The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice,Diabetologia

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The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice
Diabetologia ( IF 8.4 ) Pub Date : 2021-12-21 , DOI: 10.1007/s00125-021-05630-0
Diana Grajales _{1,

2} , Patricia Vázquez _{1,

2} , Mónica Ruíz-Rosario ₃ , Eva Tudurí _{2,

4} , Mercedes Mirasierra _{1,

2} , Vítor Ferreira _{1,

2} , Ana B Hitos _{1,

2} , Dora Koller ₅ , Pablo Zubiaur ₅ , Juan C Cigudosa ₃ , Francisco Abad-Santos ₅ , Mario Vallejo _{1,

2} , Iván Quesada _{2,

4} , Boaz Tirosh ₆ , Gil Leibowitz ₇ , Ángela M Valverde _{1,

2}

Affiliation

Aims/hypothesis

Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity.

Methods

We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg⁻¹ day⁻¹) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca²⁺ fluxes by imaging techniques.

Results

Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca²⁺ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction.

Conclusions/interpretation

Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.

Graphical abstract

中文翻译：

第二代抗精神病药物阿立哌唑调节胰岛血清素系统并诱导雌性小鼠β细胞功能障碍

目标/假设

第二代抗精神病药物 (SGA) 与精神分裂症患者 2 型糖尿病和代谢综合征的发生有关。在这项研究中，我们旨在研究两种不同的 SGA 药物奥氮平和阿立哌唑对代谢状态、胰岛功能和可塑性的影响。

方法

我们分析了 12 周龄 B6 中 β 细胞的功能适应；129 只雌性小鼠喂食了补充奥氮平或阿立哌唑的饮食（5.5-6.0 mg kg ^-1 天^-1）6 个月。在研究结束时进行葡萄糖和胰岛素耐量试验、体内葡萄糖刺激的胰岛素分泌和间接量热法。通过转录组分析和免疫荧光评估 SGA 对 β 细胞可塑性和胰岛血清素水平的影响。胰岛素分泌通过静态孵育和Ca ²⁺通量通过成像技术进行评估。

结果

与喂食对照食物的小鼠相比，用奥氮平或阿立哌唑治疗雌性小鼠 6 个月可诱导体重增加（分别为p <0.01 和p <0.05）、葡萄糖耐受不良（p <0.01）和胰岛素分泌受损（p <0.05）。与对照组相比，阿立哌唑（而不是奥氮平）诱导 β 细胞产生血清素，可能是通过增加色氨酸羟化酶 1 (TPH1) 的表达，并抑制 Ca ²⁺通量。值得注意的是，与喂食对照食物的小鼠相比，阿立哌唑增加了 β 细胞大小 ( p <0.05) 和质量 ( p <0.01)，同时激活了雷帕霉素复合物 1 (mTORC1)/S6 信号传导的机械靶标，但没有预防 β 细胞功能障碍.