RESUMO
Herein, we present a 14-year-old patient with short stature (134 cm) referred from Paediatrics to our department for complementary evaluation since growth hormone (GH) treatment failed to show any improvement. He was born premature and small for gestational age. Genital examination classified the patient as Tanner I-II with small penis and testicular size for his age. Biochemical analyses revealed normal GH levels with low serum insulin-like growth factor-1 (IGF-1). Molecular diagnosis confirmed several mutations in IGF1R and IGFALS, and so he was diagnosed with Laron Syndrome or GH insensibility and treated with IGF-1 substitutive therapy. LEARNING POINTS: Evaluation of the GH/IGF-1 axis when short stature does not respond to conservative treatment must be included in the ordinary practice.Laron Syndrome real incidence should be calculated once undiagnosed cases arise, as treatment, due to lack of market, is unaffordable.Even when adulthood is reached, and no longitudinal growth can be achieved, still IGF-1 treatment in Laron Syndrome patients should be pursued as metabolic and protective derangements could arise.
RESUMO
Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1's effects on liver by comparing wild-type controls, heterozygous igf1+/-, and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.
Assuntos
Proteínas de Fase Aguda/metabolismo , Regulação da Expressão Gênica , Hepatite/metabolismo , Mediadores da Inflamação/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , Receptores de Somatomedina/metabolismo , Proteínas de Fase Aguda/genética , Animais , Caderinas/genética , Caderinas/metabolismo , Cruzamentos Genéticos , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Desmossomos/imunologia , Desmossomos/metabolismo , Desmossomos/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Hepatite/imunologia , Hepatite/patologia , Hepatite/prevenção & controle , Injeções Subcutâneas , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/uso terapêutico , Peroxidação de Lipídeos , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Transgênicos , Estresse Oxidativo , Receptores de Somatomedina/genética , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismoRESUMO
Consistent evidence associates IGF-1 deficiency and metabolic syndrome. In this review, we will focus on the metabolic effects of IGF-1, the concept of metabolic syndrome and its clinical manifestations (impaired lipid profile, insulin resistance, increased glucose levels, obesity, and cardiovascular disease), discussing whether IGF-1 replacement therapy could be a beneficial strategy for these patients. The search plan was made in Medline for Pubmed with the following mesh terms: IGF-1 and "metabolism, carbohydrate, lipids, proteins, amino acids, metabolic syndrome, cardiovascular disease, diabetes" between the years 1963-2015. The search includes animal and human protocols. In this review we discuss the relevant actions of IGF-1 on metabolism and the implication of IGF-1 deficiency in the establishment of metabolic syndrome. Multiple studies (in vitro and in vivo) demonstrate the association between IGF-1 deficit and deregulated lipid metabolism, cardiovascular disease, diabetes, and an altered metabolic profile of diabetic patients. Based on the available data we propose IGF-1 as a key hormone in the pathophysiology of metabolic syndrome; due to its implications in the metabolism of carbohydrates and lipids. Previous data demonstrates how IGF-1 can be an effective option in the treatment of this worldwide increasing condition. It has to distinguished that the replacement therapy should be only undertaken to restore the physiological levels, never to exceed physiological ranges.
Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Síndrome Metabólica/metabolismo , Animais , Metabolismo dos Carboidratos , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Modelos BiológicosRESUMO
Insulin-like growth factor 1 (IGF-1) is an anabolic hormone with several biological activities, such as proliferation, mitochondrial protection, cell survival, tissue growth and development, anti-inflammatory, antioxidant, antifibrogenic and antiaging. This hormone plays an important role in embryological and postnatal states, being essential for normal foetal and placental growth and differentiation. During gestation, the placenta is one of the major sources of IGF-1, among other hormones. This intrauterine organ expresses IGF-1 receptors and IGF-1 binding proteins (IGFBPs), which control IGF-1 activities. Intrauterine growth restriction (IUGR) is the second most frequent cause of perinatal morbidity and mortality, defined as the inability to achieve the expected weight for gestational age. Different studies have revealed that IUGR infants have placental dysfunction and low circulating levels of insulin, IGF-1, IGF-2 and IGFBPs. Such data suggest that IGF-1 deficiency in gestational state may be one of the major causes of foetal growth retardation. The aim of this review is to study the epidemiology, physiopathology and possible causes of IUGR. Also, it intends to study the possible role of the placenta as an IGF-1 target organ. The purpose is to establish if IUGR could be considered as a novel condition of IGF-1 deficiency and if its treatment with low doses of IGF-1 could be a suitable therapeutic strategy.