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Introduction: We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST). Methods: We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0. Results: Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH. Conclusion: We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.
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Trastornos del Crecimiento , Hormona de Crecimiento Humana , Humanos , Masculino , Hormona de Crecimiento Humana/deficiencia , Adolescente , Estudios Retrospectivos , Niño , Femenino , Estatura , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/deficiencia , Prueba de Estudio Conceptual , Enanismo Hipofisario/sangreRESUMEN
The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2-7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF-1 z-scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control. PLAIN LANGUAGE SUMMARY: The KD can be an effective treatment for difficult-to-control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.
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Dieta Cetogénica , Hormona de Crecimiento Humana , Humanos , Femenino , Masculino , Niño , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/uso terapéutico , Preescolar , Estudios Retrospectivos , Trastornos del Crecimiento/dietoterapia , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/deficiencia , Estatura , Epilepsia/dietoterapiaRESUMEN
BACKGROUND: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. METHODS: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. RESULTS: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels. CONCLUSION: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. FUNDING: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.
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Enfermedades Cardiovasculares , Factores de Riesgo de Enfermedad Cardiaca , Síndrome de Laron , Humanos , Masculino , Femenino , Adulto , Enfermedades Cardiovasculares/epidemiología , Síndrome de Laron/genética , Persona de Mediana Edad , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/deficiencia , Grosor Intima-Media Carotídeo , Ecuador/epidemiología , Receptores de Somatotropina/genética , Receptores de Somatotropina/deficiencia , Análisis de la Onda del Pulso , Factores de Riesgo , Glucemia/metabolismo , Glucemia/análisis , Presión Sanguínea , Estudios de Casos y ControlesRESUMEN
INTRODUCTION: Patients with homozygous recessive mutations in STAT5B have severe progressive postnatal growth failure and insulin-like growth factor-I (IGF-I) deficiency associated with immunodeficiency and increased risk of autoimmune and pulmonary conditions. This report describes the efficacy and safety of recombinant human IGF-1 (rhIGF-1) in treating severe growth failure due to STAT5B deficiency. CASE PRESENTATION: Three siblings (P1, 4.4 year-old female; P2, 2.3 year-old male; and P3, 7 month-old female) with severe short stature (height SDS [HtSDS] -6.5, -4.9, -5.3, respectively) were referred to the Center for Growth Disorders at Cincinnati Children's Hospital Medical Center. All three had a homozygous mutation (p.Trp631*) in STAT5B. Baseline IGF-I was 14.7, 14.1, and 10.8 ng/mL, respectively (all < -2.5 SDS for age and sex), and IGFBP-3 was 796, 603, and 475 ng/mL, respectively (all < -3 SDS for age and sex). The siblings were started on rhIGF-1 at 40 µg/kg/dose twice daily subcutaneously (SQ), gradually increased to 110-120 µg/kg/dose SQ twice daily as tolerated. HtSDS and height velocity (HV) were monitored over time. RESULTS: Six years of growth data was utilized to quantify growth response in the two older siblings and 5 years of data in the youngest. Pre-treatment HVs were, respectively, 3.0 (P1), 3.0 (P2), and 5.2 (P3) cm/year. With rhIGF-1 therapy, HVs increased to 5.2-6.0, 4.8-7.1, and 5.5-7.4 cm/year, respectively, in the first 3 years of treatment, before they decreased to 4.7, 3.8, and 4.3 cm/year, respectively, at a COVID-19 pandemic delayed follow-up visit and with decreased treatment adherence. ΔHtSDS for P1 and P2 was +2.21 and +0.93, respectively, over 6 years, but -0.62 for P3 after 5 years and in the setting of severe local lipohypertrophy and suboptimal weight gain. P3 also experienced hypoglycemia that limited our ability to maintain target rhIGF-1 dosing. CONCLUSION: The response to rhIGF-1 therapy is less than observed with rhIGF-1 therapy for patients previously described with severe primary IGF-I deficiency, including patients with documented defects in the growth hormone receptor, but may still provide patients with STAT5B deficiency with an opportunity to prevent worsening growth failure.
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Insuficiencia de Crecimiento , Trastornos del Crecimiento , Factor I del Crecimiento Similar a la Insulina , Péptidos Similares a la Insulina , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Hermanos , Factor de Transcripción STAT5/genética , SíndromeRESUMEN
Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is represented by the growth hormone-insulin-like growth factor axis (GH-IGF), even if several other factors are involved in normal growth. Within the broad spectrum of growth disorders, an increased importance has been placed on growth hormone insensitivity (GHI). GHI was reported for the first time by Laron as a syndrome characterized by short stature due to GH receptor (GHR) mutation. To date, it is recognized that GHI represents a wide diagnostic category, including a broad spectrum of defects. The peculiar characteristic of GHI is the low IGF-1 levels associated with normal or elevated GH levels and the lack of IGF-1 response after GH administration. Recombinant IGF-1 preparations may be used in the treatment of these patients.
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Enanismo , Hormona de Crecimiento Humana , Factor I del Crecimiento Similar a la Insulina , Hormona de Crecimiento Humana/genética , Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/deficiencia , Humanos , Trastornos del Crecimiento/genéticaRESUMEN
The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.
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Factor II del Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina , Síndrome de Laron , Animales , Humanos , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/historia , Factor I del Crecimiento Similar a la Insulina/fisiología , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Síndrome de Laron/genética , Síndrome de Laron/historia , Síndrome de Laron/fisiopatología , Hormonas Peptídicas , Procesamiento Proteico-Postraduccional , Transducción de Señal , Somatomedinas/deficiencia , Somatomedinas/historia , Somatomedinas/fisiología , Factor II del Crecimiento Similar a la Insulina/deficiencia , Factor II del Crecimiento Similar a la Insulina/historia , Factor II del Crecimiento Similar a la Insulina/fisiología , Factor II del Crecimiento Similar a la Insulina/uso terapéuticoRESUMEN
Insulin-like growth factor 1 (IGF1) is an essential effector of the growth hormone (GH)/IGF1 axis for somatic growth regulation in mammals. However, its functions have not been thoroughly investigated in zebrafish in vivo. In this study, the igf1-deficient zebrafish model was developed using the CRISPR/Cas9 technique. In this study all the results were performed on both male and female animals. The growth of both male and female igf1-deficient zebrafish were reduced. The igf1 deficiency leads to significant complementary up-regulation of transcriptional expression levels of insulin, igf2 and igf3. This suggested that igf2 and igf3 may act with redundant functions. While the upregulation of gh1 expression can only be detected in igf1-deficient females. At the same time, significant growth retardation, fatty liver, reduced activated levels of ribosomal S6 (S6) are seen only in igf1-deficient males. On the other hand, significant hyperglycemia, elevated transcriptional expression levels of phosphenolpyruvate carboxykinase (pepck) and levels of phosphorylated extracellular signal-regulated kinase (ERK1/2), with additional reduced hepatic lactate/pyruvate (L/P) ratios can only observed in igf1-deficient females. Impaired glucose uptake has been recorded in the primary cultured hepatocytes from igf1-deficient females, but not males. Intriguingly, exposure to 17beta-estroadiol (E2) can partially ameliorated the defects of fatty liver and activation of AKT/mTOR signaling in igf1-deficient males. Our studies demonstrate the significant functions of IGF1 on somatic regulation in zebrafish, with asymmetric gender-related consequences. Our data thus suggest that the zebrafish IGF1 is preferentially required for the activation of AKT/mTOR signaling in male zebrafish, but glucose uptake in females.
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Hígado Graso , Factor I del Crecimiento Similar a la Insulina , Animales , Hígado Graso/metabolismo , Femenino , Glucosa , Trastornos del Crecimiento , Pérdida Auditiva Sensorineural , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Mamíferos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/genética , Pez Cebra/genéticaRESUMEN
BACKGROUND: Puberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex® Growth Forum Database (Eu-IGFD) Registry (NCT00903110). METHODS: The Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. RESULTS: This analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3-13.0) cm/year in boys and 6.8 (1.3-9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. CONCLUSION: Children and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.
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Factor I del Crecimiento Similar a la Insulina , Adolescente , Niño , Estudios Clínicos como Asunto , Femenino , Trastornos del Crecimiento , Pérdida Auditiva Sensorineural , Humanos , Factor I del Crecimiento Similar a la Insulina/deficiencia , Masculino , Proteínas Recombinantes , Sistema de RegistrosRESUMEN
Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF-I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, and treatment of GH/IGF-I deficiency or excess during life.
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Restricción Calórica , Metabolismo de los Hidratos de Carbono , Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lipólisis , Micronutrientes , Transducción de Señal , Hormona de Crecimiento Humana/deficiencia , Humanos , Factor I del Crecimiento Similar a la Insulina/deficienciaRESUMEN
Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.
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Hígado Graso/genética , Macrófagos/metabolismo , Anomalías Musculoesqueléticas/genética , Desarrollo Musculoesquelético/genética , Osteopetrosis/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Animales , Médula Ósea/metabolismo , Médula Ósea/patología , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Embrión de Mamíferos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/terapia , Femenino , Regulación del Desarrollo de la Expresión Génica , Técnicas de Inactivación de Genes , Genes Reporteros , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/deficiencia , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/genética , Metabolismo de los Lípidos , Hígado/metabolismo , Hígado/patología , Macrófagos/patología , Masculino , Anomalías Musculoesqueléticas/metabolismo , Anomalías Musculoesqueléticas/patología , Anomalías Musculoesqueléticas/terapia , Osteopetrosis/metabolismo , Osteopetrosis/patología , Osteopetrosis/terapia , Ratas , Ratas Transgénicas , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficienciaRESUMEN
The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak ("GH neurosecretory dysfunction," GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0-3.2 µg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to GH1 variants) but less on the role of GHSR variants. Several genetic causes of (partial) GHI are known (GHR, STAT5B, STAT3, IGF1, IGFALS defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.
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Enanismo Hipofisario , Enanismo , Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/deficiencia , Hipotonía Muscular , Síndrome de Noonan , Columna Vertebral/anomalías , Niño , Preescolar , Diagnóstico Diferencial , Enanismo/diagnóstico , Enanismo/genética , Enanismo/metabolismo , Enanismo Hipofisario/diagnóstico , Enanismo Hipofisario/genética , Enanismo Hipofisario/metabolismo , Hormona de Crecimiento Humana/genética , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Hipotonía Muscular/metabolismo , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Columna Vertebral/metabolismoRESUMEN
Atherosclerosis is the leading cause of cardiovascular disease (CVD), with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor for atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear. In the present study, we assessed the essential role of hepatic Igf1, the major source of circulating IGF-1, in atherogenesis. We generated hepatic Igf1-deficient atherosclerosis-prone apolipoprotein E (ApoE)-null mice (L-Igf1-/-ApoE-/-) using the Cre-loxP system driven by the Albumin promoter. Starting at 6 weeks of age, these mice and their littermate controls, separated into male and female groups, were placed on an atherogenic diet for 18 to 19 weeks. We show that hepatic Igf1-deficiency led to atheroprotection with reduced plaque macrophages in females, without significant effects in males. This protection from atherosclerosis in females was associated with increased subcutaneous adiposity and with impaired lipolysis. Moreover, this impaired lipid homeostasis was associated with disrupted adipokine secretion with reduced circulating interleukin-6 (IL-6) levels. Together, our data show that endogenous hepatic Igf1 plays a sex-specific regulatory role in atherogenesis, potentially through athero-promoting effects of adipose tissue-derived IL-6 secretion. These data provide potential novel sex-specific mechanisms in the pathogenesis of atherosclerosis.
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Aterosclerosis/prevención & control , Factor I del Crecimiento Similar a la Insulina/deficiencia , Hígado/metabolismo , Tejido Adiposo , Animales , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismo , Femenino , Factor I del Crecimiento Similar a la Insulina/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
OBJECTIVE: The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). DESIGN: Ongoing, open-label, observational registry (NCT00903110). METHODS: Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). RESULTS: Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years' treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. CONCLUSIONS: In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.
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Trastornos del Crecimiento/tratamiento farmacológico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adolescente , Estatura , Peso Corporal/efectos de los fármacos , Niño , Femenino , Crecimiento/efectos de los fármacos , Humanos , Hipoglucemia/sangre , Hipoglucemia/inducido químicamente , Síndrome de Laron/genética , Estudios Longitudinales , Masculino , Seguridad del Paciente , Pubertad , Resultado del Tratamiento , Adulto JovenRESUMEN
The impairment of skeletal muscle function is one of the most debilitating least understood co-morbidity that accompanies acromegaly (ACRO). Despite being one of the major determinants of these patients' poor quality of life, there is limited evidence related to the underlying mechanisms and treatment options. Although growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels are associated, albeit not indisputable, with the presence and severity of ACRO myopathies the precise effects attributed to increased GH or IGF-1 levels are still unclear. Yet, cell lines and animal models can help us bridge these gaps. This review aims to describe the evidence regarding the role of GH and IGF-1 in muscle anabolism, from the basic to the clinical setting with special emphasis on ACRO. We also pinpoint future perspectives and research lines that should be considered for improving our knowledge in the field.
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Acromegalia/metabolismo , Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/metabolismo , Enfermedades Musculares/metabolismo , Acromegalia/fisiopatología , Animales , Hormona del Crecimiento/deficiencia , Humanos , Factor I del Crecimiento Similar a la Insulina/deficiencia , Sistema de Señalización de MAP Quinasas/genética , Músculo Esquelético/fisiopatología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Human size is achieved by the coordinated expression of many genes. From conception to adulthood, a given genomic endowment is modified by highly variable environmental circumstances. During each stage of a person's life, distinct nutritional and hormonal influences continuously shape growing physical features until mature characteristics are attained. Underlying processes depend on precise provision of substrates and energy extracted by insulin action from nutrients, which allows cell proliferation, differentiation, and survival, under the concerted actions of growth hormone and insulin-like growth factor-I (IGF-I). It should be noted that growth and metabolic signaling pathways are interdependent and superimposed at multiple levels. Attainment of a fully developed human phenotype should be considered as a harmonious increment in body size rather than a simple increase in height. From this perspective we herein analyze adult features of individuals with an inactive growth hormone receptor, who consequently have severely diminished concentrations of serum insulin and endocrine IGF-I.
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Trastornos del Crecimiento/genética , Pérdida Auditiva Sensorineural/genética , Hormona de Crecimiento Humana/genética , Resistencia a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/deficiencia , Mutación/genética , Crecimiento y Desarrollo/genética , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Transducción de SeñalRESUMEN
CONTEXT: Definition of etiological subgroups of sarcopenia may help to develop targeted treatments. insulin like growth factor-I (IGF-I), Insulinlike growth factor binding protein 3 (IGFBP3), and acid labile subunit (ALS) build a ternary complex that mediates growth hormone (GH) effects on peripheral organs, such as muscle. Low GH binding protein (GHBP) as a marker of GH receptor number would hint toward GH resistance. OBJECTIVE: We aimed to analyze the association of IGF-I, IGFBP3, and ALS with sarcopenia. STUDY PARTICIPANTS AND SETTING: A total of 131 consecutively recruited patients of a geriatric ward were included in a single-center cross-sectional analysis; the nonsarcopenic patients served as controls. METHODS: Measures included sarcopenia status by hand-grip strength measurement and Skeletal Muscle Index (SMI); IGF-I, IGFBP3, ALS, GH, GHBP; body mass index (BMI); Activity of Daily Living (ADL); Mini-Mental State Examination (MMSE); routine laboratory parameters; and statistical regression modeling. RESULTS: Compared with controls, sarcopenic patients did not differ regarding age, sex, ADL, MMSE, C-reactive protein, glomerular filtration rate, and albumin serum concentrations. However, sarcopenic patients had significantly lower IGF-I, IGFBP3, and ALS. IGF-I and ALS associated significantly with sarcopenia and low hand-grip strength, even after adjustment for age, sex, BMI, and albumin, but not with low SMI. GHBP serum was low in sarcopenic patients, but normal in geriatric patients without sarcopenia. Over 60% of patients with IGF-I/ALS deficiency patients showed GH resistance. CONCLUSIONS: Our data suggest that in geriatric patients, low IGF-I/IGFBP3/ALS could be evaluated for causative connection of the sarcopenia spectrum. Low GHBP points toward potential GH resistance as one possible explanation of this deficiency.
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Hormona del Crecimiento/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/deficiencia , Sarcopenia/metabolismo , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , MasculinoRESUMEN
A 6-mo-old female Chihuahua was presented with recurrent episodes of hypoglycemia and collapse. Physical examination revealed proportionate dwarfism, retained puppy hair coat, retained deciduous teeth, and open fontanelles. Routine blood tests revealed hypoglycemia, thrombocytosis, hypoproteinemia, and elevated alkaline phosphatase activity. The urinalysis, radiographs, and ultrasonographs were unremarkable. Endocrine testing revealed that insulin-like growth factor 1 was below the detection limit; concentrations of total thyroxine, baseline cortisol, and cortisol stimulated by tetracosactide acetate were within their reference intervals. The pituitary gland showed no organic abnormalities on magnetic resonance imaging. For definitive diagnosis, we conducted the stimulation test for growth hormone (GH) release and diagnosed isolated GH deficiency. Genetic investigation revealed that the present case had 4 point mutations in intronic regions and a 6-bp deletion in exon 5 of GH1. The bioinformatics tool PROVEAN algorithm predicted that the deletion in exon 5 could be deleterious to the function of GH1.
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Enfermedades de los Perros/diagnóstico , Hipoglucemia/veterinaria , Factor I del Crecimiento Similar a la Insulina/deficiencia , Animales , Enfermedades de los Perros/etiología , Perros , Femenino , Hipoglucemia/diagnóstico , Hipoglucemia/etiología , Factor I del Crecimiento Similar a la Insulina/genética , MutaciónRESUMEN
Purpose: In heart failure with reduced ejection fraction, catabolic mechanisms have a strong negative impact on mortality and morbidity. The relationship between anabolic hormonal deficiency and heart failure with preserved ejection fraction (HFpEF) has still been poorly investigated. On the other hand, oxidative stress is recognized as a player in the pathogenesis of HFpEF. Therefore, we performed a cohort study in HFpEF aimed to (1) define the multi-hormonal deficiency prevalence in HFpEF patients; (2) investigate the relationships between hormonal deficiencies and echocardiographic indexes; (3) explore the modulatory activity of anabolic hormones on antioxidant systems. Methods: 84 patients with diagnosis of HFpEF were enrolled in the study. Plasma levels of N-terminal pro-brain natriuretic peptide, fasting glucose, insulin, lipid pattern, insulin-like growth factor-1, dehydroepiandrosterone-sulfate (DHEA-S), total testosterone (T, only in male subjects) were evaluated. Hormonal deficiencies were defined according to T.O.S.C.A. multi-centric study, as previously published. An echocardiographic evaluation was performed. Plasma total antioxidant capacity (TAC) was measured using the system metmyoglobin -H2O2 and the chromogen ABTS, whose radical form is spectroscopically revealed; latency time (LAG) in the appearance of ABTS⢠is proportional to antioxidants in sample. Results: Multiple deficiencies were discovered. DHEA-S deficiency in 87% of patients, IGF-1 in 67% of patients, T in 42%. Patients with DHEA-S deficiency showed lower levels of TAC expressed by LAG (mean ± SEM 91.25 ± 9.34 vs. 75.22 ± 4.38 s; p < 0.05). No differences between TAC in patients with or without IGF-1 deficiency were found. A trend toward high level of TAC in patients without hormonal deficiencies compared with patients with one or multiple deficiencies was found. Regarding echocardiographic parameters, Left Atrial and Left Atrial Volume Index were significantly higher in patients with low IGF-1 values (mean ± SD 90.84 ± 3.86 vs. 72.83 ± 3.78 mL; 51.03 ± 2.33 vs. 40.56 ± 2.46 mL/m2, respectively; p < 0.05). Conclusions: Our study showed high prevalence of anabolic deficiencies in HFpEF. DHEA-S seems to influence antioxidant levels; IGF-1 deficiency was associated with alteration in parameters of myocardial structure and dysfunction. These data suggest a role of anabolic hormones in the complex pathophysiological mechanisms of HFpEF and could represent the basis for longitudinal studies and investigations on possible benefits of replacement therapy.
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Antioxidantes/metabolismo , Cardiomiopatías/epidemiología , Insuficiencia Cardíaca/fisiopatología , Factor I del Crecimiento Similar a la Insulina/deficiencia , Volumen Sistólico , Testosterona/deficiencia , Disfunción Ventricular Izquierda/epidemiología , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patologíaRESUMEN
This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapyï¼compared to the untreated group,caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 hrs. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.
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Lesión Renal Aguda/patología , Factor I del Crecimiento Similar a la Insulina/genética , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/terapia , Animales , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Citocinas/genética , Citocinas/metabolismo , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica/efectos de los fármacos , Terapia Genética , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/deficiencia , Riñón/metabolismo , Riñón/patología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Proteína ORAI1/antagonistas & inhibidores , Proteína ORAI1/metabolismo , Tasa de SupervivenciaRESUMEN
The current pandemic of Covid-19 has created a paradigm for possibly gaining greater insight in two conditions:Studies since the beginning of this century have supported the view that IGF-1 deficiency in the neonate defines the basis of autism. As a result, it appears that interleukin-6 in corona virus-based infections causes reduced defenses because of suppressed IGF-1, especially in older patients. This may also portend an increase of autism in the offspring of gravidas currently affected severely by Covid-19.