RESUMO
We studied the effects of recombinant growth hormone on systemic nitric oxide (NO) formation and hemodynamics in a double-blind, placebo-controlled trial in adult patients with acquired growth hormone deficiency. 30 patients were randomly allocated to either recombinant human growth hormone (r-hGH; 2.0 IU/d) or placebo for 12 mo. In the subsequent 12 mo, the study was continued with both groups of patients receiving r-hGH. In months 1, 3, 6, 9, and 12 of each year, urine and plasma samples were collected for the determination of urinary nitrate and cyclic GMP as indices of systemic NO production, and of plasma IGF-1 levels. Cardiac output was measured in months 1, 12, and 24 by echocardiography. r-hGH induced a fourfold increase in plasma IGF-1 concentrations within the first month of treatment. Urinary nitrate and cyclic GMP excretion rates were low at baseline in growth hormone-deficient patients (nitrate, 96.8+/-7.4 micromol/mmol creatinine; cyclic GMP, 63.6+/-7.1 nmol/mmol creatinine) as compared with healthy controls (nitrate, 167.3+/-7.5 micromol/mmol creatinine; cyclic GMP, 155.2+/-6.9 nmol/mmol creatinine). These indices of NO production were significantly increased by r-hGH, within the first 12 mo in the GH group, and within the second 12 mo in the placebo group. While systolic and diastolic blood pressure were not significantly altered by r-hGH, cardiac output significantly increased by 30-40%, and total peripheral resistance decreased by approximately 30% in both groups when they were assigned to r-hGH treatment. In the second study year, when both groups were given r-hGH, there were no significant differences in plasma IGF-1, urinary nitrate, or cyclic GMP excretion, or hemodynamic parameters between both groups. In conclusion, systemic NO formation is decreased in untreated growth hormone-deficient patients. Treatment with recombinant human growth hormone normalizes urinary nitrate and cyclic GMP excretion, possibly via IGF-1 stimulation of endothelial NO formation, and concomitantly decreases peripheral arterial resistance. Increased NO formation may be one reason for improved cardiovascular performance of patients with acquired hypopituitarism during growth hormone therapy.
Assuntos
Hormônio do Crescimento/deficiência , Fator de Crescimento Insulin-Like I/metabolismo , Óxido Nítrico/metabolismo , Adulto , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , GMP Cíclico/metabolismo , GMP Cíclico/urina , Feminino , Hormônio do Crescimento/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Lipídeos/sangue , Masculino , Nitratos/metabolismo , Nitratos/urina , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.
Assuntos
Programas de Rastreamento/métodos , Neoplasia Endócrina Múltipla Tipo 1/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , DNA/sangue , DNA/genética , Feminino , Genótipo , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/genética , Núcleo Familiar , Fenótipo , Reação em Cadeia da PolimeraseRESUMO
The nature of the conversion of thyroxine (T4) to triiodothyronine (T3) and reverse triiodothyronine (rT3) was investigated in rat liver homogenate and microsomes. A 6-fold rise of T3 and 2.5-fold rise of rT3 levels determined by specific radioimmunoassays was observed over 6 h after the addition of T4. An enzymic process is suggested that converts T4 to T3 and rT3. For T3 the optimal pH is 6 and for rT3, 9.5. The converting activity for both T3 and rT3 is temperature dependent and can be suppressed by heat, H2O2, merthiolate and by 5-propyl-2-thiouracil. rT3 and to a lesser degree iodide, were able to inhibit the production of T3 in a dose related fashion. Therefore the pH dependency, rT3 and iodide may regulate the availability of T3 or rT3 depending on the metabolic requirements of thyroid hormones.
Assuntos
Fígado/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Animais , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Iodo/farmacologia , Isomerismo , Cinética , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Temperatura , Timerosal/farmacologiaRESUMO
Sex steroids are essential for accretion and maintenance of bone mass. Their importance for osteoporotic fractures in men, however, are undefined. We determined circulating levels of testosterone (T), non-SHBG-bound T (bT), free testosterone (FT), oestradiol (E2), intact parathormone (iPTH), 25-OH-vitamin D (25(OH)D), and trabecular bone mineral density at spinal level (tBMD) by single quantitative computed tomography (QCT), respectively, in elderly men 1-3.5 months after minimal traumatic hip fractures (MTHF, age=75+/-10 ys, n=27). A group of patients with non-immobilising stroke (S; age=73+/-8 ys, n=12) served as controls. Men with known secondary osteoporosis were excluded from the study. Furthermore, serum levels of T and E2 were compared to healthy controls aged 20-30 years (n=138) and 60-80 years (n=110). In addition a literature-based analysis of studies on testosterone in men hip fractures were conducted. Mean tBMD of men with MTFH (52.7+/-17.6 mg/cm3, T-score=- 4.5+/-0.6) was significantly lower than in men with S (78+/-16.3 mg/cm3, T-score=- 3.5+/-0.8). Significant differences of the means between both groups were observed for T, bT, and FT but not for E2, 25(OH)D, and iPTH, respectively. About 90 % of men with MTHF had T serum levels 2 SD below the mean of young controls. This proportion reduced to 30 % if compared with serum levels of 60-80-year-old healthy men whereas men after S remained well within the normal range adjusted for age. Mean serum levels of iPTH were within the normal range (1-6.8 pmol/l); 25(OH)D serum levels were at the lower end of the normal control levels (30-190 nmol/l). There was an inverse relationship between iPTH and 25(OH)D (r=- 0,4; p<0,03). In conclusion, low serum T is common in men with MTHF and only partly due to age. It appears to be a primary factor in fragility fractures in men and not simply secondary to morbidity following the fracture. In view of the scarce and inconsistent data published on this issue (1 longitudinal and 6 cross-sectional studies) the present study supports the patho-physiological relevance of low serum testosterone for the occurrence of MTHF in men.
Assuntos
Fraturas do Quadril/sangue , Testosterona/sangue , Idoso , Densidade Óssea , Estudos de Casos e Controles , Estudos Transversais , Estradiol/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Valores de Referência , Coluna Vertebral/anatomia & histologia , Ferimentos e LesõesRESUMO
ATP released from damaged cells or by controlled secretion could be an important factor in the formation or remodeling of bone. In a variety of other tissues ATP has been shown to control cellular processes by acting on P2-purinoceptors and activating the calcium signaling pathway. Here we demonstrate for the first time that extracellular ATP increases the intracellular free calcium [Ca2+]i concentration in normal human osteoblasts and in SaOS-2 cells, a human osteosarcoma-derived cell line, but not in ROS 17/2.8 cells. The ATP-induced increase in [Ca2+]i was dose dependent, and the concentrations of ATP required were similar to those reported to regulate cellular functions in other cell types. Although ATP is metabolized rapidly by bone cells, the effects on [Ca2+]i appeared to be mediated directly by ATP rather than one of its metabolites. Adenosine 3-thiotriphosphate, a nonhydrolyzable analog of ATP, induced similar changes in [Ca2+]i. This indicates that P2-purinoceptors are present on osteoblast-like cells and that extracellular ATP from various sources might be an important factor in the regulation of osteoblast functions.
Assuntos
Trifosfato de Adenosina/fisiologia , Desenvolvimento Ósseo/fisiologia , Remodelação Óssea/fisiologia , Osteoblastos/química , Receptores Purinérgicos/análise , Trifosfato de Adenosina/metabolismo , Cálcio/análise , Linhagem Celular , Células Cultivadas , Fura-2 , Humanos , Fotofluorografia , Valores de Referência , Espectrometria de FluorescênciaRESUMO
In the present study, the bombesin-induced changes in cytosolic free Ca2+ ([Ca2+]i) were investigated in single Fura-2 loaded SV-40 transformed hamster beta-cells (HIT). Bombesin (50-500 pM) caused frequency-modulated repetitive Ca2+ transients. The average frequency of the Ca2+ transients induced by bombesin (200 pM) was 0.58 +/- 0.02 min-1 (n = 121 cells). High concentrations of bombesin (> or = 2 nM) triggered a large initial Ca2+ transient followed by a sustained plateau or by a decrease to basal levels. In Ca(2+)- free medium, bombesin caused only one or two Ca2+ transients and withdrawal of extracellular Ca2+ abolished the Ca2+ transients. The voltage-dependent Ca2+ channel (VDCC) blockers, verapamil (50 microM) and nifedipine (10 microM), reduced amplitude and frequency of the Ca2+ transients and stopped the Ca2+ transients in some cells. Thapsigargin caused a sustained rise in [Ca2+]i in the presence of extracellular Ca2+ while in its absence the rise in [Ca2+]i was transient. Verapamil (50 microM) inhibited the thapsigargin-induced increase in [Ca2+]i by about 50%. Depletion of intracellular Ca2+ stores by repetitive stimulation with increasing concentrations of bombesin or thapsigargin in Ca(2+)-free medium caused an agonist-independent increase in [Ca2+]i when extracellular Ca2+ was restored, which was larger than in control cells that had been incubated in Ca(2+)-free medium for the same period of time. This rise in [Ca2+]i and the thapsigargin-induced increase in [Ca2+]i were only partly inhibited by VDCC-blockers. Thus, depletion of the agonist-sensitive Ca2+ pool enhances Ca2+ influx through VDCC and voltage-independent Ca2+ channels (VICC). In conclusion, the bombesin-induced Ca2+ response in single HIT cells is periodic in nature with frequency-modulated repetitive Ca2+ transients. Intracellular Ca2+ is mobilized during each Ca2+ transient, but Ca2+ influx through VDCC and VICC is required for maintaining the sustained nature of the Ca2+ response. Ca2+ influx in whole or part is activated by a capacitative Ca2+ entry mechanism.
Assuntos
Bombesina/farmacologia , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Líquido Intracelular/metabolismo , Animais , Bombesina/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Linhagem Celular Transformada , Transformação Celular Viral , Quelantes/farmacologia , Cricetinae , Relação Dose-Resposta a Droga , Ácido Egtázico/farmacologia , Inibidores Enzimáticos/farmacologia , Insulina/metabolismo , Secreção de Insulina , Líquido Intracelular/efeitos dos fármacos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/virologia , Nifedipino/farmacologia , Tapsigargina/farmacologia , Verapamil/farmacologiaRESUMO
5-Monodeiodination of T4 and T3 and 5'-monodeiodination of T4 and rT3 were studied in brain homogenates of male Sprague-Dawley rats, aged 1-60 days. Portions of the homogenates were incubated with the substrates at 37 C for 30 min. The reaction products were estimated by specific RIAs. All of the four reactions were dependent upon time, temperature, pH, and upon the concentrations of substrate, thiol, and tissue protein. Maximal reactions were obtained between 40 and 160 mM dithioerythritol. T4 5'-deiodination proceeded optimally at pH 7.4 and 0.4 microM substrate, the other reactions at pH 8.5 and 10 microM substrate. The four reactions were inactivated by heat (56 C, 30 min) and inhibited by 10(-5) M iopanoic acid. Only rT3 5'-deiodination was inhibited by 3 X 10(-4) M propylthiouracil (greater than 95%). In cerebellum, basal ganglia, brainstem, and hypothalamus both T4 and T3 5-deiodinase activity were very high in perinatal rats [up to 5.56 pmol/(min X mg protein) in hypothalamus], and decreased rapidly with age. In cortex and olfactory bulb these enzyme activities were low after birth, followed by an increase during the growth spurt [up to 632 fmol/(min X mg protein) in olfactory bulb]. T4 and rT3 5'-deiodinase activity in all brain regions studied were at their lowest in perinatal rats. During and after the growth spurt an increase was observed [up to 457 fmol/(min X mg protein) in cerebellum]. The reciprocal course of 5- and 5'-deiodination between birth and growth spurt in most of the brain regions studied might lead to a reduced intracellular thyromimetic activity during the perinatal period.
Assuntos
Encéfalo/enzimologia , Iodeto Peroxidase/metabolismo , Animais , Animais Recém-Nascidos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Ditioeritritol/farmacologia , Concentração de Íons de Hidrogênio , Ácido Iopanoico/farmacologia , Masculino , Adeno-Hipófise/enzimologia , Propiltiouracila/farmacologia , Radioimunoensaio , Ratos , Ratos Endogâmicos , Temperatura , Tiroxina/metabolismo , Fatores de Tempo , Distribuição Tecidual , Tri-Iodotironina/metabolismo , Tri-Iodotironina Reversa/metabolismoRESUMO
Insulin secretion is under multifactorial control by glucose and neurohumoral factors like acetylcholine (ACH), which activate the Ca2+/phospholipase C signaling pathway. All insulin secretagogues elevate cytosolic free Ca2+ ([Ca2+]i) that is central to the stimulation of insulin secretion. The actions of ACH on [Ca2+]i are glucose dependent but the metabolic steps involved are only partly understood. Here we have characterized the metabolic steps by which glucose exerts its synergistic effects on ACH-linked Ca2+-signals. [Ca2+]i was measured in single fura-2 loaded beta-cells. The ACH analog carbachol (3 microM) caused rise in [Ca2+]i that was strongly dependent on the extracellular glucose concentration ranging from 0-10 mM. Iodoacetate, which blocks glycolysis, thereby preventing the generation of NADH and ATP from glucose metabolism, and rotenone or antimycin, which inhibit complex 1 and 2 of the mitochondrial respiratory chain, respectively, inhibited in glucose (6 mM) the carbachol-induced Ca2+ signal to a similar extent as glucose deprivation. This demonstrates that glucose metabolism and generation of ATP through oxidative phosphorylation of energy rich substrates like NADH and FADH2 are required for carbachol-induced Ca2+ signals. While sodium arsenate, which prevents net glycolytic production of ATP without inhibiting glycolysis, had no significant effect on the carbachol-induced Ca2+-signal, the mitochondrial pyruvate transport inhibitor alpha-cyano-4-hydroxycinnamate and the Krebs cycle inhibitor monofluoroacetate strongly suppressed the rise in [Ca2+]i elicited by carbachol. While pyruvate was ineffective, methyl pyruvate, a membrane-permeant pyruvate analog, and alpha-ketoisocaproate in combination with glutamine, which are both substrates for mitochondrial ATP production, could restore the carbachol-induced Ca2+ signal in glucose-free medium. These data demonstrate for the first time that Krebs cycle metabolism of glucose and ATP formation through oxidative phosphorylation is critical for the glucose dependency of ACH-linked Ca2+-signals in mouse beta-cells, and they suggest that mitochondrial metabolism plays a key role in the interactive regulation of beta-cells by neurohumoral factors activating the Ca2+/phospholipase C signaling pathway.
Assuntos
Cálcio/metabolismo , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Metabolismo Energético , Ilhotas Pancreáticas/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Células Cultivadas , Meios de Cultura , Feminino , Glucose/metabolismo , Glucose/farmacologia , Glutamina/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Cetoácidos/farmacologia , Camundongos , NAD/metabolismo , Piruvatos/farmacologia , Transdução de Sinais , Fosfolipases Tipo C/metabolismoRESUMO
Neurotransmitters and hormones, by binding to receptors linked to adenylate cyclase or phospholipase C (PLC), increase cytosolic free Ca2+ and potentiate glucose-induced insulin release from beta-cells. Interactions between both signaling pathways may occur and be of relevance to the regulation of insulin secretion. We demonstrate here that in single insulin-secreting HIT cells, forskolin and 8-bromo-cAMP, which stimulate Ca2+ influx through voltage-dependent Ca2+ channels (VDCC), cause a marked increase in the frequency, amplitude, and duration of Ca2+ transients evoked by hormones linked to PLC, such as arginine vasopressin (AVP) or bombesin. Forskolin also potentiates AVP- or bombesin-induced insulin secretion from populations of HIT cells in the presence of elevated glucose (10 mM). BAY K 8644, an activator of VDCC, mimicked the effects of elevated cAMP on both AVP- and bombesin-induced Ca2+ transients and insulin release, which suggests that enhanced Ca2+ influx through VDCC activated by cAMP-dependent mechanisms underlies the positive interactions of both signaling pathways on Ca2+ signaling and insulin secretion. Physiologically, synergistic cross-signaling between the cAMP- and Ca2+ -phosphoinositide signaling pathway could be important for the regulation of insulin release under conditions where extracellular glucose is high and beta-cells are exposed to multiple stimuli activating adenylate cyclase or PLC at the same time.
Assuntos
8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Cálcio/metabolismo , Colforsina/farmacologia , AMP Cíclico/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/fisiologia , Transdução de Sinais , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Animais , Arginina Vasopressina/farmacologia , Bombesina/farmacologia , ATPases Transportadoras de Cálcio/antagonistas & inibidores , Linhagem Celular , Cricetinae , Ácido Egtázico/farmacologia , Inibidores Enzimáticos/farmacologia , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Cinética , Mesocricetus , Nifedipino/farmacologia , Transdução de Sinais/efeitos dos fármacos , Terpenos/farmacologia , Tapsigargina , Fatores de TempoRESUMO
Neurotransmitters and hormones, such as arginine vasopressin (AVP) and bombesin, evoke frequency-modulated repetitive Ca2+ transients in insulin-secreting HIT-T15 cells by binding to receptors linked to phospholipase C (PLC). The role of calmodulin (CaM)-dependent mechanisms in the generation of PLC-linked Ca2+ transients was investigated by use of the naphthalenesulfonamide CaM antagonists W-7 and W-13 and their dechlorinated control analogs W-5 and W-12. W-7 (10-30 microM) and W-13 (30-100 microM), but not W-5 (100 microM) and W-12 (300 microM), reversibly inhibited the AVP- and bombesin-induced Ca2+ transients. As the generation of PLC-linked Ca2+ transients requires mobilization of internal Ca2+ and Ca2+ influx through voltage-sensitive (VSCC) and -insensitive (VICC) Ca2+ channels, the effects of the W compounds on these processes were further investigated. First, W-7 dose dependently diminished K+ (45 mM)-induced Ca2+ signals (IC50, approximately 25 microM), and W-13 (100 microM) reduced the K+ (45 mM)-induced [Ca2+]i rise by about 40-60%, whereas W-5 (100 microM) and W-12 (300 microM) had no effect. In addition, W-7 (100 microM) inhibited whole cell Ca2+ currents in mouse beta-cells by about 60%. Second, pretreatment of cells (5 min) with W-7 (30 microM), but not W-5 (30 microM), inhibited agonist-induced internal Ca2+ mobilization by about 75% in Ca2+-free medium. Neither W-7 (30 microM) nor W-5 (30 microM) affected AVP (100 nM)-stimulated formation of IP3. Third, capacitative Ca2+ influx through VICC activated by thapsigargin (2 microM) in the presence of verapamil (50 microM) was inhibited by W-7 (30 microM) but not by W-5 (30 microM). As all of the W compound effects corresponded well to their reported anticalmodulin activity, a specific anticalmodulin action can be assumed. Thus, Ca2+ via activation of CaM-dependent processes could provide positive feedback on the generation of PLC-linked Ca2+ transients in HIT-T15 cells. This appears to involve CaM-dependent regulation of both mobilization of internal Ca2+ and Ca2+ influx through VSCC and VICC.
Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Calmodulina/antagonistas & inibidores , Ilhotas Pancreáticas/metabolismo , Fosfolipases Tipo C/metabolismo , Animais , Arginina Vasopressina/farmacologia , Bombesina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Membrana Celular/metabolismo , Cricetinae , Condutividade Elétrica , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Insulinoma , Neoplasias Pancreáticas , Sulfonamidas/farmacologia , Células Tumorais CultivadasRESUMO
Somatostatin, a growth hormone inhibiting factor (GHIF), was infused into 8 patients with primary hypothyroidism at a dosage of 1000 mug for 105 min. GHIF caused a suppression of TSH levels from 42.6 to 76.9% of preinfusion levels with a mean nadir of 65.0 +/- 4.0%;(mean +/- SEM).
Assuntos
Hipotireoidismo/fisiopatologia , Somatostatina , Tireotropina/antagonistas & inibidores , Idoso , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/diagnóstico , Pessoa de Meia-Idade , Hipófise/fisiopatologia , Tireotropina/sangueRESUMO
Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing's syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 +/- 2.7 yr; body mass index (BMI), 29.6 +/- 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 +/- 3.1 yr; BMI, 26.3 +/- 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing's syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing's syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.
Assuntos
Síndrome de Cushing/sangue , Proteínas/metabolismo , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Jejum , Feminino , Humanos , Hidrocortisona/sangue , Insulina/sangue , Leptina , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Caracteres SexuaisRESUMO
To determine the mechanism underlying pulsatile TSH secretion, 24-h serum TSH levels were measured in three groups of five healthy volunteers by sampling blood every 10 min. The influence of an 8-h infusion of dopamine (200 mg), somatostatin (500 micrograms), or nifedipine (5 mg) on the pulsatile release of TSH was tested using a cross-over design. The amount of TSH released per pulse was significantly lowered by these drugs, resulting in significantly decreased mean basal TSH serum levels. However, pulses of TSH were still detectable at all times. The TSH response to TRH (200 micrograms) tested in separate experiments was significantly lowered after 3 h of nifedipine infusion compared to the saline control value. Nifedipine treatment did not alter basal, pulsatile, or TRH-stimulated PRL secretion. The persistence of TSH pulses under dopamine and somatostatin treatment and the blunted TSH responses to nifedipine infusion support the hypothesis that pulsatile TSH secretion is under the control of hypothalamic TRH. The 24-h TSH secretion pattern achieved under stimulation with exogenous TRH in two patients with hypothalamic destruction through surgical removal of a craniopharyngioma provided further circumstantial evidence for this assumption. No TSH pulses and low basal TSH secretion were observed under basal conditions (1700-2400 h), whereas subsequent repetitive TRH challenge (25 micrograms/2 h to 50 micrograms/1 h) led to a pulsatile release of TSH with fusion of TSH pulses, resulting in a TSH secretion pattern strikingly similar to the circadian variation. These data suggest that pulsatile and circadian TSH secretions are predominantly controlled by TRH.
Assuntos
Hipotálamo/fisiologia , Tireotropina/metabolismo , Adulto , Ritmo Circadiano , Dopamina/farmacologia , Feminino , Humanos , Masculino , Nifedipino/farmacologia , Periodicidade , Prolactina/metabolismo , Somatostatina/farmacologia , Hormônio Liberador de TireotropinaRESUMO
Idiopathic delayed male puberty is defined as a delay of puberty beyond the age of 16, with prepubertal testosterone levels, normal gonadotropin responses to GnRH (excluding pituitary failure), and normal androgen responses to a single hCG injection (excluding testicular Leydig cell dysfunction), in absence of serious disease. Ten boys with this condition were evaluated as to their spontaneous LH, FSH, and PRL secretory patterns during a 24-h sampling period (20-min intervals). After this all patients were treated with pulsatile infusions of GnRH (25 ng/kg . pulse every 90 min for 10 days. Two groups could be distinguished by means of their pretreatment LH secretory pattern. Five patients had nighttime pulsatile elevation of LH levels, as usually occurs in early puberty. The other five patients did not have such a pattern (prepubertal type). The GnRH treatment resulted in increased LH and testosterone levels in both groups. All patients with pretreatment nighttime pulsatile LH secretion had steady pubertal development during the post-GnRH treatment observation period, whereas the other patients did not. In conclusion, among a number of tests, including chronic pulsatile GnRH treatment for 10 days, only the nocturnal LH secretory pattern differentiated delayed puberty from permanent hypothalamic hypogonadism in boys.
Assuntos
Hormônio Liberador de Gonadotropina/uso terapêutico , Puberdade Tardia/tratamento farmacológico , Adolescente , Adulto , Desidroepiandrosterona/sangue , Desidroepiandrosterona/metabolismo , Esquema de Medicação , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/administração & dosagem , Humanos , Cinética , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Masculino , Prolactina/sangue , Puberdade Tardia/sangue , Puberdade Tardia/genética , Testosterona/sangue , Testosterona/metabolismo , Fatores de TempoRESUMO
The dependency of the secretory pattern of insulin and C-peptide on either oral ingestion of the energy substrates glucose and protein or gastric distension was determined in nine healthy male subjects. To analyze secretion dynamics, high frequency blood sampling, computed estimation of individual hormone half-lives, deconvolution of data, and pulse analysis of the deconvoluted data by the Cluster program were used. After stimulation with oral glucose and protein, baseline insulin, C-peptide, and glucose levels increased in parallel, forming two or three large increases (macropulses), with a mean duration of 63.8 min. The frequency of high frequency insulin and C-peptide pulses was unchanged, whereas a significantly increased amplitude formed the basis of insulin/C-peptide macropulses after both oral stimulations. No changes in baseline insulin/C-peptide concentrations or in amplitude or frequency were observed after a challenge with 400 mL H2O (n = 3). Gastric distension with an equal volume of H2O (400 mL) did not influence pancreatic hormone secretion. Insulin and C-peptide secretions were pulsatile, with a frequency of approximately one pulse per 12 min correlated to C-peptide pulses. When calculated by multiple regression analysis glucose, insulin and C-peptide plasma levels increased simultaneously after the challenge with either glucose or protein, suggesting a neuronal or humoral intestinal-pancreatic regulation of pancreatic hormone secretion. These findings suggest that high frequency insulin and C-peptide pulses form the basis of insulin and C-peptide plasma levels after meal stimulation.
Assuntos
Glicemia/análise , Peptídeo C/metabolismo , Insulina/metabolismo , Fenômenos Fisiológicos da Nutrição , Pâncreas/metabolismo , Administração Oral , Adulto , Proteínas Alimentares/farmacologia , Glucose/farmacologia , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Fluxo Pulsátil , Fatores de Tempo , Água/farmacologiaRESUMO
The mechanisms involved in the rapid glucagon-like peptide-1 (GLP-1) release following glucose ingestion are poorly defined. Besides a direct intestinal stimulation of L cells, humoral and neuronal mechanisms have been discussed. We investigated the temporal pattern of GLP-1 release in five healthy men (aged 27.8 +/- 3.6 yr, body mass index, 23.4 +/- 1.2 kg/m2) after an overnight fast for 60 min under basal conditions and for 60 min after an oral glucose load (OGL; 100 g) in both the presence and absence of atropine (80 ng/kg min, iv). Blood was sampled every 2 min, and data were evaluated for the temporal pattern of GLP-1 secretion by several computer-assisted programs (deconvolution, Pulsar analysis, and Fourier transformation). With all methods a pulsatile pattern of plasma GLP-1 levels with a frequency of five to seven per h was detected; this remained unchanged in the different metabolic states and during atropine treatment. Glucose and GLP-1 plasma levels showed a parallel increase after OGL (OGL without atropine = control: 8.4 +/- 2.9 and 7.9 +/- 3.0 min, respectively). Atropine infusion delayed this increase significantly (16.8 +/- 8.07 and 17.4 +/- 6.61 min, respectively; P < 0.02). In contrast to plasma glucose concentrations (82.7 +/- 0.3% of control; P < 0.05), atropine infusion reduced the integrated GLP-1 pulse amplitude to 56.0 +/- 11.3% of the control levels (P < 0.05). In conclusion, GLP-1 is secreted in a pulsatile manner with a frequency comparable to that of pancreatic hormones. Mean GLP-1 plasma concentrations increase after OGL due to augmented GLP-1 pulse amplitudes but not frequency. The differential effect of atropine on glucose and GLP-1 plasma levels suggest a direct cholinergic muscarinic control of L cells.
Assuntos
Sistema Nervoso Parassimpático/fisiologia , Peptídeos/sangue , Receptores Muscarínicos/fisiologia , Adulto , Atropina/farmacologia , Peptídeo 1 Semelhante ao Glucagon , Glucose/farmacologia , Humanos , Masculino , Antagonistas Muscarínicos/farmacologia , Peptídeos/metabolismo , Fatores de TempoRESUMO
Increases in thyroid cell major histocompatibility complex (MHC) class I and class II expression have been suggested to be an important factor in the development or perpetuation of Graves' disease. It is hypothesized that elevations result in abnormal presentation of thyroid antigens to immune cells, and that iodide and/or methimazole (MMI) are effective therapeutic agents because, at least in part, of their suppression of MHC expression. In this report, we show that Graves' patients pretreated with iodide only 4 days before surgery have lower levels of MHC class I and class II RNA levels in their thyroid tissue than do patients with no iodide pretreatment (P < 0.001 and 0.03, respectively). Because patients in both groups are treated with MMI and because the change is independent of the amounts of MMI used to treat patients, the class I and class II changes cannot be ascribed to MMI. The iodide action to decrease MHC class I and class II RNA levels was duplicated using cultured human thyroid cells in vitro; the iodide effect was dependent on the iodide concentration, was not duplicated by chloride, was not associated with an alteration in cAMP levels or with a change in thyrotropin receptor RNA levels, and was evident in gamma-interferon-treated cells. The data suggest, therefore, that the therapeutic action of iodide in Graves' patients is associated with decreased MHC gene expression, that this action is a direct effect of high concentrations of iodide on the thyroid cells, and that altered MHC gene expression in the target tissue may well be associated with the development or perpetuation of Graves' disease.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Doença de Graves/imunologia , Iodetos/farmacologia , Glândula Tireoide/metabolismo , Adolescente , Adulto , Northern Blotting , Western Blotting , Células Cultivadas , Feminino , Doença de Graves/tratamento farmacológico , Humanos , Iodetos/uso terapêutico , Masculino , Metimazol/farmacologia , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Glândula Tireoide/efeitos dos fármacosRESUMO
The inhibitory action of thyroid hormones (TH) and glucocorticoids on circadian and pulsatile TSH secretion was investigated in groups of five normal men by sampling blood every 10 min for 24 h (start, 1750 h). Serum TSH was measured by a sensitive immunoradiometric assay. Continuous infusion of 50 micrograms T3 or 250 micrograms T4 for 8 h (1900-0300 h) significantly suppressed serum TSH levels (T3, P less than 0.025; T4, P less than 0.05; by paired t test). Administration of 3 g sodium ipodate 7 h before TH infusion did not alter the TSH response to T3, but T4-dependent suppression was abolished. Pulsatile TSH secretion [basally, 5.8 +/- 1.3 (+/- SD) pulses/24 h, as analyzed by the PULSAR program; 6.8 +/- 1.9 by the Cluster program] was not significantly altered by any of the experimental conditions. The additional finding of blunting of the TSH response to TRH after TH alone or ipodate and T3 suggests a predominantly pituitary feedback action of TH exerted via conversion of T4 to T3. In contrast, bolus injections of 4 mg dexamethasone (dex) at 1900 and 2200 h abolished TSH pulses for at least 6 h (PULSAR, 6.6 +/- 1.6 pulses/24 h basally vs. 3.6 +/- 3.0 under dex; Cluster, 7.0 +/- 2.7 pulses/24 h basally vs. 1.6 +/- 1.6 under dex). Dex administration also resulted in a prompt, sustained, and significant suppression of basal TSH (P less than 0.0005). Together with a normal serum TSH response to TRH (in separate experiments 1, 9, and 19 h after dex administration), these data suggest that glucocorticoid feedback occurs at a suprapituitary level.
Assuntos
Ritmo Circadiano/efeitos dos fármacos , Glucocorticoides/farmacologia , Hormônios Tireóideos/farmacologia , Tireotropina/metabolismo , Adulto , Dexametasona/farmacologia , Humanos , Ipodato/farmacologia , Masculino , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tiroxina/farmacologia , Tri-Iodotironina/farmacologiaRESUMO
The effect of elevated serum thyroid hormone concentrations on insulin-induced glucose metabolism was studied in healthy subjects before and after T4 administration (250 micrograms T4/day for 10-14 days). This treatment induced moderate hyperthyroidism (T4, 15.2 micrograms/dl; T3, 200 ng/dl). The following results were obtained. Insulin receptor binding to a 90% enriched monocyte fraction or to mitogen-stimulated cultured T lymphocytes was decreased by T4 administration, whereas insulin binding to erythrocytes was unaffected. Despite down-regulation of cellular insulin receptors, T4 administration did not alter oral glucose tolerance, but increased the disappearance of glucose after an iv load and the amount of glucose metabolized during euglycemic clamp studies infusing 1.0 or 1.5 mU insulin/kg BW X min; no effect was found at insulin infusion rates of 0.5, 2.0, and 4.0 mU/kg X min. At increasing steady state plasma glucose levels (up to 175 mg/dl) and an insulin infusion rate of 1.0 mU/kg BW X min, T4 administration reduced insulin-induced glucose metabolism. We conclude that experimental hyperthyroidism decreases insulin receptor binding but increases insulin-induced glucose metabolism during euglycemia. This may be due to the direct effect of thyroid hormones on glucose metabolism; however, during hyperglycemia, thyroid hormone induced insulin resistance is unequivocal.
Assuntos
Glicemia/metabolismo , Insulina/fisiologia , Hormônios Tireóideos/fisiologia , Administração Oral , Adulto , Teste de Tolerância a Glucose/métodos , Humanos , Hiperglicemia/sangue , Hipertireoidismo/sangue , Hipertireoidismo/induzido quimicamente , Infusões Parenterais , Masculino , Receptor de Insulina/metabolismo , Hormônios Tireóideos/sangue , Tiroxina/farmacologiaRESUMO
The circadian and pulsatile TSH secretion profiles were investigated in 5 females at the time of menstruation and 21 healthy males by sampling blood every 10 min for 24 h. Computer-assisted analysis, i.e. the Cluster and Desade programs, revealed means of 9.9 +/- 1.7 (Cluster) and 11.4 +/- 3.9 (Desade) pulses/24 h. More than 50% of the TSH pulses were detected between 2000-0400 h. Male and female subjects showed no significant difference in the basal mean and pulsatile secretion of TSH or in the TSH response to TRH (200 micrograms). Repetition of the TSH secretion analysis in 4 healthy subjects after 1, 2, and 6 months (2 subjects) revealed a significantly better cross-correlation within than between individuals (P less than 0.0001). We modulate the circadian TSH secretion pattern by acute sleep withdrawal or prolonged sleep after a night of sleep withdrawal in six healthy male volunteers. Sleep withdrawal augmented the nightly TSH secretion (mean serum TSH, 2.1 +/- 1.3 mU/L; mean TSH in sleep, 1.3 +/- 0.5 mU/L; P less than 0.05), whereas sleep after sleep withdrawal almost completely suppressed the circadian variation (mean TSH, 1.1 +/- 0.7 mU/L; P less than 0.01). This modulation is due to a significant decrease in pulse amplitude, but not to an alteration in the frequency or temporal distribution of TSH pulses.