements
Introduction Second generation antipsychotic drugs (SGAs) such as olanzapine are widely used in treating individuals with schizophrenia and bi-polar disorder and are increasingly prescribed for other conditions such as anxiety (Pringsheim and Gardner, 2014) and attention deficit disorder (Devlin and Panagiotopoulos, 2015). While these drugs lack the severe extrapyramidal side effects of the first generation compounds they have a number of unwanted metabolic complications including weight gain (Shams and Muller, 2014), dyslipidemia (Rojo et al., 2015), and impairments in glucose homeostasis (Coccurello et al., 2009). Disrupted glucose metabolism manifests within hours to days following treatment with SGAs (Albaugh et al., 2011, Chintoh et al., 2008), can occur to a large extent independent of weight gain, and is seen in both rodents (Chintoh et al., 2008) and humans (Albaugh et al., 2011). The acute effects of SGAs on increasing blood glucose are multifactorial and include impairments in insulin secretion (Chintoh et al., 2009, Chintoh et al., 2008, Johnson et al., 2005), reductions in insulin sensitivity (Chintoh et al., 2009), decreases in whole body carbohydrate oxidation (Klingerman et al., 2014) and increases in liver glucose output as measured using euglycemic-hyperinsulinemic clamps (Chintoh et al., 2009, Houseknecht et al., 2007) and pyruvate tolerance testing (Ikegami et al., 2013). The acute effects of SGAs do not show tolerance over time and remain potent even after several months of continuous treatment in rodents (Boyda et al., 2012). A key hormonal signal in the regulation of glucose production is glucagon, a 29 amino flumethasone hormone secreted by pancreatic alpha cells (Charron and Vuguin, 2015). In conditions of reduced glucose availability such as fasting, glucagon increases hepatic glucose production by increasing liver glycogen breakdown, i.e. glycogenolysis, and the de novo synthesis of glucose via gluconeogenesis (Sharabi et al., 2015). In addition, glucagon also induces the expression of key gluconeogenic enzymes such as PEPCK (Phosphoenolpyruvate carboxykinase) and G6Pase (Glucose-6-phosphatase) (Budick-Harmelin et al., 2012, Song and Chiang, 2006). The role of glucagon in mediating the hyperglycemic effects of olanzapine has not been clearly defined. In humans, sub-chronic treatment with olanzapine resulted in increases in serum glucagon concentrations (Teff et al., 2013, Vidarsdottir et al., 2010). Similarly, chronic treatment with olanzapine (6 weeks) increased circulating glucagon levels in rats (Smith et al., 2011). On the other hand, in drug naïve rats a single injection of olanzapine did not increase circulating glucagon (Nagata et al., 2016, Smith et al., 2011) whereas the related antipsychotic drug, clozapine, did (Jassim et al., 2012). The purpose of the present investigation was to more definitively address the role of glucagon signaling in mediating the acute effects of olanzapine on perturbations in glucose homeostasis. To address this question we utilized glucagon receptor knockout mice (Gcgr−/−) and examined olanzapine-mediated alterations in blood glucose, insulin resistance, whole body substrate oxidation and pyruvate-induced increases in blood glucose. We hypothesized that Gcgr−/− mice would be protected against increases in blood glucose following olanzapine treatment and this would be associated with reductions in markers of liver glucose output.
Methods
Results
Discussion Olanzapine is a commonly prescribed second-generation anti-psychotic drug. While effective in reducing psychoses these compounds possess a myriad of detrimental metabolic side effects including causing rapid increases in blood glucose levels. In the current investigation we found that mice with a global knockout of Gcgr (Gcgr−/−) were completely protected against acute olanzapine-induced hyperglycemia.