Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance

García-Tornadú, Isabel; Ornstein, Ana María; Chamson-Reig, Astrid; Wheeler, Michael B.; Hill, David J.; Arany, Edith; Rubinstein, Marcelo; Becú-Villalobos, Damasia

doi:10.1210/en.2009-0996

Cited by 125 publications

(96 citation statements)

References 59 publications

(46 reference statements)

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“…79,84 They might blunt glucosestimulated insulin release by blocking D 2 dopamine receptors or cho linergic stimulated pancreatic insulin secretion by blocking M 3 muscarinic receptors. 85 Studies quantifying the defect in insulin secretion have suggested that certain second generation anti psychotics, for example clozapi ne 75 and quetiapine, 76 might have a greater adverse effect on βcell function than other drugs in this group, at least in the short term. As well as direct effects on βcell func tion, antipsychotics might also affect central control of glucose homeostasis.…”

Section: Mechanismsmentioning

confidence: 99%

Diabetes mellitus and severe mental illness: mechanisms and clinical implications

2014

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The prevalence of diabetes mellitus is twofold to threefold higher in people with severe mental illness (SMI) than in the general population, with diabetes mellitus affecting ∼12% of people receiving antipsychotics. The consequences of diabetes mellitus are more severe and frequent in people with SMI than in those without these conditions, with increased rates of microvascular and macrovascular complications, acute metabolic dysregulation and deaths related to diabetes mellitus. Multiple complex mechanisms underlie the association between diabetes mellitus and SMI; these mechanisms include genetic, environmental and disease-specific factors, and treatment-specific factors. Although antipsychotics are the mainstay of treatment in SMI, a causative link, albeit of uncertain magnitude, seems to exist between antipsychotics and diabetes mellitus. The principles of managing diabetes mellitus in people with SMI are similar to those for the general population and should follow currently established treatment algorithms. Lifestyle interventions are needed to reduce incident diabetes mellitus. In addition, improved uptake of opportunities to screen for this disease will reduce the high prevalence of undiagnosed diabetes mellitus. Currently, people with SMI receive poorer treatment for diabetes mellitus than the general population. Thus, health-care professionals in primary care, diabetes mellitus services and mental health teams have a responsibility to ensure that patients with SMI are not disadvantaged.

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Section: Mechanismsmentioning

confidence: 99%

Diabetes mellitus and severe mental illness: mechanisms and clinical implications

2014

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“…Glucose homeostasis was studied in Drd2 –/– mice, and in isolated islets from wild-type and Drd2 –/– mice, using different pharmacological tools [67]. Drd2 –/– mice exhibited an impairment of insulin response to glucose, high fasting glucose levels, and were glucose intolerant.…”

Section: D2rs and Glucose Metabolismmentioning

confidence: 99%

New Insights into the Endocrine and Metabolic Roles of Dopamine D2 Receptors Gained from the <i>Drd2</i><sup>–/–</sup> Mouse

García-Tornadú

Millán²,

Recouvreux³

et al. 2010

Neuroendocrinology

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Dopamine D2 receptor (D2R) participation in prolactin regulation is well documented, but the role of D2Rs in the control of other hormones involved in growth, food intake and glucose metabolism has not been extensively studied. The study of D2R knockout mice (Drd2^–/–) puts forward new insights into the role of the D2R in growth hormone (GH)-releasing hormone-GH regulation, peptides involved in food intake, glucose homeostasis, as well as in prolactinoma development. The expected phenotype of chronic hyperprolactinemia and prolactinoma development was found in the Drd2^–/– mouse, and this model constitutes a valuable tool in the study of dopamine-resistant prolactinomas. Unexpectedly, these mice were growth retarded, and the importance of functional hypothalamic D2Rs in the neonatal period was revealed. In the Drd2^–/– mouse there was a failure of high neonatal GH levels and therefore the expansion of pituitary somatotropes was permanently altered. These mice also had increased food intake, and a sexually dimorphic participation of the D2R in food intake regulation is suggested. The effect described is probably secondary to D2R regulation of prolactin secretion. Furthermore, the negative modulation of D2Rs on α-melanocyte-stimulating hormone release and positive action on the hypothalamic expression of orexins reveals the complex D2R regulation of food intake. Finally, pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development in the Drd2^–/– mouse may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops. These results highlight the complex endocrine actions of the D2Rs at different levels, hypothalamus, pituitary or pancreas, which function to improve fitness, reproductive success and survival.

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“…Central D2Rs participate not only in control of locomotor activity, executive planning, motor coordination, pain perception, food intake, aggressive and reward-seeking behaviors, but also in the regulation of the GHRH-GH axis (12). Furthermore, lactotrope D2Rs mediate the tonic inhibition that dopamine exerts on prolactin synthesis and release (13), while in the periphery, dopamine regulates pancreatic endocrine function including insulin release from pancreas, and its action on adipocytes (14,15). A link has been established between obesity, growth and dopaminergic systems located both within the central nervous system (CNS) or in other tissues (11,16,17).…”

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confidence: 99%

Pituitary and Brain Dopamine D2 Receptors Regulate Liver Gene Sexual Dimorphism

et al. 2015

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Liver sexual gene dimorphism, which depends mainly on specific patterns of GH secretion, may underlie differential susceptibility to some liver diseases. Because GH and prolactin secretion are regulated by dopaminergic pathways, we studied the participation of brain and lactotrope dopamine 2 receptors (D2Rs) on liver gene sexual dimorphism, to explore a link between the brain and liver gene expression. We used global D2R knockout mice (Drd2(-/-)) and conducted a functional dissection strategy based on cell-specific Drd2 inactivation in neurons (neuroDrd2KO) or pituitary lactotropes. Disruption of neuronal D2Rs (which impaired the GH axis) decreased most of male or female-predominant class I liver genes and increased female-predominant class II genes in males, consistent with the positive (class I) or negative (class II) regulation of these genes by GH. Notably, sexual dimorphism was lost for class I and II genes in neuroDrd2KO mice. Disruption of lactotrope D2Rs did not modify class I or II genes in either sex, because GH axis was preserved. But surprisingly, 1 class II gene (Prlr) and female-predominant class I genes were markedly up-regulated in lacDrd2KO females, pointing to direct or indirect effects of prolactin in the regulation of selected female-predominant liver genes. This suggestion was strengthened in the hyperprolactinemic Drd2(-/-) female mouse, in which increased expression of the same 4 liver genes was observed, despite a decreased GH axis. We hereby demonstrate endocrine-mediated D2R actions on sexual dimorphic liver gene expression, which may be relevant during chronic dopaminergic medications in psychiatric disease.

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Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance

Cited by 125 publications

References 59 publications

Diabetes mellitus and severe mental illness: mechanisms and clinical implications

Diabetes mellitus and severe mental illness: mechanisms and clinical implications

New Insights into the Endocrine and Metabolic Roles of Dopamine D2 Receptors Gained from the <i>Drd2</i><sup>–/–</sup> Mouse

Pituitary and Brain Dopamine D2 Receptors Regulate Liver Gene Sexual Dimorphism

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