1. Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance
- Author
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David J. Hill, Marcelo Rubinstein, Edith Arany, Astrid Chamson-Reig, Ana Maria Ornstein, Michael B. Wheeler, Isabel García-Tornadú, and Damasia Becu-Villalobos
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cell division ,Blood Glucose ,Male ,Time Factors ,insulin tolerance test ,medicine.medical_treatment ,animal cell ,haloperidol ,Impaired glucose tolerance ,DOPAMINE ,Mice ,Endocrinology ,pancreas islet cell ,Insulin Secretion ,Hyperinsulinemia ,Insulin ,Glucose homeostasis ,DIABETES ,insulin release ,Insulin-Like Growth Factor I ,pancreas function ,Mice, Knockout ,Otras Medicina Básica ,article ,Immunohistochemistry ,Otras Ciencias Médicas ,Insulin oscillation ,Medicina Básica ,D2 ,priority journal ,Dopamine Agonists ,cabergoline ,Female ,medicine.drug ,medicine.medical_specialty ,CIENCIAS MÉDICAS Y DE LA SALUD ,in vitro study ,pancreas islet beta cell ,Cabergoline ,animal experiment ,Radioimmunoassay ,Biology ,Dopamine agonist ,animal tissue ,in vivo study ,cell isolation ,Insulin resistance ,Internal medicine ,Glucose Intolerance ,drug mechanism ,medicine ,glucose homeostasis ,Animals ,Ergolines ,Pancreas ,mouse ,Cell Proliferation ,Analysis of Variance ,nonhuman ,Receptors, Dopamine D2 ,dopamine 2 receptor ,animal model ,Insulin tolerance test ,medicine.disease ,Prolactin ,Glucose ,Dopamine Antagonists ,Haloperidol - Abstract
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
- Published
- 2010
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