RESUMO
Glucokinase is one of the most important regulators of fasting glucose levels. There are several mutations in the glucokinase gene (GCK) which are linked with monogenic diabetes. Recently, a polymorphism in its promoter has been described, which is associated with impaired fasting glucose levels. We present a 7 years and 7 months old boy with overweight and a familial background of diabetes in two previous generations. In the oral glucose tolerance test, he had impaired fasting glucose levels and after two hours, with a high insulin response. Laboratory abnormalities improved after weight loss, but he maintains a slight fasting hyperglycaemia. The molecular study of the most common monogenic diabetes forms, MODY subtypes 1, 2, and 3, was negative. The allelic variant G/A was however detected at the GCK promoter polymorphism rs1799884.
Assuntos
Glucoquinase/genética , Hiperglicemia/genética , Mutação , Polimorfismo Genético , Criança , Jejum , Humanos , MasculinoAssuntos
Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA/genética , Proteínas de Homeodomínio/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Humanos , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Proteína de Homoeobox de Baixa EstaturaRESUMO
CONTEXT: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity. OBJECTIVE: The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS. DESIGN AND METHODS: Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications. RESULTS: During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5' flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals. CONCLUSION: MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.
Assuntos
Estatura/genética , Proteínas de Homeodomínio/genética , Estudos de Coortes , DNA/genética , Bases de Dados de Ácidos Nucleicos , Nanismo/genética , Feminino , Dosagem de Genes , Duplicação Gênica , Transtornos do Crescimento/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Repetições de Microssatélites , Técnicas de Amplificação de Ácido Nucleico , Osteocondrodisplasias/genética , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína de Homoeobox de Baixa Estatura , EspanhaRESUMO
Preeclampsia is the development of new-onset hypertension with proteinuria after 20 weeks of gestation. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is a severe form of preeclampsia with high rates of neonatal and maternal morbidity. In recent years, loss of function of cdkn1c (a tight-binding inhibitor of G1 cyclin/cyclin-dependent kinase complexes and a negative regulator of cell proliferation) has been observed in several mouse models of preeclampsia. In this paper, we report on three women with HELLP/preeclampsia who had children with Beckwith Wiedemann syndrome, a complex genetic disorder characterised, among other findings, by overgrowth, omphalocele and macroglossia. All three children displayed mutations in CDKN1C predicted to generate truncated proteins. Two of the mutations were maternally inherited while the third was de novo. This finding suggests a fetal contribution to the maternal disease. To the best of our knowledge this is the first report of CDKN1C mutations in children born to women with preeclampsia/HELLP syndrome, thus suggesting the involvement of an imprinted gene in the pathophysiology of preeclampsia.
Assuntos
Síndrome de Beckwith-Wiedemann/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Síndrome HELLP/genética , Pré-Eclâmpsia/genética , Sequência de Bases , Síndrome de Beckwith-Wiedemann/complicações , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Síndrome HELLP/etiologia , Humanos , Recém-Nascido , Mutação/fisiologia , Pré-Eclâmpsia/etiologia , GravidezRESUMO
Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene (GCK) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 muIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation.
Assuntos
Diabetes Mellitus Tipo 1/genética , Glucoquinase/deficiência , Glucoquinase/genética , Insulina/uso terapêutico , Antibacterianos/uso terapêutico , Códon sem Sentido , Consanguinidade , Diabetes Mellitus Tipo 1/tratamento farmacológico , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/diagnóstico , Feminino , Homozigoto , Humanos , Hiperglicemia/enzimologia , Hiperglicemia/genética , Recém-Nascido , Injeções Subcutâneas , Insulina/administração & dosagem , Masculino , LinhagemRESUMO
Insulin-like growth factor-I (IGF-I) has protective effects against beta-amyloid (Abeta)-induced neuronal cell death. Because alterations of the somatostatinergic system have been described in Alzheimer's disease, we investigated the effects of the Abeta peptide and the possible protective role of IGF-I on the somatostatinergic system of the rat temporal cortex and on cell death and phosphorylated (p)-Akt levels in this area. Abeta25-35 was administered intracerebroventricularly to male rats via an osmotic minipump over 14 days (300 pmol/day). Another group received a subcutaneous IGF-I infusion (50 microg/kg/day), concomitant with Abeta25-35 administration, whereas a third group received IGF-I alone. Abeta25-35 significantly decreased the somatostatin (SRIF)-like immunoreactive content and the SRIF receptor density, as a result of a decrease in the levels of the SRIF receptor subtype 2. The inhibitory effect of SRIF on adenylyl cyclase activity was significantly lower after Abeta25-35 infusion, whereas the levels of the inhibitory G protein subunit Gialpha1, Gialpha2 or Gialpha3 were unaltered. Cell death was increased and p-Akt levels decreased in Abeta25-35-treated animals. IGF-I administration increased immunoreactive IGF-I levels in the temporal cortex and restored all parameters affected by Abeta25-35 to baseline values. These findings suggest that IGF-I prevents the deleterious effect of Abeta25-35 on the somatostatinergic system.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Somatostatina/metabolismo , Lobo Temporal/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/toxicidade , Animais , Ligação Competitiva/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Vias de Administração de Medicamentos , Antagonismo de Drogas , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fragmentos de Peptídeos/toxicidade , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar , Receptores de Somatostatina/efeitos dos fármacos , Receptores de Somatostatina/metabolismo , Lobo Temporal/metabolismoRESUMO
May-Hegglin anomaly (MHA) and Fechtner (FTNS) and Sebastian (SBS) syndromes are autosomal dominant platelet disorders that share macrothrombocytopenia and characteristic leukocyte inclusions. FTNS has the additional clinical features of nephritis, deafness, and cataracts. Previously, mutations in the nonmuscle myosin heavy chain 9 gene (MYH9), which encodes nonmuscle myosin heavy chain IIA (MYHIIA), were identified in all three disorders. The spectrum of mutations and the genotype-phenotype and structure-function relationships in a large cohort of affected individuals (n=27) has now been examined. Moreover, it is demonstrated that MYH9 mutations also result in two other FTNS-like macrothrombocytopenia syndromes: Epstein syndrome (EPS) and Alport syndrome with macrothrombocytopenia (APSM). In all five disorders, MYH9 mutations were identified in 20/27 (74%) affected individuals. Four mutations, R702C, D1424N, E1841K, and R1933X, were most frequent. R702C and R702H mutations were only associated with FTNS, EPS, or APSM, thus defining a region of MYHIIA critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness. The E1841K, D1424N, and R1933X coiled-coil domain mutations were common to both MHA and FTNS. Haplotype analysis using three novel microsatellite markers revealed that three E1841K carriers--one with MHA and two with FTNS--shared a common haplotype around the MYH9 gene, suggesting a common ancestor. The two new globular-head mutations, K371N and R702H, as well as the recently identified MYH9 mutation, R705H, which results in DFNA17, were modeled on the basis of X-ray crystallographic data. Altogether, our data suggest that MHA, SBS, FTNS, EPS, and APSM comprise a phenotypic spectrum of disorders, all caused by MYH9 mutations. On the basis of our genetic analyses, the name "MYHIIA syndrome" is proposed to encompass all of these disorders.
Assuntos
Genes Dominantes/genética , Proteínas Motores Moleculares , Mutação/genética , Cadeias Pesadas de Miosina/genética , Miosina não Muscular Tipo IIA/genética , Trombocitopenia/genética , Sequência de Aminoácidos , Cromossomos/genética , Análise Mutacional de DNA , Evolução Molecular , Éxons/genética , Haplótipos/genética , Humanos , Repetições de Microssatélites/genética , Modelos Moleculares , Dados de Sequência Molecular , Cadeias Pesadas de Miosina/química , Nefrite Hereditária/genética , Nefrite Hereditária/fisiopatologia , Miosina não Muscular Tipo IIA/química , Fenótipo , Mapeamento Físico do Cromossomo , Conformação Proteica , Alinhamento de Sequência , Relação Estrutura-Atividade , Síndrome , Terminologia como Assunto , Trombocitopenia/fisiopatologiaRESUMO
Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to control levels of T3, the active ligand for thyroid hormone receptors (TR). The D1 gene is itself T3-inducible and here, the regulation of D1 expression by TRalpha1 and TRbeta, which act as T3-dependent transcription factors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TRbeta(-/-) but not TRalpha1(-/-) mice. Liver D1 remained weakly T3 inducible in TRbeta(-/-) mice whereas induction was abolished in double mutant TRalpha1(-/-)TRbeta(-/-) mice. This indicates that TRbeta is primarily responsible for regulating D1 expression whereas TRalpha1 has only a minor role. In kidney, despite the expression of both TRalpha1 and TRbeta, regulation relied solely on TRbeta, thus revealing a marked tissue restriction in TR isotype utilization. Although TRbeta and TRalpha1 mediate similar functions in vitro, these results demonstrate differential roles in regulating D1 expression in vivo and suggest that tissue-specific factors and structural distinctions between TR isotypes contribute to functional specificity. Remarkably, there was an obligatory requirement for a TR, whether TRbeta or TRalpha1, for any detectable D1 expression in liver. This suggests a novel paradigm of gene regulation in which the TR sets both basal expression and the spectrum of induced states. Physiologically, these findings suggest a critical role for TRbeta in regulating the thyroid hormone status through D1-mediated metabolism.
Assuntos
Iodeto Peroxidase/metabolismo , Rim/enzimologia , Fígado/enzimologia , Receptores dos Hormônios Tireóideos/metabolismo , Animais , Peso Corporal , Feminino , Regulação Enzimológica da Expressão Gênica , Hipertireoidismo/enzimologia , Hipertireoidismo/genética , Hipotireoidismo/enzimologia , Hipotireoidismo/genética , Iodeto Peroxidase/genética , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Mutantes , Especificidade de Órgãos , Receptores dos Hormônios Tireóideos/deficiência , Receptores dos Hormônios Tireóideos/genética , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologiaRESUMO
Thyroid hormone signaling during a postnatal period in the mouse is essential for cochlear development and the subsequent onset of hearing. To study the control of this temporal dependency, we investigated the role of iodothyronine deiodinases, which in target tissues convert the prohormone thyroxine into triiodothyronine (T3), the active ligand for the thyroid hormone receptor (TR). Type 2 5'-deiodinase (D2) activity rose dramatically in the mouse cochlea to peak around postnatal day 7 (P7), after which activity declined by P10. This activity peak a few days before the onset of hearing suggests a role for D2 in amplifying local T3 levels at a critical stage of cochlear development. A mouse cochlear D2 cDNA was isolated and demonstrated near identity to rat D2. In situ hybridization localized D2 mRNA in periosteal connective tissue in the modiolus, the cochlear outer capsule and the septal divisions between the turns of the cochlea. Surprisingly, D2 expression in these regions that give rise to the bony labyrinth was complementary to TR expression in the sensory epithelium. Thus, the connective tissue may control deiodination of thyroxine and release of T3 to confer a paracrine-like control of TR activation. These results suggest that temporal and spatial control of ligand availability conferred by D2 provides an unexpectedly important level of regulation of the TR pathways required for cochlear maturation.
Assuntos
Cóclea/enzimologia , Regulação da Expressão Gênica no Desenvolvimento , Audição , Iodeto Peroxidase/biossíntese , Isoenzimas/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Sequência de Aminoácidos , Animais , Sequência de Bases , Cóclea/crescimento & desenvolvimento , Indução Enzimática , Hibridização In Situ , Iodeto Peroxidase/genética , Isoenzimas/genética , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Tiroxina/metabolismo , Tri-Iodotironina/biossíntese , Iodotironina Desiodinase Tipo IIRESUMO
Mice homozygous for a disruption in the alpha-subunit essential for TSH, LH, and FSH activity (alphaGsu-/-) exhibit hypothyroidism and hypogonadism similar to that observed in TSH receptor-deficient hypothyroid mice (hyt) and GnRH-deficient hypogonadal mutants (hpg). Although the five major hormone-producing cells of the anterior pituitary are present in alphaGsu-/- mice, the relative proportions of each cell type are altered dramatically. Thyrotropes exhibit hypertrophy and hyperplasia, and somatotropes and lactotropes are underrepresented. The size and number of gonadotropes in alphaGsu mutants are not remarkable in contrast to the hypertrophy characteristic of gonadectomized animals. The reduction in lactotropes is more severe in alphaGsu mutants (13-fold relative to wild-type) than in hyt or hpg mutants (4.5- and 1.5-fold, respectively). In addition, T4 replacement therapy of alphaGsu mutants restores lactotropes to near-normal levels, illustrating the importance of T4, but not alpha-subunit, for lactotrope proliferation and function. T4 replacement is permissive for gonadotrope hypertrophy in alphaGsu mutants, consistent with the role for T4 in the function of gonadotropes. This study reveals the importance of thyroid hormone in developing the appropriate proportions of anterior pituitary cell types.
Assuntos
Subunidade alfa de Hormônios Glicoproteicos/genética , Hormônio do Crescimento/biossíntese , Mutagênese , Adeno-Hipófise/patologia , Prolactina/biossíntese , Tiroxina/fisiologia , Animais , Contagem de Células , Divisão Celular , Nanismo/prevenção & controle , Hiperplasia , Hipogonadismo/genética , Hipogonadismo/patologia , Hipotireoidismo/genética , Hipotireoidismo/patologia , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Adeno-Hipófise/metabolismo , Tireotropina/deficiência , Tireotropina/genética , Tiroxina/farmacologia , Tiroxina/uso terapêuticoRESUMO
Patients with resistance to thyroid hormone (RTH) exhibit elevated thyroid hormone levels and inappropriate thyrotropin (thyroid-stimulating hormone, or TSH) production. The molecular basis of this disorder resides in the dominant inhibition of endogenous thyroid hormone receptors (TRs) by a mutant receptor. To determine the relative contributions of pituitary versus hypothalamic resistance to the dysregulated production of thyroid hormone in these patients, we developed a transgenic mouse model with pituitary-specific expression of a mutant TR (Delta337T). The equivalent mutation in humans is associated with severe generalized RTH. Transgenic mice developed profound pituitary resistance to thyroid hormone, as demonstrated by markedly elevated baseline and non-triodothyronine (T3)-suppressible serum TSH and pituitary TSH-beta mRNA. Serum thyroxine (T4) levels were only marginally elevated in transgenic mice and thyrotropin-releasing hormone (TRH) gene expression in the paraventricular hypothalamus was downregulated. After TRH administration, T4 concentrations increased markedly in transgenic, but not in wild-type mice. Transgenic mice rendered hypothyroid exhibited a TSH response that was only 30% of the response observed in wild-type animals. These findings indicate that pituitary expression of this mutant TR impairs both T3-mediated suppression and T3-independent activation of TSH production in vivo. The discordance between basal TSH and T4 levels and the reversal with TRH administration demonstrates that resistance at the level of both the thyrotroph and the hypothalamic TRH neurons are required to elevate thyroid hormone levels in patients with RTH.
Assuntos
Síndrome da Resistência aos Hormônios Tireóideos/genética , Tireotropina/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Mutação/genética , Hipófise/metabolismo , Precursores de Proteínas/genética , RNA Mensageiro/metabolismo , Receptores dos Hormônios Tireóideos/genética , Tireotropina/sangue , Hormônio Liberador de Tireotropina/genética , Tiroxina/sangue , Tri-Iodotironina/farmacologiaRESUMO
Thyroid hormone, acting through several nuclear hormone receptors, plays important roles in thermogenesis, lipogenesis and maturation of the neonatal brain. The receptor specificity for mediating these effects is largely unknown, and to determine this we developed mice lacking the thyroid hormone receptor TR alpha 1. The mice have an average heart rate 20% lower than that of control animals, both under normal conditions and after thyroid hormone stimulation. Electrocardiograms show that the mice also have prolonged QRS- and QTend-durations. The mice have a body temperature 0.5 degrees C lower than normal and exhibit a mild hypothyroidism, whereas their overall behavior and reproduction are normal. The results identify specific and important roles for TR alpha 1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarisation and control of body temperature.
Assuntos
Temperatura Corporal/genética , Frequência Cardíaca/genética , Receptores dos Hormônios Tireóideos/deficiência , Receptores dos Hormônios Tireóideos/genética , Animais , Bradicardia/genética , Bradicardia/fisiopatologia , Linhagem Celular , Feminino , Deleção de Genes , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco , Hormônios Tireóideos/sangue , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/fisiologiaRESUMO
OBJECTIVE: The effects of single and combined nutritional selenium and iodine deficiency on intracellular thyroid hormone concentrations and type II 5'-iodothyronine deiodinase (5'D-II) activity were examined in different regions of the adult rat brain. DESIGN: Four groups (n = 6) of weanling female Wistar rats proceeding from a breeding line fed a selenium-deficient or a selenium-replete diet for 3 generations, were fed selenium-deficient, iodine-deficient, combined selenium- and iodine-deficient or selenium- and iodine-replete diets for 2 months before they were killed. METHODS: Tissue thyroxine (T4) and tri-iodothyronine (T3) concentrations were determined by highly sensitive RIAs after extraction of the iodothyronines from the tissue samples. The measurement of 5'D-II was based on the release of radioiodide from the 125I-labelled substrate. RESULTS: Selenium deficiency significantly decreased tissue T3 concentrations in the hippocampus, hypothalamus and striatum to 70-80% of controls, whereas no significant changes were found in the cerebellum, cerebral cortex and brain stem. Tissue T4 concentrations were only marginally affected with the exception of a 35% increase in the cerebral cortex. Iodine deficiency dramatically diminished serum T4 levels as well as intracellular T4 concentrations in all regions examined up to 10-30% of control. In spite of a threefold enhancement of 5'D-II, the iodine-deficient animals still had a significant reduction of tissue T3 concentrations (50-65% of controls) in all regions excepting the cerebellum. The combination of selenium and iodine deficiency did not significantly alter this pattern of changes. CONCLUSIONS: These findings suggest that prolonged selenium deficiency as well as iodine deficiency may compromise thyroid hormone homeostasis in the adult brain leading to tissue hypothyroidism and therefore to impaired brain function.
Assuntos
Encéfalo/metabolismo , Iodo/deficiência , Selênio/deficiência , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Animais , Feminino , Membranas Intracelulares/metabolismo , Iodeto Peroxidase/metabolismo , Concentração Osmolar , Ratos , Ratos Wistar , Tiroxina/sangue , Distribuição TecidualRESUMO
The 24-h patterns of tissue thyroid hormone concentrations and type II 5'- and type III 5-iodothyronine deiodinase (5'D-II and 5D-III, respectively) activities were determined at 4-h intervals in different brain regions of male euthyroid rats entrained to a regular 12-h light/12-h dark cycle (lights on at 6:00 a.m.). Activity of 5'D-II, which catalyzes the intracellular conversion of thyroxine (T4) to 3,3',5-triiodo-L-thyronine (T3) in the CNS, and the tissue concentrations of both T4 and T3 exhibited significant daily variations in all brain regions examined. Periodic regression analysis revealed significant circadian rhythms with amplitudes ranging from 9 to 23% (for T3) and from 15 to 40% (for T4 and 5'D-II) of the daily mean value. 5'D-II activity showed a marked nocturnal increase (1.3-2.1-fold vs. daytime basal value), with a maximum at the end of the dark period and a minimum between noon and 4:00 p.m. 5D-III did not exhibit circadian patterns of variation in any of the brain tissues investigated. Our results disclose circadian rhythms of 5'D-II activity and thyroid hormone concentrations in discrete brain regions of rats entrained to a regular 12:12-h light-dark cycle and reveal that, in the rat CNS, T3 biosynthesis is activated during the dark phase of the photoperiod. For all parameters under investigation, the patterns of variation observed were in part regionally specific, indicating that different regulatory mechanisms may be involved in generating the observed rhythms.
Assuntos
Encéfalo/enzimologia , Ritmo Circadiano/fisiologia , Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/sangue , Análise de Variância , Animais , Comportamento Animal/fisiologia , Química Encefálica/fisiologia , Expressão Gênica/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Hormônios Tireóideos/análise , Hormônios Tireóideos/genética , Tireotropina/análise , Tireotropina/sangue , Tireotropina/genética , Tiroxina/análise , Tiroxina/sangue , Tiroxina/genética , Tri-Iodotironina/análise , Tri-Iodotironina/sangue , Tri-Iodotironina/genéticaRESUMO
The effects of lithium (LI) and carbamazepine (CBM) on thyroid hormone metabolism were investigated in 11 regions of the brain and three peripheral tissues in rats decapitated at three different times of day (4:00 A.M., 1:00 P.M., and 8:00 P.M.). Interest was focused on the changes in the two enzymes that catalyze: (1) the 5'deiodination of T4 to the biologically active T3, i.e., type II 5'deiodinase (5'D-II) and (2) the 5 (or inner-ring) deiodination of T3 to the biologically inactive 3'3-T2, i.e., type III 5 deiodinase (5D-III). A 14-day treatment with both LI and CBM induced significant reductions in 5D-III activity. However, 5'D-II activity was elevated by CBM and reduced by LI, both administered in concentrations leading to serum levels comparable with those seen in the prophylactic treatment of affective disorders. The effects were dose dependent, varied according to the region of the brain under investigation, and strongly depended on the time of death within the 24-hour rhythm. The consequences of these complex effects of LI and CBM on deiodinase activities for thyroid hormone function in the CNS and also their possible involvement in the mechanisms underlying the mood-stabilizing effects of both LI and CBM remain to be investigated.
Assuntos
Anticonvulsivantes/farmacologia , Antimaníacos/farmacologia , Química Encefálica/efeitos dos fármacos , Carbamazepina/farmacologia , Cloreto de Lítio/farmacologia , Hormônios Tireóideos/metabolismo , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Antimaníacos/administração & dosagem , Antimaníacos/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Carbamazepina/administração & dosagem , Carbamazepina/sangue , Relação Dose-Resposta a Droga , Iodeto Peroxidase/metabolismo , Cloreto de Lítio/administração & dosagem , Cloreto de Lítio/sangue , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Serum concentrations of thyroxine (T4), triiodothyronine (T3), and thyrotropine were measured in 34 patients with nonseasonal affective disorders before and after 1 week of light treatment. Nineteen of these patients received bright white light (2500 lx) and 15 dim red light (50 lx) for 2 hours daily in the mornings over a 1-week period. Slight but significant reductions in the rating scores for the depressive symptomatology were found for both the bright-and dim-light groups, but there were no significant differences between the two groups. The improvement is thus most likely a placebo effect. Surprisingly, the small changes in the severity of the depressive symptoms in the group as a whole were significantly correlated to the changes in the serum levels of T4 during the weeks of bright- and dim-light treatment, respectively. The more a patient improved, the further his or her T4 level fell and vice versa. The fluctuations in the concentrations of T4 during light treatment were significantly greater in the depressed patients than in a group of 12 healthy controls who also received bright or dim light, whereas the changes in T3 were significantly smaller than those of the healthy controls. The pronounced fluctuations in T4 levels were probably not secondary to changes in mood. Rather, they are likely to reflect changes in tissue (intracellular) metabolism of T4, which may be involved in the mechanisms underlying the fluctuations in mood in these patients.
Assuntos
Transtorno Depressivo/terapia , Fototerapia , Hormônios Tireóideos/sangue , Adulto , Idoso , Transtorno Depressivo/sangue , Transtorno Depressivo/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inventário de Personalidade , Tireotropina/sangue , Tiroxina/sangue , Resultado do Tratamento , Tri-Iodotironina/sangueRESUMO
In the present study we investigated the biochemical properties of in vitro phenolic (5'D) and tyrosyl (5D) ring deiodination and the tissue concentrations of T4, T3, and rT3 in adult human central nervous system (CNS) tissue. All samples were obtained from nontumoral tissue at autopsy (n = 6) or neurosurgical operation (n = 5). Both phenolic and tyrosyl ring deiodinase activities were demonstrable in all samples obtained intraoperatively, whereas only tyrosyl ring deiodination was evident in the tissues obtained postmortem. The phenolic ring deiodination pathway corresponded to the type II 5'-deiodinase isoenzyme with regard to its high affinity for T4 and rT3 (Km = 2.2 and 2.4 nmol/L, respectively), its insensitivity to 6-propyl-n-2-thiouracil (PTU), and the sequential reaction mechanism. No PTU-sensitive 5'-deiodination of rT3 was demonstrable. Tyrosyl ring deiodination of both T4 and T3 showed typical type III 5D kinetics (Ka, 6.5 nmol/L for T4 and 3.4 nmol/L for T3) and was PTU insensitive. Nanomolar concentrations of tissue T4, T3, and rT3 were detected in samples obtained both intraoperatively and postmortem. They were very similar to the absolute values of the apparent Km for T4, T3, and rT3 in the phenolic and tyrosyl ring deiodination pathways. In conclusion, we have demonstrated the coexistence of both phenolic and tyrosyl ring deiodinase activities in the human CNS. Their kinetic characteristics, substrate specificity, and reaction mechanisms are very similar to the corresponding type II 5'- and type III 5-iodothyronine deiodinase activities in rat brain. In contrast to the findings in the rat CNS, no PTU-sensitive phenolic ring deiodinase (i.e. type I 5'D) activity was found in the human CNS. This may explain the relatively high tissue concentrations of rT3.
Assuntos
Encéfalo/metabolismo , Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/metabolismo , Adolescente , Adulto , Idoso , Ativação Enzimática , Feminino , Humanos , Iodeto Peroxidase/química , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Fenol , Fenóis/química , Mudanças Depois da Morte , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Tri-Iodotironina Reversa/metabolismo , Tirosina/químicaRESUMO
The effects of the antidepressant desipramine on the tissue concentrations of thyroxine and triiodothyronine in 9 different regions of the brain and also in the pituitary and liver were investigated in male rats. The investigations were carried out at three different times of the light/dark cycle: 5 a.m., 1 p.m. and 11 p.m. After fourteen days' treatment with 20 mg/kg/day desipramine by gavage the concentrations of triiodothyronine in the frontal and parieto-occipital cortex were significantly higher than in the saline-treated controls, those in the hippocampus lower and those in the 6 remaining brain regions the same. In 8 areas of the brain the concentrations of thyroxine were lower in the desipramine-treated rats and the tissue ratios of triiodothyronine to thyroxine were enhanced in 6 regions. These effects are most likely the result of the action of desipramine on the activity of the isoenzyme 5'II deiodinase. This enzyme catalyzes the deiodination of thyroxine to triiodothyronine in rat brain and its activity has recently been reported to be enhanced by desipramine. The observed effects were dose-dependent and also strongly dependent upon the time within the 24 h light/dark cycle at which the hormone concentrations were measured. No effects of desipramine were seen in the pituitary or liver after 14 days' treatment, or in various areas of the central nervous system 24 h after administration. In view of the psychotropic properties of thyroid hormones, it seems possible that the observed increases in triiodothyronine concentrations, particularly in cortical areas, are involved in the mechanisms of action of desipramine.
Assuntos
Química Encefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Desipramina/farmacologia , Hormônios Tireóideos/análise , Administração Oral , Animais , Cerebelo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Hipófise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Thyroxine (T4), free T4 (fT4), triiodothyronine (T3), free T3 (fT3), reverse T3 (rT3), thyrotropin (TSH), thyroxine binding globulin (TBG), and T3 uptake were measured in 14 chronic alcoholics during withdrawal and after 21 days of abstinence. Results were compared with those of 16 healthy volunteers. During withdrawal, the fT4 and fT3 concentrations were subnormal, whereas the respective protein-bound fractions were normal. T4, T3, and TBG increased during the abstinence period, T3 and TBG being significantly higher than in normals at the second measuring time. T3 uptake values fell, but remained well within the normal range at both measuring times. During abstinence, the fT3 levels remained significantly lower than in healthy subjects. rT3 concentrations decreased, but not significantly. The TSH values were normal throughout. These results showed numerous abnormalities in the hypothalamic-pituitary-thyroid axis in alcoholics, the reasons for which are as yet unclear. The following possible interpretations are suggested: 1. The abnormally low serum fT3 and fT4 levels during withdrawal might reflect an increase in tissue uptake. 2. The increases in T4--and partly those in T3--during abstinence seem to reflect increased binding by TBG, the level of which rose markedly for reasons as yet unknown. 3. If increases in TBG during abstinence are taken into account, the decreases in rT3 concentrations may reach the level of statistical significance. These falls in rT3 concentrations may reflect an increase in rT3 metabolization (deiodination) in various tissues, including the CNS, leading to a reduction in serum rT3 bioavailability. 4. Factors such as liver disease, protein caloric malnutrition, and "psychological stress" do not fully explain all these abnormalities. A direct effect of ethanol on intracellular thyroid hormone metabolism and/or function seems conceivable.