Abstract
Aims/hypothesisSecond-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.MethodsWe 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.ResultsTreatment 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/interpretationBoth 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
Highlights
In recent years, an increased incidence of type 2 diabetes in patients taking chronic pharmacological treatment has been reported [1]
Aripiprazole-treated mice gained more weight than the controls over the treatment period (p0.05) (Fig. 1c,d)
This study provides novel findings on the effect of the second-generation antipsychotic (SGA) olanzapine and aripiprazole in inducing glucose intolerance and reducing insulin secretion
Summary
An increased incidence of type 2 diabetes in patients taking chronic pharmacological treatment has been reported [1]. In patients receiving second-generation antipsychotic (SGA) drugs [2, 3], the first-line treatment for schizophrenia, the increase in incidence varies between 10% and 20%. SGAs induce metabolic alterations, including weight gain, hyperglycaemia, insulin resistance and dyslipidaemia, which increase the risk for cardiovascular disease [2]. In a large cohort of drug-naive individuals with schizophrenia, the incidence of type 2 diabetes was augmented in those prescribed the SGA olanzapine [4]. Rajkumar et al reported that the SGAs olanzapine and aripiprazole doubled the risk for developing type 2 diabetes, whereas the first in class antipsychotic, clozapine, increased the risk by fourfold [5]. Female individuals are more susceptible to the metabolic side effects of SGAs and, preclinical studies are often performed on female rodents [6]
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