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

Abstract

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

Role of Serotonin (5-HT) in GDM Prediction Considering Islet and Liver Interplay in Prediabetic Mice during Gestation

“…Transferring preconceptionally isolated islets into a gestation-like state by incubation with high concentrations of 5-HT resulted in significant inhibition of insulin and glucagon secretion in NZO mice during stimulation with glucose. These observations are consistent with previous findings of other authors in MIN6 cells, rodents, and humans, although it should be noted that the influence of 5-HT on insulin secretion is still a matter of controversy [ 19 , 23 , 44 , 45 , 46 , 47 ]. An inhibitory effect on insulin secretion was also previously observed for the selective 5-HT re-uptake inhibitors (SSRIs) fluoxetine and sertraline in MIN6 cells as well as in mouse and human islets [ 48 , 49 ].…”

“…Recently, it has been shown that treatment of female mice with the second-generation antipsychotic (SGA) drug aripiprazole elevated Tph1 and Tph2 expression and that 5-HT content in islets increased to a level comparable to pregnant mice. Moreover, treatment with aripiprazole led to a doubling of β-cell mass and further ex vivo experiments with the SGA resulted in impaired insulin secretion [ 45 ]. These findings are in close agreement with those obtained here in prediabetic NZO mice and suggest that blockade of peripheral 5-HT synthesis might lead to an improvement of impaired GSIS and thus to a reduced risk of the development of GDM.…”

The FTO rs9939609 Variant Is Associated with Cardiometabolic Disease Risk and Dietary Energy Intakes in Children with Mental Health Disorders

“…We have reported that children treated with quetiapine have reduced insulin secretion (insulinogenic index) during an oral-glucose-tolerance test ( 37 ). Further, a recent study in a mouse model reported β-cell dysfunction, glucose intolerance, and impaired insulin secretion in female mice treated with aripiprazole ( 38 ).…”

Attenuation of Olanzapine-Induced Endoplasmic Reticulum Stress Improves Insulin Secretion in Pancreatic Beta Cells

“…We have recently reported that treatment of female mice with the SGA aripiprazole supplemented in the diet increased tryptophan hydroxylase 1 (TPH1) expression and serotonin production in pancreatic beta cells, causing beta cell dysfunction by interfering with the regulation of the serotoninergic system and also by inhibiting Ca 2+ entry [ 22 ]. However, using a similar administration route, olanzapine did not alter the expression of relevant genes related to insulin synthesis or islet function.…”

“…Interestingly, in our recent study we found that inhibition of insulin secretion in female mice receiving a chronic treatment with olanzapine seemed to be, at least in part, due to defective insulin granule maturation [ 22 ]. Amorphic insulin granules with reduced immunogold staining for mature insulin can reflect deficiencies in proinsulin processing at the ER, in which subsequent accumulation of misfolded proinsulin can exceed its functional capacity, thereby reducing insulin secretion [ 24 ].…”