RESUMEN
Type-2 diabetes mellitus (T2DM) is an expanding global health problem, involving defective insulin secretion by pancreatic ß-cells and peripheral insulin resistance, leading to impaired glucose regulation. Galectin-1-an endogenous lectin with affinity for N-acetyllactosamine (LacNAc)-containing glycans-has emerged as a regulator of inflammatory and metabolic disorders. However, the role of galectin-1 in glucose homeostasis and pancreatic ß-cell function, independently of hypercaloric diets, has not been explored. Here, we identified a phenotype compatible with T2DM, involving alterations in glucose metabolism and pancreatic insulin release, in female but not male mice lacking galectin-1 (Lgals1-/-). Compared with age-matched controls, Lgals1-/- female mice exhibited higher body weight and increased food intake ad libitum as well as after fasting and acute re-feeding. Although fasted serum insulin levels and insulin sensitivity were similar in both genotypes, Lgals1-/- female mice presented altered glucose tolerance and higher basal glucose levels depending on the fasting period. Insulin response to glucose overload was impaired, while pancreatic insulin content was enhanced in the absence of galectin-1. Accordingly, recombinant galectin-1 enhanced glucose-stimulated insulin release in vitro. Our study identifies a role for galectin-1 in regulating glucose metabolism through modulation of pancreatic insulin secretion, highlighting novel opportunities to control T2DM.
Asunto(s)
Resistencia a la Insulina , Insulina , Animales , Femenino , Galectina 1/genética , Galectina 1/metabolismo , Glucosa/metabolismo , Homeostasis , Insulina/metabolismo , Secreción de Insulina , Masculino , RatonesRESUMEN
The importance of dopamine in central nervous system function is well known, but its effects on glucose homeostasis and pancreatic ß cell function are beginning to be unraveled. Mutant mice lacking dopamine type 2 receptors (D2R) are glucose intolerant and have abnormal insulin secretion. In humans, administration of neuroleptic drugs, which block dopamine receptors, may cause hyperinsulinemia, increased weight gain and glucose intolerance. Conversely, treatment with the dopamine precursor l-DOPA in patients with Parkinson's disease reduces insulin secretion upon oral glucose tolerance test, and bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients as well as in non diabetic obese animals and humans. The actions of dopamine on glucose homeostasis and food intake impact both the autonomic nervous system and the endocrine system. Different central actions of the dopamine system may mediate its metabolic effects such as: (i) regulation of hypothalamic noradrenaline output, (ii) participation in appetite control, and (iii) maintenance of the biological clock in the suprachiasmatic nucleus. On the other hand, dopamine inhibits prolactin, which has metabolic functions; and, at the pancreatic beta cell dopamine D2 receptors inhibit insulin secretion. We review the evidence obtained in animal models and clinical studies that posited dopamine receptors as key elements in glucose homeostasis and ultimately led to the FDA approval of bromocriptine in adults with type 2 diabetes to improve glycemic control. Furthermore, we discuss the metabolic consequences of treatment with neuroleptics which target the D2R, that should be monitored in psychiatric patients to prevent the development in diabetes, weight gain, and hypertriglyceridemia.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dopaminérgicos/uso terapéutico , Glucosa/metabolismo , Acromegalia/tratamiento farmacológico , Animales , Bromocriptina/uso terapéutico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dopaminérgicos/efectos adversos , Homeostasis , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Polimorfismo Genético , Prolactinoma/tratamiento farmacológico , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMEN
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.
Asunto(s)
Sistema Endocrino/fisiología , Metabolismo/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/fisiología , Animales , Ingestión de Alimentos/genética , Ingestión de Alimentos/fisiología , Sistema Endocrino/metabolismo , Hormona del Crecimiento/metabolismo , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Ratones , Ratones Noqueados , Prolactina/metabolismo , Receptores de Dopamina D2/metabolismoRESUMEN
The role of dopaminergic receptors in the control of GH release remains controversial. The dopamine receptor 2 (D2R) knockout mouse represents a useful model to study the participation of the D2R on growth and GHRH-GH regulation. These knockout mice have hyperprolactinemia and lactotrope hyperplasia, but unexpectedly, they are also growth retarded. In D2R knockout mice there is a significant decrease in somatotrope population, which is paralleled by decreased GH content and output from pituitary cells. The sensitivity of GHRH-induced GH and cAMP release is similar between genotypes, even though the response amplitude is lower in knockouts. We point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level, and both somatostatin and GHRH mRNA expression are altered in knockout mice. The similarity of the pituitary defect in the D2R knockout mouse to that of GHRH deficient models suggests a probable mechanism. Loss of dopamine signaling via hypothalamic D2Rs at a critical age may cause inadequate GHRH secretion subsequently leading to inappropriate somatotrope lineage development. Furthermore, GH pulsatility, which depends on a regulated temporal balance between GHRH and somatostatin output might be compromised in D2R knockout mice, leading to lower IGF-I, and growth retardation.
Asunto(s)
Dopamina/fisiología , Hormona Liberadora de Hormona del Crecimiento/fisiología , Hormona del Crecimiento/fisiología , Neurotransmisores/fisiología , Acromegalia/tratamiento farmacológico , Animales , Crecimiento , Humanos , Ratones , Receptores de Dopamina D2/fisiologíaRESUMEN
We investigated the effect of fat supplementation on plasma levels of hormones related to metabolism, with special attention to leptin, in cows in early lactation and in feedlot steers. In experiment 1, 34 lactating cows received no fat or else 0.5 or 1.0 kg of partially hydrogenated oil per day in addition to their basal diet from day 20 before the expected calving date to day 70 postpartum. In experiment 2, part of the corn in the basal concentrate was replaced with 0.7 kg of the same oil such that the diets were isocaloric; 18 cows received the fat-substituted diet and 18 a control diet from day 20 before the expected calving date to day 75 postpartum. In experiment 3, calcium salts of fatty acids were added to the basal diet of 14 feedlot steers for 80 d; another 14 steers received a control diet. The basal plasma levels of leptin were higher in the cows than in the steers. Dietary fat supplementation did not affect the leptin levels in the lactating cows but lowered the levels in the feedlot steers despite greater energy intake and body fatness (body weight) in the steers receiving the supplement than in those receiving the control diet. The levels of insulin-like growth factor I and insulin were decreased with dietary fat supplementation in the lactating cows but were unaffected in the steers, suggesting that responses to fat ingestion depend on the physiological state of the animal, including age and sex. Finally, no effects of supplementary fat on the level of growth hormone were demonstrated in any of the models.
Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Grasas Insaturadas en la Dieta/administración & dosificación , Lactancia/metabolismo , Leptina/sangre , Preñez/metabolismo , Factores de Edad , Animales , Bovinos , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Femenino , Hormona del Crecimiento/sangre , Hidrogenación , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Embarazo , Distribución Aleatoria , Factores SexualesRESUMEN
Recently, the importance of the dopaminergic D2 receptor (D2R) subtype in normal body growth and neonatal GH secretion has been highlighted. Disruption of D2R alters the GHRH-GH-IGF-I axis and impairs body growth in adult male mice. The D2R knockout (KO) dwarf mouse has not been well characterized; we therefore sought to determine somatotrope function in the adult pituitary. Using immunohistochemistry and confocal microscopy, we found a significant decrease in the somatotrope population in pituitaries from KO mice (P=0.043), which was paralleled by a decreased GH output from pituitary cells cultured in vitro. In cells from adult mice the response amplitude to GHRH differed between genotypes (lower in KO), but this difference was less dramatic after taking into account the lower basal release and hormone content in the KO cells. Furthermore, there were no significant differences in cAMP generation in response to GHRH between genotypes. By Western blot, GHRH-receptor in pituitary membranes from KO mice was reduced to 46% of the level found in wildtype (WT) mice (P=0.016). Somatostatin induced a concentration-dependent decrease in GH and prolactin (PRL) secretion in both genotypes, and 1x10(-7) M ghrelin released GH in cells from both genotypes (P=0.017) in a proportionate manner to basal levels. These results suggest that KO somatotropes maintain a regulated secretory function. Finally, we tested the direct effect of dopamine on GH and PRL secretion in cells from both genotypes at 20 days and 6 months of life. As expected, we found that dopamine could reduce PRL levels at both ages in WT mice but not in KO mice, but there was no consistent effect of the neurotransmitter on GH release in either genotype at the ages studied. The present study demonstrates that in the adult male D2R KO mouse, there is a reduction in pituitary GH content and secretory activity. Our results point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level either in 1-month-old or adult mice. The similarity of the pituitary defect in the D2R KO mouse to that of GHRH-deficient models suggests a probable mechanism. A loss of dopamine signaling via hypothalamic D2Rs at a critical age causes the reduced release of GHRH from hypophyseotropic neurons leading to inadequate clonal expansion of the somatotrope population. Our data also reveal that somatotrope cell number is much more sensitive to changes in neonatal GHRH input than their capacity to develop properly regulated GH-secretory function.
Asunto(s)
Enanismo/metabolismo , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona del Crecimiento/metabolismo , Hipófisis/metabolismo , Receptores de Dopamina D2/genética , Somatostatina/farmacología , Animales , Western Blotting/métodos , Células Cultivadas , AMP Cíclico/análisis , AMP Cíclico/biosíntesis , Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Ghrelina , Inmunohistoquímica/métodos , Masculino , Ratones , Ratones Noqueados , Microscopía Confocal , Hormonas Peptídicas/farmacología , Hipófisis/citología , Hipófisis/efectos de los fármacos , Prolactina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Neuropéptido/análisis , Receptores de Neuropéptido/metabolismo , Receptores de Hormona Reguladora de Hormona Hipofisaria/análisis , Receptores de Hormona Reguladora de Hormona Hipofisaria/metabolismoRESUMEN
Dopamine receptor type 2 (D2R) knockout mice (KO) have chronic hyperprolactinemia, pituitary hyperplasia, and a moderate decrease in MSH content. They are also growth retarded evidencing an alteration in the GH-IGF-I axis. In D2R KO, lactotropes do not show dense secretory granules but degranulated cells and fewer somatotropes, gonadotropes and thyrotropes. Prolactin levels are always higher in female than in male knockouts, and in accordance, pituitary hyperplasia is observed at 8 months only in females. After 16 months of age, highly vascularized adenomas develop, especially in females. Prominent vascular channels in the hyperplastic and adenomatous pituitaries, as well as extravasated red blood cells not contained in capillaries is also a common finding. Prolactin is not the factor that enhances the hyperplastic phenotype in females while estrogen is a permissive factor. VEGF-A expression is increased in pituitaries from D2R KO. VEGF-A is expressed in follicle stellate cells. Because D2R receptors are found in lactotropes and not in follicle stellate cells, it may be inferred that a paracrine-derived factor from lactotropes is acting on follicle stellate cells to increase VEGF-A expression. VEGF-A does not induce pituitary cell proliferation, even though it enhances prolactin secretion. But it may act on adjacent endothelial cells and participate in the angiogenic process that increases the availability of different growth factors and mitogens. The D2R knockout mouse represents a unique animal model to study dopamine-resistant prolactinomas, and VEGF-A may be an alternative therapeutic target in this pathology.
Asunto(s)
Modelos Animales de Enfermedad , Ratones Noqueados/genética , Neoplasias Hipofisarias/genética , Prolactinoma/genética , Receptores de Dopamina D2/genética , Animales , Adhesión Celular , Resistencia a Antineoplásicos , Femenino , Hiperplasia/etiología , Masculino , Ratones , Neovascularización Patológica , Peliosis Hepática/etiología , Hipófisis/patología , Prolactinoma/irrigación sanguínea , Prolactinoma/complicaciones , Receptores de Dopamina D2/deficiencia , Caracteres Sexuales , Factor A de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
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.
Asunto(s)
Encéfalo/metabolismo , Hígado/metabolismo , Hipófisis/metabolismo , Receptores de Dopamina D2/metabolismo , Animales , Femenino , Regulación de la Expresión Génica/fisiología , Hormona del Crecimiento/sangre , Hormona del Crecimiento/metabolismo , Lactotrofos/metabolismo , Masculino , Ratones , Ratones Noqueados , Neuronas/metabolismo , Proteínas/genética , Proteínas/metabolismo , Receptores de Dopamina D2/genética , Caracteres SexualesRESUMEN
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.