RESUMO
Mkrn3, the maternally imprinted gene encoding the makorin RING-finger protein-3, has recently emerged as putative pubertal repressor, as evidenced by central precocity caused by MKRN3 mutations in humans; yet, the molecular underpinnings of this key regulatory action remain largely unexplored. We report herein that the microRNA, miR-30, with three binding sites in a highly conserved region of its 3' UTR, operates as repressor of Mkrn3 to control pubertal onset. Hypothalamic miR-30b expression increased, while Mkrn3 mRNA and protein content decreased, during rat postnatal maturation. Neonatal estrogen exposure, causing pubertal alterations, enhanced hypothalamic Mkrn3 and suppressed miR-30b expression in female rats. Functional in vitro analyses demonstrated a strong repressive action of miR-30b on Mkrn3 3' UTR. Moreover, central infusion during the juvenile period of target site blockers, tailored to prevent miR-30 binding to Mkrn3 3' UTR, reversed the prepubertal down-regulation of hypothalamic Mkrn3 protein and delayed female puberty. Collectively, our data unveil a novel hypothalamic miRNA pathway, involving miR-30, with a prominent role in the control of puberty via Mkrn3 repression. These findings expand our current understanding of the molecular basis of puberty and its disease states.
Assuntos
Hipotálamo/metabolismo , MicroRNAs/fisiologia , Maturidade Sexual/genética , Ubiquitina-Proteína Ligases/genética , Animais , Sítios de Ligação , Linhagem Celular , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , MicroRNAs/metabolismo , Ratos , Análise de Sequência de DNARESUMO
microRNAs (miRNAs) are a class of small endogenous RNA that play pivotal roles in both the differentiation and function of adipocytes during the development of obesity. Despite this, only a few miRNA families have been identified as key players in adipogenesis. Here, we show the relevance of the miR-19 family, miR-19a and miR-19b, in lipid accumulation and the expansion of the adipose tissue in obesity. We observed that miR-19s were upregulated in the abdominal subcutaneous adipose tissue (aSAT) of human patients with morbid obesity, whereas after bariatric surgery, their expression was reduced. In vitro experiments identified miR-19a and b as crucial actors in adipogenesis and lipid accumulation. Overall, our results suggest a novel role of the miR-19 family in the regulatory networks underlying adipogenesis and, therefore, adipose tissue dysfunction.
Assuntos
MicroRNAs , PPAR gama , Humanos , Regulação para Baixo/genética , PPAR gama/genética , PPAR gama/metabolismo , Redes Reguladoras de Genes , Adipogenia/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade/genética , Lipídeos , Diferenciação Celular/genéticaRESUMO
BACKGROUND: Ectopic pregnancy is a life-threatening condition for which novel screening tools that would enable early accurate diagnosis would improve clinical outcomes. Kisspeptins, encoded by KISS1, play an essential role in human reproduction, at least partially by regulating placental function and possibly embryo implantation. Kisspeptin levels are elevated massively in normal pregnancy and reportedly altered in various gestational pathologic diseases. Yet, the pathophysiologic role of KISS1/kisspeptin in ectopic pregnancy has not been investigated previously. OBJECTIVE: The purpose of this study was to evaluate changes of KISS1/kisspeptin levels in ectopic pregnancy and their underlaying molecular mechanisms and to ascertain the diagnostic implications of these changes. STUDY DESIGN: A total of 122 women with normal pregnancy who underwent voluntary termination of pregnancy and 84 patients who experienced tubal ectopic pregnancy were recruited. Measurements of plasma kisspeptins and KISS1 expression analyses in human embryonic/placental tissue were conducted in ectopic pregnancy and voluntary termination of pregnancy control subjects during the early gestational window (<12 weeks). Putative microRNA regulators of KISS1 were predicted in silico, followed by expression analyses of selected microRNAs and validation of repressive interactions in vitro. Circulating levels of these microRNAs were also assayed in ectopic pregnancy vs voluntary termination of pregnancy. RESULTS: Circulating kisspeptins gradually increased during the first trimester of normal pregnancy but were reduced markedly in ectopic pregnancy. This profile correlated with the expression levels of KISS1 in human embryonic/placental tissue, which increased in voluntary termination of pregnancy but remained suppressed in ectopic pregnancy. Bioinformatic predictions and expression analyses identified miR-27b-3p and miR-324-3p as putative repressors of KISS1 in human embryonic/placental tissue at <12 weeks gestation, when expression of microRNAs was low in voluntary termination of pregnancy control subjects but significantly increased in ectopic pregnancy. Yet, a significant repressive interaction was documented only for miR-324-3p, occurring at the predicted 3'-UTR of KISS1. Interestingly, circulating levels of miR-324-3p, but not of miR-27b-3p, were suppressed distinctly in ectopic pregnancy, despite elevated tissue expression of the pre-microRNA. A decision-tree model that used kisspeptin and miR-324-3p levels was successful in discriminating ectopic pregnancy vs voluntary termination of pregnancy, with a receiver-operating characteristic area under the curve of 0.95±0.02 (95% confidence interval). CONCLUSION: Our results document a significant down-regulation of KISS1/kisspeptins in early stages of ectopic pregnancy via, at least partially, a repressive interaction with miR-324-3p. Our data identify circulating kisspeptins and miR-324-3p as putative biomarkers for accurate screening of ectopic pregnancy at early gestational ages.
Assuntos
Embrião de Mamíferos/metabolismo , Kisspeptinas/metabolismo , MicroRNAs/metabolismo , Placenta/metabolismo , Gravidez Ectópica/diagnóstico , Biomarcadores/metabolismo , Estudos de Casos e Controles , Árvores de Decisões , Regulação para Baixo , Diagnóstico Precoce , Feminino , Idade Gestacional , Humanos , Kisspeptinas/genética , Gravidez , Gravidez Ectópica/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Pharmacological treatment of growth hormone deficiency (GHD) in adults began in clinical practice more than 20 years ago. Since then, a great volume of experience has been accumulated on its effects on the symptoms and biochemical alterations that characterize this hormonal deficiency. The effects on body composition, muscle mass and strength, exercise capacity, glucose and lipid profile, bone metabolism, and quality of life have been fully demonstrated. The advance of knowledge has also taken place in the biological and molecular aspects of the action of this hormone in patients who have completed longitudinal growth. In recent years, several epidemiological studies have reported interesting information about the long-term effects of GH replacement therapy in regard to the possible induction of neoplasms and the potential development of diabetes. In addition, GH hormone receptor polymorphism could potentially influence GH therapy. Long-acting GH are under development to create a more convenient GH dosing profile, while retaining the excellent safety, efficacy, and tolerability of daily GH. In this article we compile the most recent data of GH replacement therapy in adults, as well as the molecular aspects that may condition a different sensitivity to this treatment.
Assuntos
Hormônio do Crescimento/deficiência , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Adulto , Humanos , Medição de RiscoRESUMO
Human genetic studies have revealed that neurokinin B (NKB) and its receptor, neurokinin-3 receptor (NK3R), are essential elements for normal reproduction; however, the precise role of NKB-NK3R signaling in the initiation of puberty remains unknown. We investigated here the regulation of Tac2 and Tacr3 mRNAs (encoding NKB and NK3R, respectively) in female rats and demonstrated that their hypothalamic expression is increased along postnatal maturation. At puberty, both genes were widely expressed throughout the brain, including the lateral hypothalamic area and the arcuate nucleus (ARC)/medial basal hypothalamus, where the expression of Tacr3 increased across pubertal transition. We showed that central administration of senktide (NK3R agonist) induced luteinizing hormone (LH) secretion in prepubertal and peripubertal females. Conversely, chronic infusion of an NK3R antagonist during puberty moderately delayed the timing of vaginal opening (VO) and tended to decrease LH levels. The expression of NKB and its receptor was sensitive to changes in metabolic status during puberty, as reflected by a reduction in Tacr3 (and, to a lesser extent, Tac2) expression in the ARC after a 48 h fast. Yet, acute LH responses to senktide in pubertal females were preserved, if not augmented, under fasting conditions, suggesting sensitization of the NKB-NK3R-gonadotropin-releasing hormone signaling pathway under metabolic distress. Moreover, repeated administration of senktide to female rats with pubertal arrest due to chronic undernutrition rescued VO (in â¼50% of animals) and potently elicited LH release. Altogether, our observations suggest that NKB-NK3R signaling plays a role in pubertal maturation and that its alterations may contribute to pubertal disorders linked to metabolic stress and negative energy balance.
Assuntos
Metaboloma/fisiologia , Neurocinina B/fisiologia , Maturidade Sexual/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/metabolismo , Metabolismo Energético/fisiologia , Feminino , Neurocinina B/metabolismo , Ratos , Ratos Wistar , Receptores da Neurocinina-3/metabolismo , Receptores da Neurocinina-3/fisiologiaRESUMO
The most common endocrine disease in obesity is hypothyroidism and secondary endocrine alterations, including abnormal thyroid function, are frequent in obesity. It is unclear whether impaired thyroid function is the cause or the consequence of increased adiposity; furthermore, there are no clear data regarding the best way to dose levothyroxine for patients with both hypothyroidism and obesity, and the effect of bariatric surgery (BS). The aim of the present article is to review some controversial aspects of the relation between obesity and the thyroid: (1) Thyroid function in obesity and the effect of BS (2) Thyroid hormone treatment (THT) in obese patients with hypothyroidism and the effect of BS. In summary: In morbidly obese patients, TSH is moderately increased. Morbid obesity has a mild central resistance to the thyroid hormone, reversible with weight loss. In morbidly obese hypothyroid patients, following weight loss, the levothyroxine dose/kg of ideal weight did not change, albeit there was an increment in the levothyroxine dose/kg of actual weight. From a clinical practice perspective, in morbid obesity, diagnosing mild hypothyroidism is difficult, BS improves the altered thyroid function and THT can be adapted better if it is based on ideal weight.
RESUMO
The most frequent endocrine disease in obese patients is hypothyroidism. To date, there are no clear data regarding what happens to the dose of levothyroxine (LT4) after bariatric surgery (BS). The objective of the present study was to evaluate thyroid hormone replacement dose in morbidly obese hypothyroid patients after BS-induced weight loss. We explore the best type of measured or estimated body weight for LT4 dosing. We performed an observational study evaluating patients with morbid obesity and hypothyroidism who underwent BS. We included 48 patients (three men). In morbidly obese hypothyroid patients 12 months after BS-induced weight loss, the total LT4 dose or the LT4 dose/kg ideal body weight did not change, while there was a significant increase in LT4 dose/body surface area, LT4 dose/kg weight, LT4 dose/kg adjusted body weight, LT4 dose/kg body fat, and LT4 dose/kg lean body weight. There were no differences in LT4 dose and its variation between sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). The present study strongly suggests that LT4 dosing in obese hypothyroid patients can be individually adapted more precisely if it is based on ideal body weight.
RESUMO
The aim of the present study was to evaluate the relationship between GHRH-induced GH secretion in obese premenopausal women and cardiovascular risk markers or insulin resistance. Premenopausal obese women, aged 35-52 years, were studied. GH secretion, IGF-I, serum cardiovascular risk markers, insulin, leptin, mid-waist and hip circumference, total body fat, and truncal fat were measured. Subjects were classified as meeting the criteria for GH deficiency (GHD) when peak GH after stimulation with GHRH was Assuntos
Doenças Cardiovasculares/sangue
, Hormônio Liberador de Hormônio do Crescimento/metabolismo
, Hormônio do Crescimento Humano/metabolismo
, Obesidade/metabolismo
, Tecido Adiposo
, Adulto
, Doenças Cardiovasculares/diagnóstico
, HDL-Colesterol/metabolismo
, LDL-Colesterol/metabolismo
, Feminino
, Hormônio do Crescimento/deficiência
, Humanos
, Resistência à Insulina
, Síndrome Metabólica/sangue
, Síndrome Metabólica/diagnóstico
, Pessoa de Meia-Idade
, Obesidade/complicações
, Fatores de Risco
RESUMO
Endocrine disorders are common in obesity, including altered somatotropic axis. Obesity is characterized by reduced growth hormone (GH) secretion, although the insulin-like growth factor-1 (IGF-1) values are controversial. The aim of this study was to evaluate the effect of weight loss after bariatric surgery in the GH-IGF-1 axis in extreme obesity, in order to investigate IGF-1 values and the mechanism responsible for the alteration of the GH-IGF-1 axis in obesity. We performed an interventional trial in morbidly obese patients who underwent bariatric surgery. We included 116 patients (97 women) and 41 controls (30 women). The primary endpoint was circulating GH and IGF-1 values. Circulating IGF-1 values were lower in the obese patients than in the controls. Circulating GH and IGF-1 values increased significantly over time after surgery. Post-surgery changes in IGF-1 and GH values were significantly negatively correlated with changes in C-reactive protein (CRP) and free T4 values. After adjusting for preoperative body mass index (BMI), free T4 and CRP in a multivariate model, only CRP was independently associated with IGF-1 values in the follow-up. In summary, severe obesity is characterized by a functional hyposomatotropism at central and peripheral level that is progressively reversible with weight loss, and low-grade chronic inflammation could be the principal mediator.
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Endocrine abnormalities are common in obesity, including altered thyroid function. The altered thyroid function of obesity may be due to a mild acquired resistance to the thyroid hormone. The aim of this study was to investigate the effect of weight loss after bariatric surgery (BS) on resistance to thyroid hormones in patients with extreme obesity compared with a control group. We performed an observational study evaluating patients with extreme obesity who underwent BS. We included 106 patients (83 women) and 38 controls (24 women). The primary endpoint was the thyrotroph thyroxine resistance index (TT4RI) and thyroid stimulating hormone (TSH) index (TSHRI). The parameters were studied before and after surgery. TSHRI and TT4RI were higher in the obese patients than in the control group. TT4RI and TSHI decreased significantly over time after surgery, with this decrease being associated with the excessive body mass index (BMI) loss and C-reactive protein (CRP). In extreme obesity, BS promotes a significant decrease in the increased TT4RI and TSHI. This decrease of TT4RI and TSHI is progressive over time after BS and significantly associated with excess BMI lost and CRP. Extreme obesity is characterized by a mild reversible central resistance to thyroid hormones.
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Bariatric surgery (BS) is the most effective treatment for obesity and has a positive impact on cardiometabolic risk and in the remission of type 2 diabetes. Following BS, the majority of fat mass is lost from the subcutaneous adipose tissue depot (SAT). However, the changes in this depot and functions and as well as its relative contribution to the beneficial effects of this surgery are still controversial. With the aim of studying altered proteins and molecular pathways in abdominal SAT (aSAT) after body weight normalization induced by BS, we carried out a proteomic approach sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis. These results were complemented by Western blot, electron microscopy and RT-qPCR. With all of the working tools mentioned, we confirmed that after BS, up-regulated proteins were associated with metabolism, the citric acid cycle and respiratory electron transport, triglyceride catabolism and metabolism, formation of ATP, pyruvate metabolism, glycolysis/gluconeogenesis and thermogenesis among others. In contrast, proteins with decreased values are part of the biological pathways related to the immune system. We also confirmed that obesity caused a significant decrease in mitochondrial density and coverage, which was corrected by BS. Together, these findings reveal specific molecular mechanisms, genes and proteins that improve adipose tissue function after BS characterized by lower inflammation, increased glucose uptake, higher insulin sensitivity, higher de novo lipogenesis, increased mitochondrial function and decreased adipocyte size.
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INTRODUCTION: Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue. RESEARCH DESIGN AND METHODS: We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up. RESULTS: Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction. CONCLUSIONS: Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.
Assuntos
Cirurgia Bariátrica , Fenômenos Bioquímicos , Diabetes Mellitus Tipo 2 , MicroRNAs , Obesidade Mórbida , Humanos , MicroRNAs/genética , Obesidade Mórbida/genética , Obesidade Mórbida/cirurgiaRESUMO
The first "growth hormone secretagogues" (GHSs) were discovered by Bowers et al. in 1977. In 1996 the GHSs receptor (GHS-R 1a) was cloned. The endogenous ligand for this receptor, ghrelin, was not identified until 1999. Synthetic molecules termed GHSs are substances that stimulate growth hormone (GH) release, via a separate pathway distinct from GH releasing hormone (GHRH)/somatostatin. Ghrelin displays strong GH-releasing activity through the activation of the GHS-R 1a. Apart from stimulating GH secretion, ghrelin and many synthetic GHSs: 1) stimulate prolactin and ACTH secretion; 2) negatively influence the pituitary-gonadal axis; 3) stimulate appetite and positive energy balance; 4) modulate pancreatic endocrine function and affect glucose levels; 5) have cardiovascular actions. The control of ghrelin secretion is not well established at present, although nutrition is an important regulator. Investigators have exploited the ability of GHSs and ghrelin to release GH by mechanisms different from GHRH as a diagnostic tool, which is the present main clinical use of some GHSs. As an alternative to GH, GH deficient conditions could be treated with any substance which would release endogenous GH, such as synthetic GHSs. It is likely that GHSs, acting as either agonists or antagonists on different pathophysiological processes, might have some other clinical impact and therapeutic potential. At least theoretically ghrelin receptor antagonists could be anti-obesity drugs, as blockers of the orexigenic signal from the gastrointestinal tract to the brain. Inverse agonists of the ghrelin receptor, by blocking the constitutive receptor activity, might lower the set-point for hunger between meals.
Assuntos
Grelina/administração & dosagem , Hormônio do Crescimento/efeitos dos fármacos , Receptores de Grelina/efeitos dos fármacos , Animais , Fármacos Antiobesidade/farmacologia , Grelina/metabolismo , Hormônio do Crescimento/metabolismo , Humanos , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Receptores de Grelina/metabolismoRESUMO
Obesity is associated with several endocrine abnormalities, including thyroid dysfunction. The objective of this study was to investigate the effect of weight loss after bariatric surgery on thyroid-stimulating hormone (TSH) levels in euthyroid patients with morbid obesity. We performed an observational study, evaluating patients with morbid obesity submitted to bariatric surgery. We included 129 patients (92 women) and 31 controls (21 women). Clinical, anthropometric, biochemical, and hormonal parameters were evaluated. The primary endpoint was circulating TSH (µU/mL). Fasting TSH levels were higher in the obese group (3.3 ± 0.2) than in the control group (2.1 ± 0.2). The mean excessive body mass index (BMI) loss (EBMIL) 12 months after bariatric surgery was 72.7 ± 2.1%. TSH levels significantly decreased in the obese patients after surgery; 3.3 ± 0.2 vs. 2.1 ± 0.2 before and 12 months after surgery, respectively. Free thyroxine (T4) (ng/dL) levels significantly decreased in the obese patients after surgery; 1.47 ± 0.02 vs. 1.12 ± 0.02 before and 12 months after surgery, respectively. TSH decreased significantly over time, and the decrement was associated with the EBMIL. In euthyroid patients with morbid obesity, weight loss induced by bariatric surgery promotes a significant decline of the increased TSH levels. This decrement of TSH is progressive over time after surgery and significantly associated with excess BMI loss.
Assuntos
Cirurgia Bariátrica , Obesidade Mórbida/cirurgia , Glândula Tireoide/metabolismo , Tireotropina/sangue , Redução de Peso , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/fisiopatologia , Estudos Retrospectivos , Glândula Tireoide/fisiopatologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Evidence suggests that the adipocyte-derived hormone resistin (RSTN) directly regulates both feeding and peripheral metabolism through, so far, undefined hypothalamic-mediated mechanisms. Here, we demonstrate that the anorectic effect of RSTN is associated with inappropriately decreased mRNA expression of orexigenic (agouti-related protein and neuropeptide Y) and increased mRNA expression of anorexigenic (cocaine and amphetamine-regulated transcript) neuropeptides in the arcuate nucleus of the hypothalamus. Of interest, RSTN also exerts a profound nutrition-dependent inhibitory effect on hypothalamic fatty acid metabolism, as indicated by increased phosphorylation levels of both AMP-activated protein kinase and its downstream target acetyl-coenzyme A carboxylase, associated with decreased expression of fatty acid synthase in the ventromedial nucleus of the hypothalamus. In addition, we also demonstrate that chronic central RSTN infusion results in decreased body weight and major changes in peripheral expression of lipogenic enzymes, in a tissue-specific and nutrition-dependent manner. Thus, in the fed state central RSTN is associated with induced expression of fatty acid synthesis enzymes and proinflammatory cytokines in liver, whereas its administration in the fasted state does so in white adipose tissue. Overall, our results indicate that RSTN controls feeding and peripheral lipid metabolism and suggest that hepatic RSTN-induced insulin resistance may be mediated by central activation of de novo lipogenesis in liver.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Hipotálamo/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Resistina/farmacologia , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Ingestão de Alimentos/efeitos dos fármacos , Jejum/metabolismo , Hipotálamo/metabolismo , Injeções Intraventriculares , Resistência à Insulina/fisiologia , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Resistina/administração & dosagem , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Malnutrition is very prevalent among patients with chronic renal failure. The role of derangements in the gut-brain axis for regulation of appetite in the genesis of anorexia of these patients has not been adequately investigated. Design. Following a randomized, crossover design, we analysed plasma levels of peptide YY (PYY)(1-36) and PYY(3-36) both fasting and after a standardized oral mixed meal or intraperitoneal glucose infusion in 10 stable uraemic patients undergoing peritoneal dialysis and 8 healthy controls, matched for age, gender and body mass index. Main results. Median baseline plasma levels of PYY(1-36) in the different provocation tests oscillated between 406 and 460 pg/mL in patients, as compared with 73 and 100 pg/mL in controls (P < 0.001). Corresponding values for PYY(3-36) oscillated between 235 and 267 pg/mL in patients, versus 56 and 70 pg/mL in controls (P < 0.001). The association of high levels of PYY(3-36) and normal levels of acylated ghrelin (when compared with healthy controls) configurated a markedly pro-anorexigenic pattern in patients. Neither oral intake nor intraperitoneal glucose resulted in significant changes in plasma levels of PYY(1-36) or PYY(3-36) in subjects with renal failure, in contrast with the expected postprandial rise observed in healthy controls (41% for PYY(1-36), P = 0.04 and 32% for PYY(3-36), P = 0.02, median values). CONCLUSIONS: Baseline plasma levels of PYY(1-36) or PYY(3-36) are markedly elevated in patients with renal failure undergoing peritoneal dialysis. Provocation studies disclose a marked disregulation in the postprandial secretion of these anorexigenic peptides, when compared with healthy controls. These findings may contribute to clarify the complex pathogenesis of anorexia of chronic renal failure.
Assuntos
Soluções para Diálise/farmacologia , Alimentos Formulados , Glucose/farmacologia , Peptídeo YY/sangue , Diálise Peritoneal , Insuficiência Renal/sangue , Insuficiência Renal/terapia , Adulto , Idoso , Anorexia/etiologia , Anorexia/fisiopatologia , Apetite/fisiologia , Estudos de Casos e Controles , Doença Crônica , Estudos Cross-Over , Feminino , Glucose/administração & dosagem , Humanos , Infusões Parenterais , Masculino , Desnutrição/etiologia , Desnutrição/fisiopatologia , Pessoa de Meia-Idade , Insuficiência Renal/complicaçõesRESUMO
BACKGROUND: Peptide YY (PYY) is a 36 amino acid peptide synthesized mostly by intestinal L cells. This peptide reaches its nadir during fasting and increases immediately after meals. After food intake, two molecular forms are released, PYY(1-36) and PYY(3-36). PYY(3-36) reduces food intake in both humans and rodents. There is scarce information about plasmatic concentrations of PYY, especially of PYY(3-36), after food ingestion, and their relationship to ghrelin. OBJECTIVES: To study PYY(1-36) and PYY(3-36) secretory response after a mixed meal, and its relationship to total and acylated ghrelin secretion in healthy subjects. SUBJECTS AND METHOD: We studied eight healthy subjects, 4 women and 4 men, with a median age of 53 (range, 36-59) years. After an overnight fast, the subjects received either a mixed standard meal (400ml Isosource Energy® [159kcal/100ml]) or placebo (400ml of water) orally in random order on two different days. Blood samples were obtained at 0, 30, 45, 60 and 120 min for measurement of PYY(1-36), PYY(3-36), total ghrelin and acylated ghrelin. Comparisons were made by Wilcoxon's test. Numerical correlations were performed using Spearman's test. P-values ≤ 0.05 were considered significant. RESULTS: After a mixed meal, PYY(1-36) reached a peak of (median [range]) 141.5 (81-198) pg/ml. There was no response to placebo, with a peak of 92.5 (46-219) pg/ml (p=0.04). The area under the curve (AUC) of PYY(1-36) levels after a mixed meal were 14,865 (8,032-19,822) pg/ml/min and after placebo were 8,992 (4,455-21,382) pg/ml/min (p=0.06). After ingestion of a mixed meal, PYY(3-36) reached a peak of 92.5 (59-135) pg/ml, with no response to placebo (46.5 [30-66] pg/ml) (p = 0.02). The AUC of PYY(3-36) levels after a mixed meal were 9,086 (6,412-14,970) pg/ml/min, and after placebo were 4,984 (3,142-6,772) pg/ml/min (p=0.012). The quotient between nadir total ghrelin/peak PYY(1-36) was markedly diminished after food ingestion, with preprandial values of 7.44 (3.64-14.56) and postprandial values of 3.55 (1.64-7.16) (p=0.03). The former quotient was unmodified by placebo. The quotient between nadir acylated ghrelin/peak PYY(3-36) was markedly diminished after ingestion of a mixed meal, with preprandial values of 2.03 (0.92-3) and postprandial values of 0.73 (0.26-1.27) (p=0.02). This quotient was unmodified by placebo. CONCLUSIONS: In healthy subjects, blood levels of both PYY(1-36) and PYY(3-36) increase after ingestion of a mixed meal. Simultaneously, total and acylated ghrelin levels diminish. The quotient between nadir acylated ghrelin/peak PYY(3-36) diminishes after a mixed meal. All these data suggest the possible contribution of these peptides to appetite regulation after ingestion.
RESUMO
OBJECTIVE: The pathophysiology of ghrelin secretion in acromegaly is unclear. Our aim was to study circulating fasting ghrelin levels and their response to oral glucose in acromegalic patients and normal control subjects. DESIGN AND PATIENTS: 9 acromegalic patients (4 male, 5 female; 59.4+/-3.6 years; 28.6+/-1.0 kg/m2) and 9 age and BMI matched healthy control subjects (4 male, 5 female; 59.1+/-1.4 years; 26.5+/-0.8 kg/m2) were included. We obtained blood samples for glucose, insulin, GH, total ghrelin and acylated ghrelin at times 0, 30, 60, 90 and 120 minutes after 75 g of oral glucose. RESULTS: Fasting GH and IGF-I were statistically different between patients and controls: GH (microg/l): 6.7+/-1.4 vs. 0.8+/-0.4, p<0.01; IGF-I (ng/ml): 414+/-75 vs. 86+/-6, p<0.01. Fasting total ghrelin (pg/ml) were similar in the patient and in the control group, 916+/-132 vs. 844+/-169, p=ns. In both groups total ghrelin levels decreased during oral glucose, and nadir total ghrelin was lower than fasting ghrelin: patients: 916+/-132 vs. 747+/-95, p<0.05; controls: 844+/-169 vs. 625+/-90, p<0.05). The AUCs of total ghrelin (pg/ml*min) were not different between the two groups: 98953+/-13052 vs. 83773+/-13096, p=ns). Fasting acylated ghrelin (pg/ml) were similar in the patient and the control group 65+/-13 pg/ml vs.74+/-14 pg/ml, p=ns. In both groups acylated ghrelin levels decreased during oral glucose, and nadir acylated ghrelin levels were lower than basal acylated ghrelin levels: patients: 65+/-13 vs. 42+/-6, p<0.05; controls: 74+/-14 pg/ml vs. 37+/-4 pg/ml, p<0.05). The AUCs of acylated ghrelin (pg/ml*min) were not different between the two groups: patients: 6173+/-992 vs. controls 8648+/-2742, p=ns). In acromegalic patients there was a negative correlation between fasting, both total and acylated, ghrelin and both fasting and post oral glucose insulin levels. CONCLUSIONS: These data suggest that circulating total and acylated ghrelin in acromegaly is regulated by insulin and not by GH hypersecretion.
Assuntos
Acromegalia/metabolismo , Adenoma/complicações , Glicemia/metabolismo , Jejum/sangue , Grelina/sangue , Neoplasias Hipofisárias/complicações , Acromegalia/etiologia , Acilação , Adenoma/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Grelina/metabolismo , Teste de Tolerância a Glucose , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Neoplasias Hipofisárias/metabolismo , Valores de Referência , Estatísticas não ParamétricasRESUMO
CONTEXT: The diagnosis of adult GH deficiency requires confirmation with a GH stimulation test. Oral glucose (OG) administration affects GH secretion, initially decreasing and subsequently stimulating GH secretion. OBJECTIVE: The aim of this study was to investigate the diagnostic efficacy and safety of a long OG test (LOGT) as a stimulus of GH secretion for the diagnosis of adult GH deficiency (AGHD). DESIGN: Prospective experimental cross-sectional study. SETTINGS: The study was conducted at the Endocrinology department of the University Hospital of a Coruña, Spain. PARTICIPANTS AND METHODS: We included 60 (40 women) AGHD patients (15) and controls (45) paired 1:3, of similar age, sex and BMI. The area under the curve (AUC) and peak were calculated for GH. The Mann-Whitney test was used to compare the different groups. ROC curve analyses were used. p-Values<0.05 were considered as statistically significant. INTERVENTIONS: The intervention consisted of orally administering 75g oral glucose administration; GH was obtained every 30min for a total of 300min. MAIN OUTCOME MEASUREMENT: Peak GH area under receiver operating characteristic curve (ROC-AUC) following LOGT. RESULTS: Peak GH (µg/L) levels were lower in the AGHD patients (0.26±0.09) than in the controls (4.00±0.45), p<0.001. After LOGT, with the ROC plot analysis the best peak GH cut-point was 1.0µg/L, with 100% sensitivity, 78% specificity, ROC-AUC of 0.9089 and 81.82% accuracy. There were no relevant adverse events during any of the LOGT. CONCLUSIONS: The LOGT could be a cheap, safe, convenient and effective test for the diagnosis of AGHD.