Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance

Autores
Garcia Tornadu, Isabel Andrea; Ornstein, Ana Maria; Chamson Reig, Astrid; Wheeler, Michael B.; Hill, David J.; Arany, Edith; Rubinstein, Marcelo; Becu, Damasia
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2(-/-)) mice and in isolated islets from wild-type and Drd2(-/-) mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2(-/-) male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2(-/-) mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2(-/-) mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic beta-cell mass in Drd2(-/-) mice and decreased beta-cell replication in 2-month-old Drd2(-/-) mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops
Fil: Garcia Tornadu, Isabel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina
Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina
Fil: Chamson Reig, Astrid. Lawson Health Research Institute; Canadá
Fil: Wheeler, Michael B.. University of Toronto. Departments of Physiology and Medicine ; Canadá
Fil: Hill, David J.. Lawson Health Research Institute; Canadá
Fil: Arany, Edith. Lawson Health Research Institute; Canadá
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiologia, Biologia Molecular y Celular. Laboratorio de Fisiologia y Biologia Molecular; Argentina
Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina
Materia
Dopamine
Insulin
Glucose
D2
Diabetes
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/14664
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/14664
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intoleranceGarcia Tornadu, Isabel AndreaOrnstein, Ana MariaChamson Reig, AstridWheeler, Michael B.Hill, David J.Arany, EdithRubinstein, MarceloBecu, DamasiaDopamineInsulinGlucoseD2Diabeteshttps://purl.org/becyt/ford/3.5https://purl.org/becyt/ford/3https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2(-/-)) mice and in isolated islets from wild-type and Drd2(-/-) mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2(-/-) male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2(-/-) mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2(-/-) mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic beta-cell mass in Drd2(-/-) mice and decreased beta-cell replication in 2-month-old Drd2(-/-) mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance developsFil: Garcia Tornadu, Isabel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Chamson Reig, Astrid. Lawson Health Research Institute; CanadáFil: Wheeler, Michael B.. University of Toronto. Departments of Physiology and Medicine ; CanadáFil: Hill, David J.. Lawson Health Research Institute; CanadáFil: Arany, Edith. Lawson Health Research Institute; CanadáFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiologia, Biologia Molecular y Celular. Laboratorio de Fisiologia y Biologia Molecular; ArgentinaFil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaOxford University Press2010-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/14664Garcia Tornadu, Isabel Andrea; Ornstein, Ana Maria; Chamson Reig, Astrid; Wheeler, Michael B.; Hill, David J.; et al.; Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance; Oxford University Press; Endocrinology; 151; 4; 4-2010; 1441-14500013-72271945-7170enginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2009-0996info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2009-0996info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:11:01Zoai:ri.conicet.gov.ar:11336/14664instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:11:02.028CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
title Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
spellingShingle Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
Garcia Tornadu, Isabel Andrea
Dopamine
Insulin
Glucose
D2
Diabetes
title_short Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
title_full Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
title_fullStr Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
title_full_unstemmed Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
title_sort Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance
dc.creator.none.fl_str_mv Garcia Tornadu, Isabel Andrea
Ornstein, Ana Maria
Chamson Reig, Astrid
Wheeler, Michael B.
Hill, David J.
Arany, Edith
Rubinstein, Marcelo
Becu, Damasia
author Garcia Tornadu, Isabel Andrea
author_facet Garcia Tornadu, Isabel Andrea
Ornstein, Ana Maria
Chamson Reig, Astrid
Wheeler, Michael B.
Hill, David J.
Arany, Edith
Rubinstein, Marcelo
Becu, Damasia
author_role author
author2 Ornstein, Ana Maria
Chamson Reig, Astrid
Wheeler, Michael B.
Hill, David J.
Arany, Edith
Rubinstein, Marcelo
Becu, Damasia
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Dopamine
Insulin
Glucose
D2
Diabetes
topic Dopamine
Insulin
Glucose
D2
Diabetes
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.5
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2(-/-)) mice and in isolated islets from wild-type and Drd2(-/-) mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2(-/-) male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2(-/-) mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2(-/-) mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic beta-cell mass in Drd2(-/-) mice and decreased beta-cell replication in 2-month-old Drd2(-/-) mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops
Fil: Garcia Tornadu, Isabel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina
Fil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina
Fil: Chamson Reig, Astrid. Lawson Health Research Institute; Canadá
Fil: Wheeler, Michael B.. University of Toronto. Departments of Physiology and Medicine ; Canadá
Fil: Hill, David J.. Lawson Health Research Institute; Canadá
Fil: Arany, Edith. Lawson Health Research Institute; Canadá
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiologia, Biologia Molecular y Celular. Laboratorio de Fisiologia y Biologia Molecular; Argentina
Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina
description The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2(-/-)) mice and in isolated islets from wild-type and Drd2(-/-) mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2(-/-) male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2(-/-) mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2(-/-) mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic beta-cell mass in Drd2(-/-) mice and decreased beta-cell replication in 2-month-old Drd2(-/-) mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops
publishDate 2010
dc.date.none.fl_str_mv 2010-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/14664
Garcia Tornadu, Isabel Andrea; Ornstein, Ana Maria; Chamson Reig, Astrid; Wheeler, Michael B.; Hill, David J.; et al.; Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance; Oxford University Press; Endocrinology; 151; 4; 4-2010; 1441-1450
0013-7227
1945-7170
url http://hdl.handle.net/11336/14664
identifier_str_mv Garcia Tornadu, Isabel Andrea; Ornstein, Ana Maria; Chamson Reig, Astrid; Wheeler, Michael B.; Hill, David J.; et al.; Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance; Oxford University Press; Endocrinology; 151; 4; 4-2010; 1441-1450
0013-7227
1945-7170
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2009-0996
info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2009-0996
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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