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OBJECTIVE: Antiepileptic drugs (AEDs) are associated with reduced bone density, balance impairment, and increased fracture risk in adults. However, pediatric data are limited. Therefore, we aimed to examine bone, muscle, and balance outcomes in young patients taking AEDs. METHODS: We undertook a case-control study utilizing an AED exposure-discordant matched-pair approach. Subjects were aged 5-18 years with at least 12 months of AED exposure. Pairs were twins, nontwin siblings and first cousins, sex- and age-matched (to within 2 years), allowing for greater power than with unrelated control subjects. Dual energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and muscle force/balance were tested, with questionnaires were administered for bone health and epilepsy details. RESULTS: Twenty-three pairs were recruited, (median age 12.9 years [subjects] and 13.5 years [controls])-7 twin, 14 sibling, and 2 cousin pairs. Those taking AEDs had an increased prevalence of fractures (15 fractures in 8 subjects, compared with 4 fractures in 3 controls, p < 0.01). Trabecular volumetric bone mineral density (vBMD) measured by pQCT at the 4% site (tibia) was reduced by 14% (p = 0.03) in subjects. Subjects exerted a decreased maximum force compared to body weight (Fmax total/g) at the tibia. There were no differences seen in either bone mineral parameters measured by DXA or balance measures. SIGNIFICANCE: Young people taking AEDs reported more fractures and had reductions in tibial vBMD and lower limb muscle force compared to their matched controls. These findings suggest that further exploration of bone health issues of young patients on AED therapy is required. Longitudinal studies are required to confirm these changes in the muscle-bone unit and to further explore the clinical outcomes.
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Anticonvulsivantes/efectos adversos , Densidad Ósea/efectos de los fármacos , Enfermedades en Gemelos/diagnóstico por imagen , Fracturas Óseas/diagnóstico por imagen , Desarrollo de Músculos/efectos de los fármacos , Adolescente , Anticonvulsivantes/administración & dosificación , Australia/epidemiología , Densidad Ósea/fisiología , Estudios de Casos y Controles , Niño , Preescolar , Enfermedades en Gemelos/inducido químicamente , Enfermedades en Gemelos/epidemiología , Epilepsia/diagnóstico por imagen , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Femenino , Fracturas Óseas/inducido químicamente , Fracturas Óseas/epidemiología , Humanos , Masculino , Desarrollo de Músculos/fisiología , Sistema de Registros , Resultado del TratamientoRESUMEN
Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15-yr-old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti-emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glucagón/administración & dosificación , Hipoglucemia/inducido químicamente , Insulina de Acción Prolongada/efectos adversos , Administración Intravenosa , Adolescente , Diabetes Mellitus Tipo 1/sangre , Sobredosis de Droga , Hormonas/administración & dosificación , Humanos , Hipoglucemia/sangre , Hipoglucemiantes/efectos adversos , MasculinoRESUMEN
The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors. In addition to these local peri-cellular activities, IGFBP-2 exerts other key functions within the nucleus, where IGFBP-2 directly or indirectly promotes transcriptional activation of specific genes. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumour growth and metastasis.
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OBJECTIVE: We analyzed mRNA expression of X-linked inhibitor of apoptosis protein (XIAP) in patients with Turner syndrome (TS) and examined its association with phenotypic features. SUBJECTS AND METHODS: XIAP mRNA expression levels were investigated in 98 patients with TS in total RNA extracted from blood leucocytes by real time quantitative polymerase chain reaction. RESULTS: Levels of XIAP mRNA were significantly lower in patients with bicuspid aortic valves (BAV; n=13) than those without (log XIAP -1.17±0.3 vs. -0.94±0.2, p=0.002). Significantly higher expression of XIAP mRNA was seen in patients with a mosaic karyotype and renal malformations (log XIAP -0.79±0.3 vs. -1.0±0.3, p=0.03). No correlations were seen between XIAP and other manifestations. CONCLUSION: Abnormal expression of XIAP may be an important underlying mechanism in the development of BAV and renal malformations in TS. However, abnormal XIAP mRNA expression, as determined from peripheral mononuclear cells, does not appear to explain all the somatic and visceral stigmata of TS.
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Válvula Aórtica/anomalías , Enfermedades de las Válvulas Cardíacas/metabolismo , Riñón/anomalías , Síndrome de Turner/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Adolescente , Adulto , Anciano , Válvula Aórtica/metabolismo , Enfermedad de la Válvula Aórtica Bicúspide , Niño , Preescolar , Femenino , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/genética , Humanos , Lactante , Leucocitos Mononucleares/metabolismo , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Síndrome de Turner/complicaciones , Síndrome de Turner/genética , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Adulto JovenRESUMEN
OBJECTIVE: This study examined illness-related change in intelligence quotient (IQ) in a cohort of youth with type 1 diabetes studied prospectively from disease onset in childhood to follow-up 12 years later in late adolescence/early adulthood. RESEARCH DESIGN AND METHODS: Participants included type 1 diabetes patients (n = 95; mean age at follow-up 21.3 years) and healthy control participants (HCs; n = 67; mean age at follow-up 21.0 years) from a cohort followed prospectively. Measures included Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children-Revised, and Wechsler Abbreviated Scale of Intelligence and prospective collection of data on metabolic control history. RESULTS: Young people with type 1 diabetes showed greater decline in verbal IQ (VIQ) and full-scale IQ (FSIQ), but not performance IQ (PIQ), than HCs. Within the diabetes group, a younger age at diabetes onset was associated with a decline in PIQ and FSIQ (P ≤ 0.001). A history of hypoglycemic seizures was associated with a decline in VIQ (P = 0.002). Long-term metabolic control was not associated with changes in IQ. Interaction terms were not significant, suggesting no moderating effect of one diabetes-related variable over another. CONCLUSIONS: The presence of diabetes may negatively influence some aspects of IQ over time. Specific illness risk factors, such as an earlier age of disease onset and a history of hypoglycemic seizures, appear to put the young person at greater risk. Academic progress of children identified as at risk should be monitored and educational supports provided if necessary.
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Diabetes Mellitus Tipo 1/psicología , Inteligencia , Adolescente , Edad de Inicio , Glucemia/metabolismo , Estudios de Casos y Controles , Niño , Diabetes Mellitus Tipo 1/sangre , Cetoacidosis Diabética/sangre , Cetoacidosis Diabética/psicología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Escalas de Wechsler , Adulto JovenRESUMEN
AIMS: Waist circumference (WC) measurement is a useful tool in the assessment of overweight/obese individuals, but standard measures may miss an apron of 'overhanging' fat (termed 'panniculus'). The objective of this study was to assess whether, in clinically overweight/obese youth, 'pannicular' WC better correlates with fat mass than a standard WC measurement. METHODS: Standard and pannicular WC, alongside body composition (BC) measures, were collected from 181 consultations on 127 overweight and obese children/adolescents (52% male; mean (standard deviation) age 12.5 (3.4) years). Correlation coefficients describe associations between WC and measures of BC, and between ΔWC and ΔBC, while linear regression models assessed which of the WC measures explained more of the variability in BC and ΔBC over time. RESULTS: Standard and pannicular WC were highly correlated (r = 0.95). Correlation coefficients with measures of BC were generally greater for pannicular than standard WC, with greatest correlations seen for whole body (r = 0.94 vs. 0.85, respectively) and truncal (r = 0.86 vs. 0.77) fat mass. Furthermore, pannicular and Δpannicular WC explained more variability in truncal fat and Δtruncal fat than the standard measure of WC. CONCLUSIONS: These data show that pannicular, rather than standard, WC measurements better correlate with absolute measures of fat mass, and their change over time, in clinically overweight/obese youth.
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Adiposidad , Obesidad/patología , Sobrepeso/patología , Circunferencia de la Cintura , Adolescente , Composición Corporal , Niño , Impedancia Eléctrica , Femenino , Humanos , Modelos Lineales , Masculino , Estudios RetrospectivosRESUMEN
Leptin is produced from white adipose tissue and acts primarily to regulate energy balance. Obesity is associated with leptin resistance and increased circulating levels of leptin. Leptin has recently been shown to influence levels of IGF binding protein-2 (IGFBP-2), a protein that is reduced in obesity and type 2 diabetes. Overexpression of IGFBP-2 protects against obesity and type 2 diabetes. As such, IGFBP-2 signaling may represent a novel pathway by which leptin regulates insulin sensitivity. We sought to investigate how leptin regulates skeletal muscle IGFBP-2 levels and to assess the impact of this on insulin signaling and glucose uptake. In vitro experiments were undertaken in cultured human skeletal myotubes, whereas in vivo experiments assessed the effect of intracerebroventricular leptin on peripheral skeletal muscle IGFBP-2 expression and insulin sensitivity in sheep. Leptin directly increased IGFBP-2 mRNA and protein in human skeletal muscle through both signal transducer and activator of transcription-3 and phosphatidylinositol 3-kinase signaling, in parallel with enhanced insulin signaling. Silencing IGFBP-2 lowered leptin- and insulin-stimulated protein kinase B phosphorylation and glucose uptake. In in vivo experiments, intracerebroventricular leptin significantly increased hind-limb skeletal muscle IGFBP-2, an effect completely blocked by concurrent peripheral infusion of a ß-adrenergic blocking agent. Sheep receiving central leptin showed improvements in glucose tolerance and circulating insulin levels after an iv glucose load. In summary, leptin regulates skeletal muscle IGFBP-2 by both direct peripheral and central (via the sympathetic nervous system) mechanisms, and these likely impact on peripheral insulin sensitivity and glucose metabolism.
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Regulación de la Expresión Génica , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Leptina/farmacología , Sistema Nervioso Simpático/efectos de los fármacos , Animales , Western Blotting , Células Cultivadas , Femenino , Humanos , Insulina/metabolismo , Leptina/metabolismo , Músculo Esquelético , ARN Interferente Pequeño , Reacción en Cadena en Tiempo Real de la Polimerasa , OvinosRESUMEN
PURPOSE OF REVIEW: Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings. RECENT FINDINGS: This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes. SUMMARY: New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life.
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Anomalías Múltiples/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Macrosomía Fetal/genética , Trastornos del Crecimiento/genética , Deformidades Congénitas de la Mano/genética , Síndrome de Proteo/genética , Tumor de Wilms/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/psicología , Adolescente , Niño , Preescolar , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/psicología , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/psicología , Femenino , Macrosomía Fetal/diagnóstico , Macrosomía Fetal/psicología , Deformidades Congénitas de la Mano/diagnóstico , Deformidades Congénitas de la Mano/psicología , Humanos , Lactante , Masculino , Mutación , Fenotipo , Pronóstico , Síndrome de Proteo/diagnóstico , Síndrome de Proteo/psicología , Tumor de Wilms/diagnóstico , Tumor de Wilms/psicologíaRESUMEN
There is increasing evidence for glucose fluctuation playing a role in the damaging effects of diabetes on various organs, including the brain. We aimed to study the effects of glycaemic variation (GV) upon mitochondrial activity using an in vitro human neuronal model. The metabolic disturbance of GV in neuronal cells, was mimicked via exposure of neuroblastoma cells SH-SY5Y to constant glucose or fluctuating (i.e. 6 h cycles) for 24 and 48 h. Mitochondrial dehydrogenase activity was determined via MTT assay. Cell mitochondrial activity (MTT) was moderately decreased in constant high glucose, but markedly decreased following 24 and 48 h of cyclical glucose fluctuations. Glucose transport determined via 2-deoxy-D-[1-(14)C] glucose uptake was regulated in an exaggerated manner in response to glucose variance, accompanied by modest changes in GLUT 1 mRNA abundance. Osmotic components of these glucose effects were investigated in the presence of the osmotic-mimics mannitol and L: -glucose. Both treatments showed that fluctuating osmolality did not result in a significant change in mitochondrial activity and had no effects on (14)Cglucose uptake, suggesting that adverse effects on mitochondrial function were specifically related to metabolically active glucose fluctuations. Apoptosis gene expression showed that both intrinsic and extrinsic apoptotic pathways were modulated by glucose variance, with two major response clusters corresponding to (i) glucose stress-modulated genes, (ii) glucose mediated osmotic stress-modulated genes. Gene clustering analysis by STRING showed that most of the glucose stress-modulated genes were components of the intrinsic/mitochondrial apoptotic pathway including Bcl-2, Caspases and apoptosis executors. On the other hand the glucose mediated osmotic stress-modulated genes were mostly within the extrinsic apoptotic pathway, including TNF receptor and their ligands and adaptors/activators/initiators of apoptosis. Fluctuating glucose levels have a greater adverse effect on neuronal cell energy regulation mechanisms than either sustained high or low glucose levels.
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Glucemia/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/genética , Diferenciación Celular , Línea Celular Tumoral , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Manitol/farmacología , Neuroblastoma/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Concentración OsmolarRESUMEN
OBJECTIVE: 2 Childhood-onset type 1 diabetes is associated with neurocognitive deficits, but there is limited evidence to date regarding associated neuroanatomical brain changes and their relationship to illness variables such as age at disease onset. This report examines age-related changes in volume and T2 relaxation time (a fundamental parameter of magnetic resonance imaging that reflects tissue health) across the whole brain. RESEARCH DESIGN AND METHODS: Type 1 diabetes, N = 79 (mean age 20.32 ± 4.24 years), and healthy control participants, N = 50 (mean age 20.53 ± 3.60 years). There were no substantial group differences on socioeconomic status, sex ratio, or intelligence quotient. RESULTS: Regression analyses revealed a negative correlation between age and brain changes, with decreasing gray matter volume and T2 relaxation time with age in multiple brain regions in the type 1 diabetes group. In comparison, the age-related decline in the control group was small. Examination of the interaction of group and age confirmed a group difference (type 1 diabetes vs. control) in the relationship between age and brain volume/T2 relaxation time. CONCLUSIONS: We demonstrated an interaction between age and group in predicting brain volumes and T2 relaxation time such that there was a decline in these outcomes in type 1 diabetic participants that was much less evident in control subjects. Findings suggest the neurodevelopmental pathways of youth with type 1 diabetes have diverged from those of their healthy peers by late adolescence and early adulthood but the explanation for this phenomenon remains to be clarified.
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Encéfalo/fisiología , Diabetes Mellitus Tipo 1/fisiopatología , Adolescente , Adulto , Factores de Edad , Encéfalo/anatomía & histología , Femenino , Humanos , Masculino , Análisis de Regresión , Adulto JovenRESUMEN
The pathophysiology of cerebral oedema (CE) in diabetic ketoacidosis (DKA) remains enigmatic. We investigated the role of the idiogenic osmol taurine and aquaporin channels in an in vitro model, the SH-SY5Y neuroblastoma cell line, by sequentially mimicking DKA-like hyperglycemia/hypertonicity and hypotonic fluid therapy. Exposure to DKA-like hyperosmolarity led to shrinkage, while hypotonic fluid exposure led to cell swelling and impaired viability. Low sodium compensated in part for elevated glucose, pointing to a critical role for overall osmolality. Taurine, was synthesized and retained intracellularly during DKA-like hypertonicity, and released during hypotonicity, in part mitigating neuronal swelling. Metabolic labeling showed that the rate of taurine release was inadequate to fully prevent neuronal swelling during hypotonic fluid therapy following DKA-like hypertonicity. Under these conditions, Aquaporin4 & 9 channels were respectively down and up-regulated. Our study provides further novel insights into molecular mechanisms contributing to CE in DKA and its therapy.
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Acuaporinas/fisiología , Edema Encefálico/fisiopatología , Complicaciones de la Diabetes , Taurina/fisiología , Secuencia de Bases , Edema Encefálico/complicaciones , Línea Celular Tumoral , Cartilla de ADN , Humanos , Técnicas In Vitro , Mitocondrias/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The growth hormone/insulin-like growth factor-I (IGF-I) axis is at the centre of normal human childhood growth. Six well characterised binding proteins (IGFBP-1 to IGFBP-6) act as general carriers of IGF-I, but they also modulate IGF-I bioavailability and activity in a tissue-specific, and developmentally appropriate, manner. Recent findings also point to several binding proteins possessing specific 'lGF-independent' actions and, in particular, there is now substantial evidence linking IGFBP-2 with nutritional status and insulin sensitivity. IGFBP-2 concentrations are reduced in obesity, and further reductions are seen in those with Type 2 diabetes. As IGFBP-2 is the major IGFBP expressed in infancy, and is also the predominant IGFBP produced from adipocytes, it is ideally positioned to act as a keystone between nutrition, growth and metabolism. Childhood obesity is associated with an increased risk of long-term morbidity and mortality, but the factors that determine which obese children will develop these long-term complications are not fully understood. IGFBP-2 may be integrally involved in the molecular processes that govern the development of obesity and subsequent weight-related disease. Within this manuscript, we explore the associations between IGFBP-2 and obesity with a particular emphasis on how an increased understanding of the role of IGFBP-2 in metabolism may lead to improvements in the prevention and treatment of childhood obesity.
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Desarrollo Infantil/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/fisiología , Síndrome Metabólico/fisiopatología , Obesidad/fisiopatología , Niño , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/fisiología , Humanos , Síndrome Metabólico/metabolismo , Obesidad/metabolismoRESUMEN
IGF binding protein (IGFBP)-2 is one of the most significant genes in the signature of major aggressive cancers. Previously, we have shown that IGFBP-2 enhances proliferation and invasion of neuroblastoma cells, suggesting that IGFBP-2 activates a protumorigenic gene expression program in these cells. Gene expression profiling in human neuroblastoma SK-N-SHEP (SHEP)-BP-2 cells indicated that IGFBP-2 overexpression activated a gene expression program consistent with enhancement of tumorigenesis. Regulation was significant for genes involved in proliferation/survival, migration/adhesion, and angiogenesis, including the up-regulation of vascular endothelial growth factor (VEGF) mRNA (>2-fold). Specific transcriptional activation of the VEGF gene by IGFBP-2 overexpression was demonstrated via cotransfection of a VEGF promoter Luciferase construct in SHEP-BP-2. Cotransfection of VEGF promoter Luciferase construct with IGFBP-2 protein in wild-type SHEP cells indicated that transactivation of VEGF promoter only occurs in the presence of intracellular IGFBP-2. Cell fractionation and immunofluorescence in SHEP-BP-2 cells demonstrated nuclear localization of IGFBP-2. These findings suggest that transcriptional activation of VEGF promoter is likely to be mediated by nuclear IGFBP-2. The levels of secreted VEGF (up to 400 pg/10(6) cells) suggested that VEGF might elicit angiogenic activity. Hence, SHEP-BP-2 cells and control clones cultured in collagen sponge were xenografted onto chick embryo chorioallantoic membrane. Neomicrovascularization was observed by 72 h, solely in the SHEP-BP-2 cell xenografts. In conclusion, our data indicate that IGFBP-2 is an activator of aggressive behavior in cancer cells, involving nuclear entry and activation of a protumorigenic gene expression program, including transcriptional regulation of the VEGF gene and consequent proangiogenic activity of NB cell xenografts in vivo.
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Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Neovascularización Patológica/genética , Regiones Promotoras Genéticas , Factor A de Crecimiento Endotelial Vascular/genética , Fraccionamiento Celular , Línea Celular Tumoral , Regulación de la Expresión Génica , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Neovascularización Patológica/metabolismo , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
While oestrogen is recognized to play a key role in regulating growth, particularly in relation to epiphyseal fusion, the mechanisms that mediate its effects are still unclear. We utilized an in vitro model of chondrogenesis, the RCJ3.1C5.18 cell line, to explore the effect of oestrogen on this process. We demonstrated the presence of oestrogen receptors (ER) α and ß in these cells, with increased abundance of both receptor sub-types evident as the cells differentiated. ERα localized to the nucleus, suggesting it was signalling by genomic pathways, while ERß was seen predominantly in the cytoplasm, suggesting it may be utilizing non-genomic signalling. While exogenous oestrogen had no effect on proliferation or differentiation, we found some evidence for the endogenous production of oestrogen (intracrinology), as suggested by the expression of aromatase in these cells. Selective ERα blockade with methyl piperidinopyrazole (MPP) led to a significant reduction in both proliferation and differentiation, while ERß blockade with R,R tetrahydrochrysene (THC) led to an increase in these parameters. This is in keeping with results from mouse knockout models suggesting that unopposed ERß signalling leads to an inhibition of skeletal growth. Our results are further evidence for the importance of differential ER signalling in regulating chondrogenesis. Future studies examining in vivo effects of these agents are required to extrapolate these findings to a mammalian model.
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Condrogénesis/efectos de los fármacos , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/antagonistas & inhibidores , Placa de Crecimiento/efectos de los fármacos , Animales , Aromatasa/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Línea Celular , Proliferación Celular/efectos de los fármacos , Condrocitos/citología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrogénesis/fisiología , Crisenos/farmacología , Placa de Crecimiento/citología , Técnicas In Vitro , Ratones , Modelos Animales , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
The aim of this study was to investigate effects of dietary supplementation with fat or sugar on body composition (BC) and insulin sensitivity (IS) in maturing pigs. Fifty newborn pigs randomized to a control diet or 18% saturated fat (SF), 18% monounsaturated fat (MUF), 18% mixed fat (MF), or 50% sucrose (SUC), from 1 to 16 weeks of age. Outcomes included weight gain, BC (dual energy X-ray absorptiometry, DXA), IS (fasting insulin and hyperinsulinaemic-euglycaemic clamps), fasting Non-Esterified Fatty Acid (NEFA) concentrations, and mRNA expression of genes involved in lipogenesis and IS in skeletal muscle (SM), subcutaneous (SAT), and visceral adipose tissue (VAT). In vitro studies examined direct effects of fatty acids on insulin-like growth factor-binding protein 2 (IGFBP2) mRNA in C2C12 myotubes. While SUC-fed pigs gained most weight (due to larger quantities consumed; P < 0.01), those fed fat-enriched diets exhibited more weight gain per unit energy intake (P < 0.001). Total (P = 0.03) and visceral (P = 0.04) adiposity were greatest in MUF-fed pigs. Whole-body IS was decreased in those fed fat (P = 0.04), with fasting insulin increased in MUF-fed pigs (P = 0.03). SM IGFBP2 mRNA was increased in MUF-fed pigs (P = 0.009) and, in all animals, SM IGFBP2 mRNA correlated with total (P = 0.007) and visceral (P = 0.001) fat, fasting insulin (r = 0.321; P = 0.03) and change in NEFA concentrations (r = 0.285; P = 0.047). Furthermore, exposure of in vitro cultured myotubes to MUF, but not SF, reduced IGFBP2 mRNA suggesting a converse direct effect. In conclusion, diets high in fat, but not sugar, promote visceral adiposity and insulin resistance in maturing pigs, with evidence that fatty acids have direct and indirect effects on IGFBP2 mRNA expression in muscle.
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Composición Corporal , Grasas de la Dieta/administración & dosificación , Ácidos Grasos Monoinsaturados/farmacología , Resistencia a la Insulina , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Grasa Intraabdominal/metabolismo , Obesidad Abdominal/etiología , Animales , Línea Celular , Dieta , Sacarosa en la Dieta/farmacología , Ingestión de Energía , Ayuno , Ácidos Grasos no Esterificados/sangre , Humanos , Insulina/sangre , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Ratones , Fibras Musculares Esqueléticas/efectos de los fármacos , Obesidad Abdominal/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Porcinos , Aumento de Peso/efectos de los fármacosRESUMEN
Childhood overweight and obesity is highly prevalent within society. In the majority of individuals, weight gain is the result of exposure to an 'obesogenic' environment, superimposed on a background of genetic susceptibility brought about by evolutionary adaptation. These individuals tend to be tall in childhood with a normal final adult height, as opposed to those who have an underlying monogenic cause where short stature is more common (although not universal). Identifying genetic causes of weight gain, or tall stature and overgrowth, within this setting can be extremely problematic and yet it is imperative that clinicians remain alert, as identification of a genetic diagnosis has major implications for the individual, family and potential offspring. Alongside this, the recognition of new genetic mutations in this area is furthering our knowledge on the important mechanisms that regulate childhood growth and body composition. This review describes the genetic syndromes associated with obesity and overgrowth.
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Obesidad/genética , Sobrepeso/genética , Anomalías Múltiples/genética , Arritmias Cardíacas/genética , Síndrome de Beckwith-Wiedemann/genética , Composición Corporal/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Fertilización In Vitro/efectos adversos , Enfermedades Genéticas Ligadas al Cromosoma X , Predisposición Genética a la Enfermedad , Gigantismo/genética , Síndrome de Hamartoma Múltiple/genética , Deformidades Congénitas de la Mano/genética , Cardiopatías Congénitas/genética , Homocistinuria/genética , Humanos , Discapacidad Intelectual/genética , Síndrome de Klinefelter/genética , Síndrome de Marfan/genética , Obesidad/etiología , Proopiomelanocortina/genética , Proproteína Convertasas/genética , Síndrome de Sotos/genética , Síndrome , Aumento de Peso/genéticaRESUMEN
BACKGROUND: Childhood obesity is associated with the early development of diseases such as type 2 diabetes and cardiovascular disease. Unfortunately, to date, traditional methods of research have failed to identify effective prevention and treatment strategies, and large numbers of children and adolescents continue to be at high risk of developing weight-related disease. AIM: To establish a unique 'biorepository' of data and biological samples from overweight and obese children, in order to investigate the complex 'gene × environment' interactions that govern disease risk. METHODS: The 'Childhood Overweight BioRepository of Australia' collects baseline environmental, clinical and anthropometric data, alongside storage of blood samples for genetic, metabolic and hormonal profiles. Opportunities for longitudinal data collection have also been incorporated into the study design. National and international harmonization of data and sample collection will achieve required statistical power. RESULTS: Ethical approval in the parent site has been obtained and early data indicate a high response rate among eligible participants (71%) with a high level of compliance for comprehensive data collection (range 56% to 97% for individual study components). Multi-site ethical approval is now underway. CONCLUSIONS: In time, it is anticipated that this comprehensive approach to data collection will allow early identification of individuals most susceptible to disease, as well as facilitating refinement of prevention and treatment programs.
Asunto(s)
Investigación Biomédica , Bases de Datos Factuales , Obesidad , Adolescente , Australia , Niño , Preescolar , Comorbilidad , Recolección de Datos , Humanos , Obesidad/genética , Sobrepeso , Factores de Riesgo , Pérdida de PesoRESUMEN
Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved.
Asunto(s)
Inhibidores de la Aromatasa/efectos adversos , Desarrollo Óseo/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/fisiopatología , Hiperplasia Prostática/etiología , Animales , Densidad Ósea/efectos de los fármacos , Densidad Ósea/fisiología , Desarrollo Óseo/fisiología , Huesos/patología , Niño , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/patología , Trastornos del Crecimiento/fisiopatología , Humanos , Letrozol , Hormona Luteinizante/sangre , Masculino , Nitrilos/efectos adversos , Próstata/efectos de los fármacos , Próstata/patología , Hiperplasia Prostática/patología , Ratas , Ratas Wistar , Maduración Sexual/fisiología , Testículo/efectos de los fármacos , Testículo/patología , Triazoles/efectos adversosRESUMEN
OBJECTIVE: Type 1 diabetes in youth and community controls were compared on functional outcomes. Relationships were examined between psychosocial variables at diagnosis and functional outcome 12 years later. RESEARCH DESIGN AND METHODS: Participants were subjects with type 1 diabetes (n = 110, mean age 20.7 years, SD 4.3) and control subjects (n = 76, mean age 20.8 years, SD 4.0). The measures used included the Youth Self-Report and Young Adult Self-Report and a semi-structured interview of functional outcomes. Type 1 diabetes participants also provided information about current diabetes care and metabolic control from diagnosis. RESULTS: Type 1 diabetes participants and control subjects reported similar levels of current well-being but for the youth with type 1 diabetes, the mental health referral rates over the previous 12 years were higher by 19% and school completion rates were lower by 17%. Over one-third of clinical participants were not currently receiving specialist care and this group had higher mental health service usage in the past (61 vs. 33%) and lower current psychosocial well- being. Within the type 1 diabetes group, behavior problems, high activity, and low family cohesion at diagnosis predicted lower current well-being, but were not associated with metabolic control history. Poorer metabolic control was associated with higher mental health service usage. CONCLUSIONS: Type 1 diabetes participants report similar levels of current psychosocial well-being compared with control subjects, but higher levels of psychiatric morbidity since diagnosis and lower school completion rates. Psychiatric morbidity was associated with poor metabolic control and failure to transition to tertiary adult diabetes care.