Growth regulation最新文献

The goal of our study was to compare the clinical usefulness of plasma insulin-like growth factor-I (IGF-I) (with and without binding protein extraction) and IGF binding protein-3 (IGFBP-3) measurements in the diagnosis of growth hormone (GH) disorders in adults. IGF-I and IGFBP-3 concentrations were measured in 25 acromegalic and 25 GH-deficient adult (GHDA) subjects (20-76 years) by comparison to a control population (n = 81) after age and sex stratification. In untreated acromegaly, IGF-I and IGFBP-3 were clearly increased (10 times the mean of controls for unextracted IGF-I, 4 times for extracted IGF-I and 2 times for IGFBP-3). Using the mean + 2SD of the control population as the cut-off point, the sensitivity of IGF-I for the diagnosis of acromegaly was higher than that of IGFBP-3 (unextracted IGF-I: 96% and extracted IGF-I: 100% vs IGFBP-3: 76%). In GHDAs, IGF-I and IGFBP-3 were decreased (34% of the mean of controls for unextracted IGF-I, 37% for extracted IGF-I and 70% for IGFBP-3). Using the mean - 2SD of the control population as the cut-off point, the sensitivity of IGF-I measurement for the diagnosis of GHDA was relatively low, but better for unextracted (68%) than for extracted IGF-I (52%). The sensitivity of IGFBP-3 was much lower (36%), thus invalidating this parameter for the diagnosis of GHDA. Our observations demonstrate that IGF-I measurement is a more powerful tool than IGFBP-3 measurement for the diagnosis of GH disorders in adults. Both IGF-I and IGFBP-3 are very useful for the diagnosis of acromegaly, but they are less reliable for diagnosing GHDA, as normal IGF-I or IGFBP-3 values do not rule out GH deficiency.

The aberrant body composition of 10 patients with active acromegaly was used to evaluate the validity and limitations of several models and methods to assess body composition. Body composition was determined using either a two-compartment model, dividing the body in a body fat (BF) compartment and a fat-free mass (FFM) compartment, or a four-compartment model in which the FFM compartment comprises the three following components: body cell mass, extracellular water and the fat-free extracellular solids. The measurement techniques consisted of anthropometry, bioelectrical impedance analysis (BIA)-applying various established regression equations-tritiated water dilution, whole body 40K-counting, and whole body computed tomography (CT). This latter method was used as the reference technique. Assessment of total body water using BIA - applying the RJL or Kushner equation-correlated significantly with the assessment using tritiated water dilution (P < 0.01). Body fat assessment using the two-compartment model based on either tritiated water dilution or BIA-applying the RJL or Lukaski equation-as well as body fat assessment using the four-compartment model based on tritiated water dilution and whole body 40K-counting were significantly correlated with body fat assessment using CT (P < 0.01) and resulted in good agreement with each other with respect to the absolute values of the body fat determination. BIA using other regression equations overestimated body fat by 7.2-13.7 kg. Whole body 40K-counting was significantly correlated with CT-determined muscle plus skin volume (P < 0.001). CT-calibrated anthropometric predictions significantly overestimated body fat. It is concluded that in patients with active acromegaly, the determination of body composition using either certain two-compartment models based on measurement of total body water or bioelectrical impedance, or a four-compartment model based on total body water and total body potassium measurements show good agreement with CT-determined body composition.

Despite early evidence from studies performed soon after its discovery, the role of human growth hormone (GH) in metabolic processes during adulthood has, until recently, been largely ignored. The importance of GH in the regulation of body composition in the adult is clearly demonstrated by the abnormalities seen in "nature's experiments', i.e. acromegaly and GH deficiency. Body composition has been shown to change favourably following successful treatment of acromegaly. Formal replacement studies in adult GH-deficient patients, made possible by the recent advent of recombinant GH, have also shown dramatic changes in body composition, with increases in lean body mass and reductions in fat mass towards normality and associated improvements in physical performance. Thus, adult GH deficiency, like acromegaly, has become widely accepted as a distinct clinical entity warranting treatment.

We examined in a factorial design the effect of dietary protein (45%, 52% and 60%) and lipids (8%, 12%, 17%) on growth performance and circulating growth hormone (GH) levels of fingerling sea bream (5-month-old) fed to satiation with self-feeders. Daily weight gain (2.6-2.9%) and feed gain ratio (1.1-1.3) of fish fed high protein-low lipid diets were comparable to those found in fast growing strains of rainbow trout. However, increasing hyperphagia in association with the decrease of daily weight gain and feed conversion efficiency were found with the decrease of dietary protein:energy ratio. This growth impairment was linked to increased concentrations of circulating GH, which would exacerbate glucose and lipid intolerance. We consider the elevated concentration of circulating GH to be a risk factor leading to some state of metabolic starvation, in which feeding behavior and feed conversion efficiency are largely altered. From our results, it can be also concluded that circulating and pituitary GH availability decreases progressively from 1- to 3-year-old fish. This blunted GH synthesis and release is discussed in relation to age decrease in the optimum dietary protein:energy ratio.

IGFBP-3 contains a carboxyterminal basic region which, when present as an isolated 18 amino acid peptide (P3), binds heparin, associates with cultured endothelial cells and stimulates glucose uptake. The P3 molecule has now been modified relative to charge, amino acid sequence and size to determine structure-function relationships relative to four properties of P3: affinity for heparin; inhibition of IGFBP-3 binding; stimulation of glucose uptake; and displacement of bFGF from the extracellular matrix of endothelial cells. Results indicate: (1) the presence or absence of heparin binding was concordant with the presence/absence of the other three properties; (2) the number of basic amino acids was an important, if not limiting, factor for each property; (3) the order of potency of the basic amino acids was arginine = lysine > > histidine; (4) the unrelated, basic protein, protamine, mimics all properties of P3; and (5) the putative consensus heparin-binding sequence of P3 was not essential for any of the P3 activities.

Catch-up or compensatory growth is known as a physiological phenomenon. However, most studies of catch-up growth were based on measurements of body weight, whereas changes in longitudinal bone growth remained largely undescribed. The present study describes the dynamics of both weight and longitudinal bone growth using mikro-knemometry, during normal feeding, severe food restriction (starvation), and refeeding of 14 intact and 28 GH-deficient male rats. Starvation induced rapid weight loss (P < 0.001), and stunted leg growth (P < 0.001). Refeeding led to rapid catch-up in weight of up to 4 times above normal daily weight gain, both in intact and GH-deficient animals, whereas an equivalent compensation of lower leg growth remained undetectable. Intact and GH-deficient animals show a circaseptan spontaneous variation of growth velocity (mini growth spurts). During starvation, mini growth spurts disappear, and return to normal after refeeding with no evidence of catch-up. In GH-deficient animals, GH (1 IU/rat, administered twice daily s.c. at 10:00 hand 16:00 h) was capable of augmenting catch-up in weight and, to a lesser extent, in leg length increment.

Testosterone regulation of antler growth may be via the insulin-like growth factors (IGFs). Using histological autoradiography we have measured the specific binding of IGF-I and IGF-II to antler sections during normal growth and during the maturation which follows testosterone treatment of adult fallow deer. In antlers from 20 to 100 days following casting, IGF-I binding was constant within each histological region until 80 days. Between this time and 100 days there was decreased binding to chondrocytes (P < or = 0.01) and increased binding to the reserve mesenchyme/perichondrium (P < or = 0.001). Following testosterone treatment, IGF-I binding declined in dermis (P < or = 0.05), reserve mesenchyme/perichondrium (P < or = 0.05), and chondroblasts (P < or = 0.01). Specific binding of IGF-II showed no change during normal or testosterone-stimulated growth. In conclusion, the regulation of antler maturation by testosterone may include IGF action, probably via the Type 1 IGF receptor.

Previous studies involving fetal decapitation or hypophysectomy, and the treatment of neonates with hormones or antibodies, have suggested that changes in pituitary hormone status during the perinatal period may influence later body composition. In the present study, rats were treated for the first 21 days of life with twice daily subcutaneous injections of saline, recombinant bovine growth hormone (bGH) or pituitary ovine prolactin (oPRL). The bGH and oPRL were administered at doses of 0.2 or 0.4 microgram/g bodyweight/day. One-third of the rats in each treatment group were slaughtered at each of days 21, 60 and 120 of life and measurements made of: length and weight of the body; weights of bones and muscle groups in the hindlimb; weights of four fat depots (120-day group only); and the content of nitrogen (N) and fat in the carcass. bGH, but not oPRL, treatment increased weight of the femur and humerus (across ages) but neither treatment had marked effects on weights of muscle groups, carcass weight or carcass N content at any age. Both bGH and oPRL treatment significantly reduced weight of the subcutaneous scapular fat depot and reduced carcass fat content, but only in animals aged 120 days (i.e. 99 days after the cessation of treatment). It is concluded that treatment of rats with bGH and oPRL during the immediate postnatal period specifically retards the ability of animals to deposit body fat in later life by mechanisms which differ from those involved in the classical lipolytic/antilipogenic effects of bGH.

Osteoblast-like UMR-106.01 rat osteosarcoma cells express high affinity growth hormone (GH) receptors (GHRs). Because osteoblasts secrete insulin-like growth factor binding protein-5 (IGFBP-5), we evaluated whether it also modulates GH binding and GHR expression in UMR cells. Human recombinant intact IGFBP-5 stimulated 125I-hGH binding in a dose-dependent manner (dose range 300-3000 ng/ml), inducing an increase to 193.6 +/- 2.1% of control binding at 3000 ng/ml (P < 0.001). Carboxy-truncated IGFBP-5 also stimulated GH binding but with less potency (125 +/- 2.7% of control at 3000 ng/ml, P < 0.01). GHRs identified by chemical crosslinking of 125I-hGH to cell monolayers increased after treatment with IGFBP-5 and decreased in response to insulin-like growth factor-I (IGF-I). GHR mRNA levels, as quantitated by a solution hybridization RNAse protection assay, increased up to 3 to 7-fold in a time-dependent manner by intact IGFBP-5 but not by carboxy-truncated IGFBP-5. An antiserum to IGFBP-5 reduced basal GH binding to 56.7 +/- 4.3% of control value at a concentration of 0.5% (P < 0.001), showing that IGFBP-5 produced by the cells is a strong regulator of GH binding. IGFBP-5 antiserum also decreased GH binding to 85.9 +/- 0.9% of IGFBP-5 stimulated value (P < 0.001), showing the specificity of IGFBP-5 stimulation. To determine whether the GHR upregulation was physiologically significant, cell proliferation was evaluated after coincubation of IGFBP-5 with low, non-stimulatory concentrations of GH. IGFBP-5 (1000 ng/ml) induced cell proliferation to 116.2 +/- 3.2% of control levels, and coincubation with hGH at 10 ng/ml induced an increase to 133.3 +/- 0.1% of control levels. We conclude that exogenous and endogenous IGFBP-5 upregulate GHR mRNA levels and GH binding and this interaction potentiates GH-stimulated mitogenesis in osteoblastic cells.

The presence of growth hormone (GH) receptor (GHR) gene transcripts and GH-binding sites in guinea pig liver suggests normal expression and translation of a GHR gene in these animals. Guinea pigs are, however, resistant to GH action and appear to lack the circulating GH-binding proteins (GHBPs) that result from alternate splicing of the GHR message or from cleavage of the extracellular binding domain of membrane GHRs. The paradoxical absence of circulating GHBPs in guinea pigs was therefore examined. The presence of GHR/GHBP mRNA in guinea pig liver was confirmed by Northern blotting. In addition to a 4.4 kb transcript that probably encodes a full-length receptor, an additional 1.9 kb transcript was detected that may encode a binding protein, although this transcript is larger than rat GHBP mRNA. The possibility that these transcripts may be translated into GHBPs was assessed immunologically. A 46 kDa protein, identical in size to rat GHBP, was specifically detected in guinea pig liver by a monoclonal antibody (MAb 4.3) raised against the hydrophilic tail of rat GHBP. A single protein of approximately 48 kDa was also detected by MAb 4.3 in proteins precipitated from guinea pig serum by a polyclonal antibody raised against the rat GHBP. This protein was slightly larger than the two proteins (46 kDa and 40 kDa) in rat serum labelled by the same method. The presence of a putative GHBP in guinea pig serum was also supported by the cross-reactivity of guinea pig serum with a monoclonal antibody (MAb 263) raised against rat GHBP. The binding of radioiodinated hGHBP to this antibody was inhibited, in a dose-related way and parallel to that of the standard, by serial dilutions of guinea pig serum, indicating immunoreactive GHBP concentrations > 500 ng/ml. Immunoreactive GHBP concentrations in other mammalian serum (from rats, rabbits, pigs, cattle, horses, goats, dogs and humans) were, in contrast, < 30 ng/ml. Guinea pig sera similarly cross-reacted, but to a lesser degree, in other radioimmunoassays for rGHBP, in which p(Ab)1 or MAb 4.3 were used as the primary antibodies. Nevertheless, despite these immunological findings, hGH binding activity could not be detected in guinea pig serum using a number of different radioligand binding assays. These results suggest the novel presence of abundant, but possibly defective, GHBP-like proteins in guinea pig serum. The immunological detection of the hydrophilic sequence of rat GHBP in guinea pig hepatic and serum proteins also suggests that GHBPs in this species arise from the truncated GHR gene transcript identified in guinea pig liver.