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Antipsychotic (AP) medications, such as olanzapine (OLZ), are used in the treatment of schizophrenia and a growing number of 'off-label' conditions. A single dose of OLZ causes robust increases in blood glucose within minutes of treatment. The purpose of the current study was to investigate whether interventions that increase circulating ketone bodies (fasting, β-hydroxybutyrate (βHB), ketone esters or a ketogenic diet (KD)) would be sufficient to protect against the acute metabolic side effects of OLZ. We demonstrate that fasting or the short-term consumption of a KD protects against OLZ-induced hyperglycaemia, independent of alterations in whole-body insulin action, and in parallel with a blunted rise in serum glucagon. Interestingly, the effects of fasting and KDs were not recapitulated by acutely increasing circulating concentrations of ketone bodies through treatment with βHB or oral ketone esters, approaches which increase ketone bodies to physiological or supra-physiological levels, respectively. Collectively, our findings demonstrate that fasting and the short-term consumption of a KD can protect against acute AP-induced perturbations in glucose homeostasis, whereas manipulations which acutely increase circulating ketone bodies do not elicit the same beneficial effects. KEY POINTS: Antipsychotic medications cause rapid and robust increases in blood glucose. Co-treatment approaches to offset these harmful metabolic side effects have not been identified. We demonstrate that fasting or the consumption of a short-term ketogenic diet, but not treatment with β-hydroxybutyrate or oral ketone esters, protects against acute antipsychotic-induced hyperglycaemia. The protective effects of fasting and ketogenic diets were paralleled by reductions in serum glucagon, but not improvements in whole-body insulin action., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Olanzapine (OLZ) is used in the treatment of schizophrenia and a growing number of "off-label" conditions. Although effective in reducing psychoses, OLZ causes rapid impairments in glucose and lipid homeostasis. The purpose of this study was to investigate if voluntary physical activity via wheel running (VWR) would protect against the acute metabolic side effects of OLZ. Male C57BL/6J mice remained sedentary or were provided with running wheels overnight, before treatment with OLZ either at the beginning of the light cycle, or 7 or 24 h following the cessation of VWR. Prior VWR protected against OLZ-induced hyperglycemia immediately and 7 h following a bout of overnight wheel running. Protection against, hyperglycemia immediately following VWR was associated with increased insulin tolerance and an attenuated OLZ-induced increase in the serum glucagon:insulin ratio. The protective effect of VWR against OLZ-induced increases in hyperglycemia and glucagon:insulin ratio was maintained in high-fat fed, and AMPK β1-deficient mice, models which display a potentiated OLZ-induced increase in blood glucose. Repeated OLZ treatment did not impair VWR performance and protection against the acute effects of OLZ on blood glucose was present after 1 wk of daily OLZ treatment in mice given access to running wheels. In contrast to the effects on glucose metabolism, VWR, for the most part, did not impact OLZ-induced perturbations in lipolysis, liver triglyceride accumulation, or whole body substrate oxidation. Collectively, our findings demonstrate the efficacy of voluntary physical activity as an approach to protect against OLZ-induced impairments in glucose metabolism. NEW & NOTEWORTHY The antipsychotic medication olanzapine causes rapid and large increases in blood glucose. We demonstrate that a prior bout of voluntary overnight wheel running can protect against this harmful side effect and is likely mediated by reductions in olanzapine-induced increases in the circulating glucagon to insulin ratio. This study highlights the powerful effects of voluntary activity in conditions of treatment with antipsychotic medications.

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing psychoses, acute olanzapine treatment causes hyperglycemia. Pharmacological agonists of the glucagon-like peptide 1 (GLP1) receptor have been shown to offset weight gain associated with chronic SGA administration. It is not known whether GLP1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine whether pharmacological targeting of the GLP1 receptor would be sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine and/or the GLP1 receptor agonists liraglutide and exendin 4, and the blood glucose response was measured. We found that liraglutide or exendin 4 completely protected male mice against olanzapine-induced hyperglycemia in parallel with increases in circulating insulin (liraglutide, exendin 4) and reductions in glucagon (liraglutide only). In additional experiments, female mice, which are protected from acute olanzapine-induced hyperglycemia, displayed hyperglycemia, increases in glucagon, and reductions in insulin when treated with olanzapine and the GLP1 receptor antagonist exendin 9-39 compared with olanzapine treatment alone. Although in some instances the pharmacological targeting of the GLP1 receptor attenuated indexes of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signaling through the GLP1 receptor can remarkably influence acute olanzapine-induced hyperglycemia, and from the standpoint of protecting against acute excursions in blood glucose, GLP1 receptor agonists should be considered as an adjunct treatment approach. NEW & NOTEWORTHY Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Olanzapine (OLZ) is a second-generation antipsychotic that is used to treat schizophrenia but also causes acute hyperglycemia. This study aimed to determine if the ablation of AMPK β1-containing complexes potentiates acute OLZ-induced metabolic dysfunction and if the activation of AMPK β1 suppresses these effects. Female AMPK β1 -/- or wild-type (WT) control mice were treated with OLZ, and changes in blood glucose, serum and liver metabolites, whole-body fuel oxidation, and pyruvate-induced increases in blood glucose were measured. Additionally, WT mice were cotreated with OLZ and A769662, a specific AMPK β1 activator, and we determined if cotreatment protected against acute, OLZ-induced metabolic dysfunction. OLZ-induced increases in blood glucose were exacerbated in AMPK β1 -/- mice compared with WT mice, and this was paralleled by greater OLZ-induced increases in markers of liver glucose production, such as pyruvate tolerance, serum glucagon, and glucagon responsiveness. Cotreatment with A769662 attenuated OLZ-induced increases in blood glucose, serum nonesterified fatty acid, and glycerol. Furthermore, this effect was absent in AMPK β1 -/- mice, consistent with A769662's specificity for the AMPK β1 subunit. Reductions in AMPK activity potentiate the effects of acute OLZ treatment on blood glucose, whereas specifically targeting AMPK β1-containing complexes is sufficient to protect against OLZ-induced hyperglycemia.-Shamshoum, H., Medak, K. D., Townsend, L. K., Ashworth, K. E., Bush, N. D., Hahn, M. K., Kemp, B. E., Wright, D. C. AMPK β1 activation suppresses antipsychotic-induced hyperglycemia in mice.

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. Pharmacological agonists of the glucagon-like peptide-1 (GLP1) receptor have been shown to offset weight-gain associated with chronic SGA administration and mitigate the acute metabolic side effects of SGAs. The purpose of this study was to determine if increasing endogenous GLP1 is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine, in the absence or presence of an oral glucose tolerance test (OGTT), and a combination of compounds to increase endogenous GLP1. These include the non-nutritive sweetener allulose which acts to induce GLP1 secretion but not other incretins, the DPPiv inhibitor sitagliptin which prevents degradation of active GLP1, and an SSTR5 antagonist which relieves inhibition on GLP1 secretion. We hypothesized that this cocktail of agents would increase circulating GLP1 to supraphysiological concentrations and would protect against olanzapine-induced perturbations in glucose and lipid homeostasis. We found that 'triple treatment' increased both active and total GLP1 and protected against olanzapine-induced perturbations in lipid and glucose metabolism under glucose stimulated conditions and this was paralleled by an attenuation in the olanzapine induced increase in the glucagon:insulin ratio. Our findings provide evidence that pharmacological approaches to increase endogenous GLP1 could be a useful adjunct approach to reduce acute olanzapine-induced perturbations in lipid and glucose metabolism. [ABSTRACT FROM AUTHOR]

Antipsychotic (AP) medications are associated with an increased risk for developing metabolic side effects including weight gain, dyslipidemia, hypertension, type 2 diabetes (T2D), and cardiovascular disease. Previous reviews have focused on the chronic metabolic side effects associated with AP use. However, an underappreciated aspect of APs are the rapid perturbations in glucose and lipid metabolism that occur with each dose of drug. The purpose of this narrative review is to summarize work examining the peripheral mechanisms of acute olanzapine-induced related metabolic disturbances. We also discuss recent studies that have attempted to elucidate treatment approaches to mitigate AP-induced impairments in fuel metabolism. [ABSTRACT FROM AUTHOR]