The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice
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...
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| Veröffentlicht in: | Diabetologia 2022-03, Vol.65 (3), p.490-505 |
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| creator | Grajales, Diana Vázquez, Patricia Ruíz-Rosario, Mónica Tudurí, Eva Mirasierra, Mercedes Ferreira, Vítor Hitos, Ana B. Koller, Dora Zubiaur, Pablo Cigudosa, Juan C. Abad-Santos, Francisco Vallejo, Mario Quesada, Iván Tirosh, Boaz Leibowitz, Gil Valverde, Ángela M. |
| description | 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 Ca
2+
fluxes by imaging techniques.
Results
Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (
p |
| doi_str_mv | 10.1007/s00125-021-05630-0 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8803721</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2612379454</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-2e535f888142305ac173d6f8644f33cd7552f0658b8571ce42e18bbabcff975c3</originalsourceid><addsrcrecordid>eNp9kUuLFDEUhYMoTtv6B1xIwI2b0jyr0htBBl8w4GYEdyGVuunOUJWUSUpo_4v_1VT3OD4WrrI43zk39x6EnlLykhLSvcqEUCYbwmhDZMtJQ-6hDRWcNUQwdR9tVr2hqv1ygR7lfEMI4VK0D9EFFzvOKOcb9OP6ADiDjWFo9hAgmeJjwCYUP-ejPcTiLR7Ssscm-dnPyXyPI-ApDstoCmRcTv4US6zmfYXzMReYsA94NsEmMGuCzyOUXGOHKgyLrcYeisEWxhEPx-yWYE-Dq83BZNYR3sJj9MCZMcOT23eLPr97e335obn69P7j5ZurxopOlIaB5NIppahgnEhjaceH1qlWCMe5HTopmSOtVL2SHbUgGFDV96a3zu06afkWvT7nzks_wWAhlGRGPSc_mXTU0Xj9txL8Qe_jN60U4V295Ba9uA1I8esCuejJ53U5EyAuWbOWMt7thBQVff4PehOXFOp6lWKCcC5rT1vEzpRNMecE7u4zlOi1fX1uX9f29al9vZqe_bnGneVX3RXgZyBXKewh_Z79n9if6LG_EA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2624033500</pqid></control><display><type>article</type><title>The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Grajales, Diana ; Vázquez, Patricia ; Ruíz-Rosario, Mónica ; Tudurí, Eva ; Mirasierra, Mercedes ; Ferreira, Vítor ; Hitos, Ana B. ; Koller, Dora ; Zubiaur, Pablo ; Cigudosa, Juan C. ; Abad-Santos, Francisco ; Vallejo, Mario ; Quesada, Iván ; Tirosh, Boaz ; Leibowitz, Gil ; Valverde, Ángela M.</creator><creatorcontrib>Grajales, Diana ; Vázquez, Patricia ; Ruíz-Rosario, Mónica ; Tudurí, Eva ; Mirasierra, Mercedes ; Ferreira, Vítor ; Hitos, Ana B. ; Koller, Dora ; Zubiaur, Pablo ; Cigudosa, Juan C. ; Abad-Santos, Francisco ; Vallejo, Mario ; Quesada, Iván ; Tirosh, Boaz ; Leibowitz, Gil ; Valverde, Ángela M.</creatorcontrib><description><![CDATA[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 Ca
2+
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 Ca
2+
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]]></description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-021-05630-0</identifier><identifier>PMID: 34932133</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Antipsychotic Agents - adverse effects ; Antipsychotics ; Aripiprazole ; Aripiprazole - metabolism ; Aripiprazole - pharmacology ; Beta cells ; Body weight gain ; Calcium imaging ; Calorimetry ; Cell size ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - metabolism ; Diet ; Drug development ; Female ; Glucose ; Glucose tolerance ; Human Physiology ; Humans ; Immunofluorescence ; Insulin ; Insulin secretion ; Internal Medicine ; Intolerance ; Islets of Langerhans - metabolism ; Medicine ; Medicine & Public Health ; Mental disorders ; Metabolic Diseases ; Metabolic syndrome ; Mice ; Olanzapine ; Olanzapine - adverse effects ; Olanzapine - metabolism ; Patients ; Psychotropic drugs ; Rapamycin ; Schizophrenia ; TOR protein ; Transcriptomics ; Tryptophan ; Tryptophan hydroxylase</subject><ispartof>Diabetologia, 2022-03, Vol.65 (3), p.490-505</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-2e535f888142305ac173d6f8644f33cd7552f0658b8571ce42e18bbabcff975c3</citedby><cites>FETCH-LOGICAL-c474t-2e535f888142305ac173d6f8644f33cd7552f0658b8571ce42e18bbabcff975c3</cites><orcidid>0000-0002-0403-6647 ; 0000-0002-6422-0323 ; 0000-0002-6519-8885 ; 0000-0002-9699-6353 ; 0000-0003-3763-0391 ; 0000-0002-6150-4320 ; 0000-0002-9332-6979 ; 0000-0001-8067-6577 ; 0000-0001-8999-2605 ; 0000-0003-1192-9045 ; 0000-0002-0023-8903 ; 0000-0002-0107-9510 ; 0000-0002-0415-0466 ; 0000-0002-9808-514X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00125-021-05630-0$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00125-021-05630-0$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34932133$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grajales, Diana</creatorcontrib><creatorcontrib>Vázquez, Patricia</creatorcontrib><creatorcontrib>Ruíz-Rosario, Mónica</creatorcontrib><creatorcontrib>Tudurí, Eva</creatorcontrib><creatorcontrib>Mirasierra, Mercedes</creatorcontrib><creatorcontrib>Ferreira, Vítor</creatorcontrib><creatorcontrib>Hitos, Ana B.</creatorcontrib><creatorcontrib>Koller, Dora</creatorcontrib><creatorcontrib>Zubiaur, Pablo</creatorcontrib><creatorcontrib>Cigudosa, Juan C.</creatorcontrib><creatorcontrib>Abad-Santos, Francisco</creatorcontrib><creatorcontrib>Vallejo, Mario</creatorcontrib><creatorcontrib>Quesada, Iván</creatorcontrib><creatorcontrib>Tirosh, Boaz</creatorcontrib><creatorcontrib>Leibowitz, Gil</creatorcontrib><creatorcontrib>Valverde, Ángela M.</creatorcontrib><title>The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><addtitle>Diabetologia</addtitle><description><![CDATA[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 Ca
2+
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 Ca
2+
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]]></description><subject>Animals</subject><subject>Antipsychotic Agents - adverse effects</subject><subject>Antipsychotics</subject><subject>Aripiprazole</subject><subject>Aripiprazole - metabolism</subject><subject>Aripiprazole - pharmacology</subject><subject>Beta cells</subject><subject>Body weight gain</subject><subject>Calcium imaging</subject><subject>Calorimetry</subject><subject>Cell size</subject><subject>Diabetes</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diet</subject><subject>Drug development</subject><subject>Female</subject><subject>Glucose</subject><subject>Glucose tolerance</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Insulin</subject><subject>Insulin secretion</subject><subject>Internal Medicine</subject><subject>Intolerance</subject><subject>Islets of Langerhans - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mental disorders</subject><subject>Metabolic Diseases</subject><subject>Metabolic syndrome</subject><subject>Mice</subject><subject>Olanzapine</subject><subject>Olanzapine - adverse effects</subject><subject>Olanzapine - metabolism</subject><subject>Patients</subject><subject>Psychotropic drugs</subject><subject>Rapamycin</subject><subject>Schizophrenia</subject><subject>TOR protein</subject><subject>Transcriptomics</subject><subject>Tryptophan</subject><subject>Tryptophan hydroxylase</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kUuLFDEUhYMoTtv6B1xIwI2b0jyr0htBBl8w4GYEdyGVuunOUJWUSUpo_4v_1VT3OD4WrrI43zk39x6EnlLykhLSvcqEUCYbwmhDZMtJQ-6hDRWcNUQwdR9tVr2hqv1ygR7lfEMI4VK0D9EFFzvOKOcb9OP6ADiDjWFo9hAgmeJjwCYUP-ejPcTiLR7Ssscm-dnPyXyPI-ApDstoCmRcTv4US6zmfYXzMReYsA94NsEmMGuCzyOUXGOHKgyLrcYeisEWxhEPx-yWYE-Dq83BZNYR3sJj9MCZMcOT23eLPr97e335obn69P7j5ZurxopOlIaB5NIppahgnEhjaceH1qlWCMe5HTopmSOtVL2SHbUgGFDV96a3zu06afkWvT7nzks_wWAhlGRGPSc_mXTU0Xj9txL8Qe_jN60U4V295Ba9uA1I8esCuejJ53U5EyAuWbOWMt7thBQVff4PehOXFOp6lWKCcC5rT1vEzpRNMecE7u4zlOi1fX1uX9f29al9vZqe_bnGneVX3RXgZyBXKewh_Z79n9if6LG_EA</recordid><startdate>20220301</startdate><enddate>20220301</enddate><creator>Grajales, Diana</creator><creator>Vázquez, Patricia</creator><creator>Ruíz-Rosario, Mónica</creator><creator>Tudurí, Eva</creator><creator>Mirasierra, Mercedes</creator><creator>Ferreira, Vítor</creator><creator>Hitos, Ana B.</creator><creator>Koller, Dora</creator><creator>Zubiaur, Pablo</creator><creator>Cigudosa, Juan C.</creator><creator>Abad-Santos, Francisco</creator><creator>Vallejo, Mario</creator><creator>Quesada, Iván</creator><creator>Tirosh, Boaz</creator><creator>Leibowitz, Gil</creator><creator>Valverde, Ángela M.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0403-6647</orcidid><orcidid>https://orcid.org/0000-0002-6422-0323</orcidid><orcidid>https://orcid.org/0000-0002-6519-8885</orcidid><orcidid>https://orcid.org/0000-0002-9699-6353</orcidid><orcidid>https://orcid.org/0000-0003-3763-0391</orcidid><orcidid>https://orcid.org/0000-0002-6150-4320</orcidid><orcidid>https://orcid.org/0000-0002-9332-6979</orcidid><orcidid>https://orcid.org/0000-0001-8067-6577</orcidid><orcidid>https://orcid.org/0000-0001-8999-2605</orcidid><orcidid>https://orcid.org/0000-0003-1192-9045</orcidid><orcidid>https://orcid.org/0000-0002-0023-8903</orcidid><orcidid>https://orcid.org/0000-0002-0107-9510</orcidid><orcidid>https://orcid.org/0000-0002-0415-0466</orcidid><orcidid>https://orcid.org/0000-0002-9808-514X</orcidid></search><sort><creationdate>20220301</creationdate><title>The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice</title><author>Grajales, Diana ; Vázquez, Patricia ; Ruíz-Rosario, Mónica ; Tudurí, Eva ; Mirasierra, Mercedes ; Ferreira, Vítor ; Hitos, Ana B. ; Koller, Dora ; Zubiaur, Pablo ; Cigudosa, Juan C. ; Abad-Santos, Francisco ; Vallejo, Mario ; Quesada, Iván ; Tirosh, Boaz ; Leibowitz, Gil ; Valverde, Ángela M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-2e535f888142305ac173d6f8644f33cd7552f0658b8571ce42e18bbabcff975c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Antipsychotic Agents - adverse effects</topic><topic>Antipsychotics</topic><topic>Aripiprazole</topic><topic>Aripiprazole - metabolism</topic><topic>Aripiprazole - pharmacology</topic><topic>Beta cells</topic><topic>Body weight gain</topic><topic>Calcium imaging</topic><topic>Calorimetry</topic><topic>Cell size</topic><topic>Diabetes</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diet</topic><topic>Drug development</topic><topic>Female</topic><topic>Glucose</topic><topic>Glucose tolerance</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Immunofluorescence</topic><topic>Insulin</topic><topic>Insulin secretion</topic><topic>Internal Medicine</topic><topic>Intolerance</topic><topic>Islets of Langerhans - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mental disorders</topic><topic>Metabolic Diseases</topic><topic>Metabolic syndrome</topic><topic>Mice</topic><topic>Olanzapine</topic><topic>Olanzapine - adverse effects</topic><topic>Olanzapine - metabolism</topic><topic>Patients</topic><topic>Psychotropic drugs</topic><topic>Rapamycin</topic><topic>Schizophrenia</topic><topic>TOR protein</topic><topic>Transcriptomics</topic><topic>Tryptophan</topic><topic>Tryptophan hydroxylase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grajales, Diana</creatorcontrib><creatorcontrib>Vázquez, Patricia</creatorcontrib><creatorcontrib>Ruíz-Rosario, Mónica</creatorcontrib><creatorcontrib>Tudurí, Eva</creatorcontrib><creatorcontrib>Mirasierra, Mercedes</creatorcontrib><creatorcontrib>Ferreira, Vítor</creatorcontrib><creatorcontrib>Hitos, Ana B.</creatorcontrib><creatorcontrib>Koller, Dora</creatorcontrib><creatorcontrib>Zubiaur, Pablo</creatorcontrib><creatorcontrib>Cigudosa, Juan C.</creatorcontrib><creatorcontrib>Abad-Santos, Francisco</creatorcontrib><creatorcontrib>Vallejo, Mario</creatorcontrib><creatorcontrib>Quesada, Iván</creatorcontrib><creatorcontrib>Tirosh, Boaz</creatorcontrib><creatorcontrib>Leibowitz, Gil</creatorcontrib><creatorcontrib>Valverde, Ángela M.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grajales, Diana</au><au>Vázquez, Patricia</au><au>Ruíz-Rosario, Mónica</au><au>Tudurí, Eva</au><au>Mirasierra, Mercedes</au><au>Ferreira, Vítor</au><au>Hitos, Ana B.</au><au>Koller, Dora</au><au>Zubiaur, Pablo</au><au>Cigudosa, Juan C.</au><au>Abad-Santos, Francisco</au><au>Vallejo, Mario</au><au>Quesada, Iván</au><au>Tirosh, Boaz</au><au>Leibowitz, Gil</au><au>Valverde, Ángela M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice</atitle><jtitle>Diabetologia</jtitle><stitle>Diabetologia</stitle><addtitle>Diabetologia</addtitle><date>2022-03-01</date><risdate>2022</risdate><volume>65</volume><issue>3</issue><spage>490</spage><epage>505</epage><pages>490-505</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract><![CDATA[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 Ca
2+
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 Ca
2+
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]]></abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>34932133</pmid><doi>10.1007/s00125-021-05630-0</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-0403-6647</orcidid><orcidid>https://orcid.org/0000-0002-6422-0323</orcidid><orcidid>https://orcid.org/0000-0002-6519-8885</orcidid><orcidid>https://orcid.org/0000-0002-9699-6353</orcidid><orcidid>https://orcid.org/0000-0003-3763-0391</orcidid><orcidid>https://orcid.org/0000-0002-6150-4320</orcidid><orcidid>https://orcid.org/0000-0002-9332-6979</orcidid><orcidid>https://orcid.org/0000-0001-8067-6577</orcidid><orcidid>https://orcid.org/0000-0001-8999-2605</orcidid><orcidid>https://orcid.org/0000-0003-1192-9045</orcidid><orcidid>https://orcid.org/0000-0002-0023-8903</orcidid><orcidid>https://orcid.org/0000-0002-0107-9510</orcidid><orcidid>https://orcid.org/0000-0002-0415-0466</orcidid><orcidid>https://orcid.org/0000-0002-9808-514X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-186X |
| ispartof | Diabetologia, 2022-03, Vol.65 (3), p.490-505 |
| issn | 0012-186X 1432-0428 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8803721 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Animals Antipsychotic Agents - adverse effects Antipsychotics Aripiprazole Aripiprazole - metabolism Aripiprazole - pharmacology Beta cells Body weight gain Calcium imaging Calorimetry Cell size Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - metabolism Diet Drug development Female Glucose Glucose tolerance Human Physiology Humans Immunofluorescence Insulin Insulin secretion Internal Medicine Intolerance Islets of Langerhans - metabolism Medicine Medicine & Public Health Mental disorders Metabolic Diseases Metabolic syndrome Mice Olanzapine Olanzapine - adverse effects Olanzapine - metabolism Patients Psychotropic drugs Rapamycin Schizophrenia TOR protein Transcriptomics Tryptophan Tryptophan hydroxylase |
| title | The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T17%3A54%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20second-generation%20antipsychotic%20drug%20aripiprazole%20modulates%20the%20serotonergic%20system%20in%20pancreatic%20islets%20and%20induces%20beta%20cell%20dysfunction%20in%20female%20mice&rft.jtitle=Diabetologia&rft.au=Grajales,%20Diana&rft.date=2022-03-01&rft.volume=65&rft.issue=3&rft.spage=490&rft.epage=505&rft.pages=490-505&rft.issn=0012-186X&rft.eissn=1432-0428&rft_id=info:doi/10.1007/s00125-021-05630-0&rft_dat=%3Cproquest_pubme%3E2612379454%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2624033500&rft_id=info:pmid/34932133&rfr_iscdi=true |