ABSTRACT
La talla baja idiopática (TBI) incluye a un grupo heterogéneo de pacientes con fallas en su crecimiento. Una causa probable de TBI puede ser la insensibilidad a la GH (IGH). La proteína de unión de GH de alta afinidad (GHBP) se genera por el clivaje proteolítico de la porción extracelular del receptor de GH (GHR) y su determinación se propone como un marcador periférico del nivel de GHR en los tejidos. El objetivo de este trabajo fue evaluar los niveles de GHBP circulantes y su asociación con factores de crecimiento y el polimorfismo del exón 3 del gen GHR en niños con TBI. Los niños con TBI presentaron talla, IMC, IGF-I, IGFBP-3, ALS y niveles de GHBP significativamente más bajos que un grupo de niños de edad comparable (p<0.001). El genotipo del exón 3 del GHR no fue un factor determinante de las diferencias observadas. La máxima respuesta de GH de los tests de estímulo de secreción correlacionó negativa y significativamente con los niveles de GHBP (r= -0.28, p= 0.012). Los perfiles de distribución de la concentración de GHBP, IGF-I, ALS y BP3 expresadas en score de desvío estándar (SDE) en la TBI, mostraron un sesgo hacia niveles bajos. En conclusión, los marcadores de acción de GH y los niveles de GHBP fueron bajos en la TBI, independientemente del genotipo del exón 3 del gen GHR. En un subgrupo de niños con TBI, niveles disminuidos de GHBP y de componentes del sistema de los IGFs, colaborarían en la evaluación de la IGH sugiriendo la búsqueda de defectos en el GHR.
Idiopathic Short Stature (ISS) includes a heterogeneous group of children with growth failure. One possible explanation for the growth failure is a reduced responsiveness to growth hormone (GH). Human circulating GH is partially bound to a highaffinity binding protein (GHBP) which is derived from proteolytical cleavage of the extracellular domain of the GH receptor. Many reports have demonstrated a close relationship between GHBP and liver GH receptor status in physiological conditions and diseases. Moreover, serum GHBP measurement has been proposed as an useful peripheral index of GH receptor abundance. Our objective was the evaluation of serum GHBP levels and its probable association with serum growth factors (IGF-I, IGFBP-3 and ALS) and the exon 3 polymorphism of the extracellular domain of the GHR gene in ISS children. Children with ISS presented significantly lower height SDS, BMI SDS, serum components of the IGFs system and GHBP concentration as compared to an age-matched control group of normal children (p<0.001). Interestingly, exon 3 genotype did not influence the differences observed in these parameters. The maximal GH response obtained after two GH provocative tests inversely and significantly correlated to GHBP serum levels (r= -0.28, p= 0.012). A frequency study showed a deviation to low SDS values of serum GHBP, IGF-I, IGFBP-3 and ALS. Conclusion: 1- in children with ISS the exon 3 genotype of the GHR gene is not a factor that could explain the lower levels observed in circulating GHBP concentration and components of the IGFs system; 2- low serum GHBP together with low IGF-I, IGFBP-3 or ALS levels would help pointing to GH insensitivity due to GH receptor gene abnormalities in ISS.
Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , Human Growth Hormone/biosynthesis , Failure to Thrive/etiology , Biomarkers/metabolism , Human Growth Hormone/genetics , Intercellular Signaling Peptides and Proteins/geneticsABSTRACT
La hormona de crecimiento humana (hGH) circula parcialmente unida a su proteína de transporte de alta afinidad (GHBP) la cual resulta del clivaje proteolítico del dominio extracelular del receptor de GH. Recientemente la enzima TACE se identificó como la metaloproteasa responsable del clivaje y liberación de GHBP a circulación. Aunque aún se desconoce la función específica de esta proteína de transporte, distintos trabajos en la literatura demuestran efectos que potencian y efectos inhibitorios sobre la acción de GH. Por otro lado, existen evidencias que demuestran una fuerte relación entre la GHBP y el nivel de receptor de GH en el hígado en situaciones fisiológicas y patológicas. Esto permitió proponer a la determinación de GHBP en suero como un marcador periférico de la abundancia del receptor de GH en los tejidos. La determinación de la concentración de GHBP sería de especial interés para evaluar pacientes con diagnóstico probable de insensibilidad a la acción de GH y orientar el posterior estudio de anormalidades en el gen del receptor de GH. En la presente revisión, también se abordan dificultades metodológicas relacionadas a la medición de GHBP sérica.
Human circulating growth hormone (GH) is partly bound to a high-affinity binding protein (GHBP) which is derived from proteolytical cleavage of the extracellular domain of the GH receptor. Recently, the metalloproteinase TACE has been identified as an important enzyme responsive for inducing GHBP shedding. Although the specific function of GHBP is not fully known, both enhancing and inhibitory roles of this binding protein on GH action have been proposed. Many reports have demonstrated a close relationship between GHBP and the liver GH receptor status in physiological conditions and diseases. Moreover, serum GHBP measurement has been proposed as an useful peripheral index of the GH receptor abundance. Related to the latter, circulating GHBP concentration would be of special interest for the evaluation of GH insensitivity due to GH receptor gene abnormalities. In addition, the present review also focus on methodological problems concerning serum GHBP measurement.
ABSTRACT
BACKGROUND: As GHBP is believed to be derived from proteolytic cleavage of the extracellular domain of the GH receptor and may be regarded as an intrinsic part of the GH-IGF-1 axis, an effect of body composition on circulating GHBP levels may be expected. We investigated GHBP variations in obesity with varying glucose tolerance and its relationship to body fat distribution, sex hormones, insulin secretion, and the GH-IGF-1 axis. METHODS: Bioelectrical impedence for measurement of total body fat and computed tomography for visceral fat and subcutaneous fat at umbilicus level were performed in 69 obese Koreans and 21 lean Koreans. Insulin secretion in response to an oral glucose tolerance test (OGTT) and a GH stimulation test by L-dopa, growth hormone-binding protein (GHBP), insulin-like growth factor (IGF)-1 and sex hormones (estrone, estradiol, total and free testosterone) were measured. RESULTS: Obese type 2 DM group had the highest GHBP levels and the most visceral fat amount. GHBP levels were most strongly correlated with the ratio of visceral fat area to body weight (VWR) above other parameters (r=0.725, p<0.001). Insulin- and free fatty acid-area under the curve (AUC) during OGTT and IGF-1 level were also positively correlated with GHBP levels (r=0.474, p<0.005; r=0.572, p<0.005; r=0.453, p<0.005). GH-AUC to L-dopa stimulation test was negatively correlated with GHBP levels (r=0.432, p<0.005). The GHBP level was slightly higher in females than in male in the same glucose tolerance category. In males, total and free testosterone levels were negatively correlated with GHBP levels (r=-0.516, p<0.001;r=-0.653, p<0.001). Stepwise multiple linear regression analysis showed that VWR, FFA-and insulin-AUC significantly contributed to the variability of GHBP (r=0.58). CONCLUSION: We demonstrated that 1) visceral fat amount was mainly determined GHBP levels in obese subjects with varying glucose tolerance; 2) hyperglycemia per se did not influence GHBP level, whereas insulin and FFA could play a role in regulation of GHBP level. 3) The constant concentration of IGF-1 despite GH hyposecretion suggests that increased GHBP level retlect GHBP hypersensitivity in order to compensate for decreased GH secretion in obesity; 5) the lower level of GHBP in males might be explained at least in part by a suppressive effect of androgen.