Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. While 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 if GLP-1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine if 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 GLP-1 receptor agonists liraglutide or exendin 4 and the blood glucose response 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 (5 ug, IP) compared to olanzapine treatment alone. While in some instances the pharmacological targeting of the GLP1 receptor attenuated indices of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signalling 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.

中文翻译：

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GLP1受体激动剂可预防急性奥氮平诱发的高血糖症

奥氮平是第二代抗精神病药（SGA），用于治疗精神分裂症和许多标签外疾病。急性奥氮平治疗虽然可以有效减少精神病，但会引起高血糖症。胰高血糖素样肽1（GLP1）受体的药理激动剂已显示出可以抵消与慢性SGA给药相关的体重增加。尚不清楚GLP-1受体激动剂是否能减轻SGA的急性代谢副作用。在此背景下，我们试图确定GLP1受体的药理学靶向是否足以预防急性奥氮平诱导的葡萄糖和脂质体内稳态损害。用奥氮平和/或GLP-1受体激动剂利拉鲁肽或exendin 4处理雄性C57BL / 6J小鼠，并测量血糖反应。我们发现liraglutide或exendin 4完全保护雄性小鼠免受olanzapine诱导的高血糖的同时，还增加了循环胰岛素（liraglutide，exendin 4）和胰高血糖素的减少（仅liraglutide）。在其他实验中，与奥氮平治疗相比，用奥氮平和GLP1受体拮抗剂Exendin 9-39（5 ug，IP）治疗时，免受急性奥氮平诱导的高血糖症侵袭的雌性小鼠表现出高血糖，胰高血糖素升高和胰岛素减少的现象。单独。虽然在某些情况下，GLP1受体的药理靶向作用减弱了奥氮平诱导的脂解指数，但肝脏甘油三酸酯积累的增加并未受到影响。