The phosphorylation status of insulin-like growth factor-binding protein-1 in prepubertal obese children

OBJECTIVE: We measured the total and nonphosphorylated insulin-like growth factor-binding protein (IGFBP)-1 concentrations in obese children to determine the effect of obesity on the status of IGFBP-1 phosphorylation. We also measured the serum levels of insulin, total and free IGF-I, and IGFBP-3 to investigate their relationships to the IGFBP-1 phosphorylation status in obese subjects. SUBJECTS AND METHODS: Nineteen prepubertal obese and 15 age-matched control children were included in the study. The serum levels of total and nonphosphorylated IGFBP-1 were determined by noncompetitive RIAs. RESULTS: The serum levels of total and nonphosphorylated IGFBP-1 were significantly lower in the obese group (48.7+/-5.6 microgram/l, P<0.001 and 11.1+/-1.9 microgram/l, P<0.01 respectively) than in the controls (86.7+/-9.0 microgram/l and 28.8+/-6.2 microgram/l respectively). However, the ratio of nonphosphorylated IGFBP-1 to total IGFBP-1 did not differ significantly between the obese and control groups. The circulating free IGF-I level was significantly higher in the obese children than in the controls (P<0.05), while the serum levels of insulin, total IGF-I and IGFBP-3 were not significantly different between the two groups. A stepwise regression analysis of the combined group revealed that only the total IGFBP-1 level was an independent predictor of the free IGF-I concentration (P<0.001). CONCLUSION: The present study shows that both total and nonphosphorylated IGFBP-1 concentrations are decreased in obese children and the increased free IGF-I level in obese children is related to the reduced total IGFBP-1 level, but unrelated to the change in the IGFBP-1 phosphorylation status.     

The use of insulin-like growth factor 1 reference values for the diagnosis of growth hormone deficiency in prepubertal children

OBJECTIVE: This study was done to determine whether the use of reference values obtained in children with idiopathic short stature (ISS) improved the clinical value of serum insulin-like growth factor I (IGF-1) as a tool for diagnosing GH deficiency (GHD) in prepubertal children. PATIENTS AND METHODS: Serum IGF-1 was measured with a new IRMA kit (IGFI-RIA CT, Cis Bio, Gif sur Yvette, France) in 168 prepubertal normal children and in prepubertal children with ISS (n = 68), organic GHD due to a craniopharyngioma (oGHD, n = 15) and permanent idiopathic GHD (iGHD, n = 28). RESULTS: IGF-1 was lower (P < 0.001) in iGHD than in either ISS or oGHD and was below the fifth percentile of the normal range in 29/68 ISS (43%), 8/15 oGHD (53%) and 28/28 (100%) iGHD patients. Three oGHD (20%) and two iGHD (7%) patients had a serum IGF-1 below the fifth percentile of the normal group but above the fifth percentile of the ISS group. Thus, a serum IGF-1 below the fifth percentile of the normal group distinguished between normal children and iGHD with 100% sensitivity, between normal and oGHD with 53% sensitivity and between normal and all GHD (idiopathic + organic) with 84% sensitivity; the overall specificity was only 57%. Conversely, a serum IGF-1 below the fifth percentile of the ISS population distinguished between ISS and iGHD with 93% sensitivity, between ISS and oGHD with 33% sensitivity and between ISS and all GHD with 72% sensitivity; the overall specificity was then 95%. CONCLUSIONS: A serum IGF-1 within the normal range virtually excludes idiopathic GHD but does not rule out organic GHD, whereas an IGF-1 below the ISS range is strongly in favour of GHD, after exclusion of poor nutritional status and/or liver disease. An IGF-1 below the normal range but in the idiopathic short stature range gives no definitive conclusion even when it is associated with a low GH peak. Thus, whereas reference values obtained in normal children must be used to interpret serum IGF-1 in short prepubertal children, reference data obtained in idiopathic short stature children should also be taken into account.     

Exon 3-deleted genotype of growth hormone receptor (GHRd3) positively influences IGF-1 increase at generation test in children with idiopathic short stature

CONTEXT: A GHR-exon 3 polymorphism has been reported to influence the growth response to hGH therapy in short stature children. None of these studies provided data on IGF-1 generation test. OBJECTIVE: To evaluate the influence of the GHR-exon 3 polymorphism on the generation test in children with idiopathic short stature (ISS). DESIGN AND PATIENTS: A total of 45 prepubertal ISS children were submitted to IGF-1 and IGFBP-3 generation test (4 days of hGH 33 microg/kg/day). Children were genotyped for GHR-exon 3: full-length (fl) and exon 3-deleted (d3) alleles. MEASUREMENTS: IGF-1 and IGFBP-3 increment as absolute values and standard deviation scores (SDS). RESULTS: Basal clinical and laboratory data were similar among patients with different genotypes (fl/fl vs. fl/d3 or d3/d3). All patients presented IGF-1 increase >or= 15 microg/l at generation test. Children with GHRd3 allele, as a group, presented a statistically significant higher IGF-1 SDS increase at generation test than children homozygous for GHRfl allele (1.0 ranging from 0.1 to 3.7 for fl/fl vs. 1.2 ranging from 0.3 to 4.4 for fl/d3 and d3/d3; P = 0.037). Multiple linear regression found a positive association between increase in IGF-1 SDS with chronological age (P = 0.007) and GHR genotype (P = 0.027), which together explain 24% of the variability of IGF-1 SDS increment at generation test. There was no difference in IGFBP-3 generation test between the two genotype groups. Conclusion: This study demonstrates that ISS children carrying the GHRd3 allele, as a group, present a slightly higher GH sensitivity regarding short-term IGF-1 generation during hGH stimulus than children homozygous for GHRfl allele.     

Skin fibroblasts of children with idiopathic short stature show an increased mitogenic response to IGF-I and secrete more IGFBP-3

OBJECTIVE AND PATIENTS: To study differences in cellular parameters of GH and IGF-I responsiveness in skin fibroblasts of 14 children with idiopathic short stature (ISS) treated with recombinant human GH and 13 children with normal height. Secondly, to investigate whether these cellular parameters can predict the growth response to GH treatment in children with ISS. DESIGN AND MEASUREMENTS: The mitogenic responsiveness to GH and IGF-I was investigated by 3H-Thymidine incorporation. Insulin-like growth factor binding protein-3 (IGFBP-3) levels in the media were measured by radioimmunoassay (RIA). RESULTS: No significant mitogenic responses were observed to various doses of GH (1000, 5000 or 50.000 ng/ml) in children with ISS or controls. ISS fibroblasts showed an increased mitogenic response to IGF-I (10 ng/ml) compared to controls (mean +/- SD 5.9 +/- 2.4- vs. 4.2 +/- 1.5-fold stimulation, P < 0.05), and GH enhanced this effect in both groups. IGFBP-3 secretion was increased in ISS fibroblasts when compared to controls under all conditions examined (basal, 200 and 5000 ng/ml GH, 10 ng/ml IGF-I for 24 and 48 h). High IGFBP-3 levels were related to low mitogenic responses to IGF-I or to GH + IGF-I in children with ISS (r = -0.7, P < 0.05), but not in controls. Within the ISS group, an enhanced mitogenic response to IGF-I in vitro was related to more extreme short stature before GH treatment (r = -0.70, P < 0.05) and to a relatively impaired response to high dose GH treatment in vivo (r = -0.52, P < 0.05). CONCLUSION: The demonstration of high IGFBP-3 levels and enhanced mitogenic response to IGF-I shows that ISS fibroblasts have different cellular characteristics compared to controls of normal height. It is hypothesized that in ISS an alteration of the signal transduction pathway between the GH receptor and IGFBP-3 synthesis results in a local imbalance with high IGFBP-3 levels and lower IGF-I availability for the IGF-I receptor. This may be reflected by an increased IGF-I responsiveness in vitro which is associated with an impaired capacity to grow in vivo.     

Serum levels of adiponectin and IGFBP-1 in short children born small for gestational age

OBJECTIVE: The aim of this study was to quantify serum adiponectin concentrations in short children born small for gestational age (SGA) compared with those in children born appropriate for gestational age (AGA), and to assess the relationship between the serum levels of adiponectin and insulin-like growth factor binding protein-1 (IGFBP-1) known as a predictor of the development of type 2 diabetes mellitus and cardiovascular disease. SUBJECTS AND METHODS: Sixteen prepubertal short children born SGA and 20 short children born AGA, matched for age, body mass index, height, pubertal status, gestational age, bone age and midparental height, were included in the study. The serum levels of adiponectin, IGFBP-1, insulin and insulin-like growth factor-I (IGF-I) were measured in the fasting state. RESULTS: The levels of serum adiponectin were significantly lower in the SGA than in AGA children (10.5 +/- 4.2 vs. 13.9 +/- 5.1 micro g/ml, P < 0.05). The levels of serum IGFBP-1, insulin and IGF-I were all similar in both groups. Overall, there was a significant positive correlation between adiponectin and IGFBP-1 (r = 0.40, P < 0.05). CONCLUSIONS: Our results suggest that hypoadiponectinaemia in short SGA children without catch-up growth may reflect insulin resistance and imply a higher risk of developing type 2 diabetes mellitus. Additionally, adiponectin may be a more sensitive indicator for latent insulin resistance than IGFBP-1 in short SGA children.     

重组人生长激素治疗不同生长激素分泌状态青春前期矮小患儿追赶性生长模式分析

目的 比较不同生长激素(GH)分泌状态矮小患儿重组人生长激素(rhGH)治疗后的初始追赶性生长模式,初步探讨其机制.方法 回顾性分析62例青春前期不同GH分泌状态矮小患儿对rhGH治疗1年半的追赶性生长模式并定期监测体格指标、促生长素轴的血清指标和骨龄.结果 各组在初始追赶性生长的幅度相似,特发性矮小(ISS)组比完全性生长激素缺乏症(GHD)组更早出现生长减速,并与生长激素结合蛋白(GHBP)水平降低和胰岛素样生长因子结合蛋白3的标准差分数(SDS)增值较小显著相关.GH激发峰值(Ghmax)>7μg/L的部分性GHD组与ISS组有类同的生长追赶的模式.结论 GH受体的降调节和受体后效应的降低可能是ISS组较早出现生长减速的机制.以Ghmaxμg/L作为GHD诊断的界值并相应选择rhGH治疗剂量有更充分的依据和临床意义.     

The serum levels of proinsulin and their relationship with IGFBP-1 in obese children

AIM: Serum proinsulin (PI) levels were investigated in obese children to determine whether PI is a sensitive indicator of insulin resistance, as previously shown in adults with type 2 diabetes mellitus (DM), and to evaluate their relationship with insulin-like growth factor-binding protein-1 (IGFBP-1) known as a predictor of the development of cardiovascular disease in diabetic adults. SUBJECTS AND METHODS: Forty-two obese children without DM (age, 12.1 +/- 1.5 year) and 42 age-matched control children were included in the study. The serum levels of PI, immunoreactive insulin (IRI), IGFBP-1 and free insulin-like growth factor-1 (IGF-1) were measured in the fasting state. RESULTS: The fasting levels of serum PI and IRI were significantly higher in obese children than in controls (PI, 10.5 +/- 6.8 vs. 5.6 +/- 2.0 pmol/l, p < 0.001; IRI, 72.0 +/- 41.8 vs. 32.7 +/- 19.5 pmol/l, p < 0.001). Serum IGFBP-1 levels were significantly lower in obese children than in controls (37.7 +/- 24.6 vs. 76.3 +/- 26.5 microg/l, p < 0.001). The ratio of PI to IRI (calculated as molar ratios) did not differ significantly between obese and control subjects (0.16 +/- 0.08 vs. 0.19 +/- 0.11, p = 0.08). For the whole group, serum PI levels correlated positively with IRI and inversely with IGFBP-1 (IRI, r = 0.67, p < 0.001; IGFBP-1, r = -0.49, p < 0.001). Serum IGFBP-1 levels correlated inversely with both BMI and IRI (BMI, r = -0.73, p < 0.001; IRI, r = -0.60, p < 0.001). Multiple regression analysis revealed that the best predictive parameters for IGFBP-1 were BMI and PI (R2 = 0.57, p < 0.001 and p < 0.05, respectively). CONCLUSION: These findings suggest that fasting serum PI levels may be a better predictor than fasting insulin levels for the future development of type 2 DM and cardiovascular disease in obese children, and PI, in addition to insulin, contributes to the suppression of hepatic IGFBP-1 production.     

Serum insulin-like growth factor type 1, insulin-like growth factor-binding protein-1, and insulin-like growth factor-binding protein-3 concentrations in patients with thyroid dysfunction.

Thyroid hormones play a role in the regulation of insulin-like growth factor type 1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) expression, and both IGF-1 and IGFBPs have been shown to be related to the function and growth of the thyroid. Our aim was to evaluate serum concentrations of IGF-1, IGFBP-1, and IGFBP-3 in patients with thyroid dysfunction before and after normalization of thyroid function. The study was performed in 86 patients with thyroid dysfunction (43 hyperthyroid and 43 hypothyroid patients) and 17 euthyroid subjects. Serum growth hormone (GH), insulin, IGF-1, IGFBP-1, and IGFBP-3 were measured in all patients before and after normalizing serum thyroid hormone concentrations. Hyperthyroid patients showed IGF-1 (198.8 +/- 17.0 microg/L) and IGFBP-3 levels (4.2 +/- 0.2 mg/L) similar to those found in the control group (217.9 +/- 20.3 microg/L and 4.2 +/- 0.3 mg/L, respectively). After therapy these levels significantly decreased to 156.6 + 11.1 microg/L (p < 0.01) and 3.3 +/- 0.1 mg/L (p < 0.001), respectively. IGFBP-1 concentrations were clearly higher than those found in controls (22.7+/- 2.6 vs. 5.7 +/- 1.5 microg/L, p < 0.001) and exhibited a significant reduction after therapy for thyroid hyperfunction (11.0 +/- 1.7 microg/L, p < 0.001). Patients with hypothyroidism showed serum concentrations of IGF-1 (161.5 +/- 13.1 microg/L, p < 0.05) and IGFBP-3 (3.2 +/- 0.3 microg/L, p < 0.05) significantly lower than those found in healthy volunteers. However, replacement therapy with levothyroxine did not induce any significant modification of these concentrations (152.6 +/- 10.6 microg/L and 3.2 +/- 0.2 mg/L, respectively). Similarly, patients with thyroid hypofunction exhibited raised levels of IGFBP-1 (15.5 +/- 0.9 microg/L, p < 0.05 vs. control group) that were significantly decreased after therapy (8.8 +/- 1.4 microg/L, p < 0.01). The results of the present study show that thyroid status affects GH/IGF axis. Hypothyroidism is associated with significant reductions of IGF-1 and IGFBP-3, and IGFBP-1 is elevated in both hypothyroidism and hyperthyroidism.     

Do growth hormone (GH) serial sampling,insulin‐like growth factor‐I (IGF‐I) or auxological measurements have an advantage over GH stimulation testing in predicting the linear growth response to GH therapy?

OBJECTIVE: To compare the relative utility of GH secretion via pharmacological stimulation, overnight serial sampling, IGF-I levels and auxological variables as predictors of change in height standard deviation score (deltaHt SDS) during GH treatment. DESIGN: A multicentre observational study. PATIENTS: Prepubertal children (n = 825) with idiopathic growth failure who were subsequently treated with GH were divided into two groups, based on their maximum GH response to pharmacological stimulation testing: (1) idiopathic GH deficiency (IGHD), defined by a maximum GH response < 10 microg/l (n = 300); and (2) idiopathic short stature (ISS), with a maximum GH response > or = 10 microg/l (n = 525) (GH conversion factor: 3 IU = 1 mg). MEASUREMENTS: Overnight spontaneous GH secretion was measured in all patients. The following characteristics of spontaneous GH secretion were studied: maximum or peak GH, mean peak GH, number of GH peaks, pooled GH, mean GH, and approximate entropy of GH secretion. RESULTS: Although children with IGHD had lower indices of spontaneous GH secretion, there were no differences between IGHD and ISS groups in baseline Ht SDS, growth rate or IGF-I level. The dose and duration of GH therapy were similar. There was no statistically significant difference in the mean (+/- SD) change in Ht SDS (deltaHt SDS) in the two groups (IGHD 1.3 +/- 0.9 and ISS 1.2 +/- 0.8). Measures of spontaneous secretion, such as peak GH, mean of GH peaks, mean area under GH peaks, and mean GH, as well as IGF-I concentrations, were all statistically significantly correlated with deltaHt SDS in IGHD children (P < 0.0001). A significant correlation was also observed for pooled GH (P = 0.002) and approximate entropy (P = 0.01). Children with the most severe ISS (Ht SDS < -3.33) demonstrated a more disorganized pattern of GH secretion compared to children who were not as short (Ht SDS -2.33 to -1.64), as indicated by a higher approximate entropy (0.673 +/- 0.193 vs. 0.607 +/- 0.161, P < 0.004). This increased disorder in GH secretion was accompanied by lower IGF-I levels (104 +/- 99 microg/l vs. 137 +/- 74 microg/l, P < 0.001), even though pooled GH concentrations were indistinguishable between the two groups (2.2 +/- 1.3 microg/l vs. 2.0 +/- 1.0 microg/l). Children with IGHD demonstrated lower approximate entropy than did those with ISS (0.551 +/- 0.235 vs. 0.631 +/- 0.182, P < 0.0001). Duration of GH treatment, height deficit and genetic potential (midparental Ht SDS) were the most important variables influencing deltaHt SDS in children receiving GH therapy. Maximum stimulated GH, IGF-I and indices of spontaneous GH secretion also correlated with deltaHt SDS, but their relative importance varied among diagnostic groups. CONCLUSIONS: Patients with GH deficiency demonstrate a reduced capacity for GH secretion, while those with idiopathic short stature exhibit a more disorderly and less functional secretory pattern. Although effective in predicting a response to GH treatment in patients with severe GH deficiency, overnight serial sampling is less practical than other methods currently available. In addition, serial sampling was less useful as a predictor of growth response to exogenous GH in patients with idiopathic short stature.     

Serum IGF-I and IGFBP-3 levels for the assessment of disease activity of acromegaly

To assess the disease activity of acromegaly in patients, we measured the changes in serum growth hormone (GH) levels during oral glucose tolerance test and the basal serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP-3) in 29 acromegalic patients and 30 health persons served as normal controls. Based on the clinical and laboratory criteria, acromegaly was in an active state of disease in 18 patients and was inactive in the other 11 patients. Basal serum IGF-I levels were 177+/-116 ng/ml (mean+/-SD), 250+/-135 ng/ml and 810+/-297 ng/ml in the normal subjects, the inactive and active acromegalic patients, respectively. Basal serum IGFBP-3 levels were 1.71+/-1.29 microg/ml, 2.98+/-0.96 microg/ml and 6.82+/-1.31 microg/ml in the normal controls, the inactive and active acromegalic patients, respectively. Serum levels of IGF-I and IGFBP-3 significantly correlated with each other in the normal subjects as well as the patients. Both IGF-I and IGFBP-3 levels were significantly higher in the group of patients with active acromegaly than inactive acromegalic patients and the normal subjects but there was not statistically difference between the normal controls and the inactive acromegalics. While serum IGF-I levels presented considerable overlapping instances among the three groups, the serum IGFBP-3 of inactive patients and the normal controls could rarely reach 4.44 ng/ml, the lowest value of the active acromegalics. The serum IGF-I and IGFBP-3 levels declined with increased age in normal controls, but not in the patients with acromegaly. There was no sex predilection of serum IGF-I and IGFBP-3 found in our study. The results of this study indicated that the serum IGFBP-3 level is an important laboratory parameter for assessing growth hormone function in humans, and might be a more reliable discrimination for the disease activity of acromegaly than the serum IGF-I is.     

Cord serum insulin-like growth factor binding protein-1 and -3: effect of maternal diabetes and relationships to fetal growth

OBJECTIVES: Insulin-like growth factor binding protein-1 and -3 (IGFBP-1 and -3) are the main insulin-like growth factor (IGF) carriers in fetal blood whose concentrations are regulated by hormonal factors such as insulin. IGFBPs may regulate fetal growth by altering the biological activity of IGF-I and IGF-II. We studied the effect of maternal diabetes on cord serum IGFBP-1 and IGFBP-3 levels, and the usability of IGFBP-1 and IGFBP-3 in the detection of birth weight variations. METHODS: Cord serum IGFBP-1 and IGFBP-3 concentrations were measured at birth by immunofluorometric assays in 67 pregnancies with type 1 diabetes and in 62 normal pregnancies. RESULTS: Concentrations of IGFBP-1 in cord serum were lower in diabetic pregnancies than in normal pregnancies (156 +/- 28 microg/l vs 266 +/- 29 microg/l, P = 0.007), whereas those of IGFBP-3 did not differ significantly (3327 +/- 158 microg/l vs 2982 +/- 105 microg/l, P = 0.076). IGFBP-1 correlated negatively and IGFBP-3 positively with birth weight z-score in diabetic pregnancies. The trend was similar in normal pregnancies. In multiple regression models, birth weight z-score was significantly associated with IGFBP-1 in diabetic and normal pregnancies, and with IGFBP-3 in diabetic pregnancies.CONCLUSION: Maternal diabetes is associated with suppressed levels of IGFBP-1 in cord serum, whereas those of IGFBP-3 do not change markedly. In diabetic pregnancies, both cord serum IGFBP-1 and IGFBP-3 correlate with fetal growth.     

Effect of acute elevation of IGF-I on circulating GH, TSH, insulin, IGF-II and IGFBP-3 levels in non-endocrine short stature (NESS)

It is not clear whether acute and slight elevation of serum IGF-I, which does not affect blood glucose levels, modulates circulating GH levels. To clarify this, small doses of recombinant human IGF-I (rhIGF-I, 5 microg/kg, i.v.) were administered as a bolus to 10 children with non-endocrine short stature (NESS) (5 males and 5 females, 11.2+/-0.7 yr old) after an overnight fast. Physiological saline was administered intravenously to sex- and age-matched NESS controls (5 males and 5 females, 10.9+/-0.7 yr old). The changes of serum GH, TSH, PRL, IGF-I, IGF-II, IGFBP-3, T4, T3 and plasma glucose levels after the administration were compared to those of the control subjects. Serum IGF-I levels increased significantly from 15 to 150 min after injection compared to those in the control group. The peak value was observed at 15 min (delta increment, 74.6+/-11.8 microg/l). At 15 min after the injection, serum insulin was suppressed significantly (p<0.05), although plasma glucose levels were not modified significantly. Serum TSH showed a significant decrease by rhIGF-I at 15 min and 60 min, whereas serum T4 and T3 levels were not modified. Serum GH was also significantly suppressed at 60 min (p<0.02) and showed a rebound increase at 120 min (p<0.05). Serum IGFBP-3 levels after rhIGF-I were higher than controls at 90 min and 150 min. No significant changes of serum PRL, IGF-II, (IGF-I plus IGF-II)/IGFBP-3 ratios were observed after the IGF-I injection compared to controls. These results indicate that circulating IGF-I is a physiological regulator of GH secretion in normal children, since the changes of IGF-I after the small doses of rhlGF-I administration were within physiological ranges and did not affect plasma glucose levels.     

The insulin-like growth factor-I response to growth hormone is increased in prepubertal children with obesity and tall stature

CONTEXT: Children with obesity [body mass index (BMI) > +2 sd score (SDS)] and children with constitutional tall stature [CTS; height > +2 SDS)] have normal-high serum IGF-I levels, associated with a low and broad range of GH secretion, respectively. This suggests increased sensitivity to GH, whereas children with idiopathic short stature (ISS; height < -2 SDS) are believed to have decreased GH sensitivity. OBJECTIVE, DESIGN, AND MAIN OUTCOME MEASURE: To compare the responsiveness to GH in 62 prepubertal children (43 females, 19 males) with obesity, CTS, or ISS and 26 controls (15 females, 11 males; height and BMI -2 to +2 SDS), we used an IGF-I generation test and studied the IGF-I concentration 24 h after a single injection of GH (2 mg/m2). PATIENTS: Twenty patients with obesity, 20 with CTS, 22 with ISS, and 26 controls were studied. The mean age was 8.3 +/- 2.9 yr, with no difference in age or gender between groups. RESULTS: Compared with controls, the mean IGF-I increment was 80% higher in obese children and 36% higher in tall children (P < 0.05 obese or tall vs. control children; P = 0.05 obese vs. tall children). Conversely, the IGF-I increment was similar in short compared with control children, despite a mean baseline IGF-I 62% lower in short children (P < 0.05 vs. controls). In all groups, the IGF-I increment was correlated with the BMI SDS or the fat mass percentage (r = 0.51-0.58, P < 0.05). CONCLUSION: Obese children tend to have greater GH responsiveness than tall children, and both have greater GH responsiveness than controls. GH responsiveness was similar in controls and short children, despite a lower baseline IGF-I in short children. Whether the differences in the IGF-I response to GH between these children reflect differences in the respective anabolic (growth promotion) and metabolic (i.e. insulin action modulation) roles of circulating IGF-I is unknown.     

Novel application of IGF-I and IGFBP-3 generation tests in the diagnosis of growth hormone axis disturbances in children with beta-thalassaemia

OBJECTIVE: Children with beta-thalassaemia major (beta-thal) frequently have growth retardation in the presence of low serum IGF-I and a normal GH response to pharmacological stimulation suggesting that they have GH insensitivity (GHIS). This study was carried out to study the cause of their growth retardation. DESIGN: We studied IGF-I and IGFBP-3 generation after exogenous GH administration for four days, in 15 prepubertal controls (C) and 41 prepubertal beta-thal patients divided into three groups according to their growth status: (Group 1) 15 with normal growth (N-thal) (Group 2) 16 with decelerated growth (D-thal) and (Group 3) 10 with short stature (S-thal), in order to determine whether GHIS is the cause of their growth retardation. MEASUREMENTS: IGF-I and IGFBP-3 were measured daily, before and for 4 days after daily administration of 0.1 IU/kg hGH, in 3 groups of prepubertal beta-thal patients and normal controls. RESULTS: N-thal and C had similar basal serum IGF-I (142 +/- 52 and 196 +/- 56 ng/ml, respectively) and IGFBP-3 concentrations (2.07 +/- 0.49 and 2.66 +/- 0.41 mg/l, respectively) as well as a similar percent increase of IGF-I (101 +/- 23% and 104 +/- 37%, respectively) and IGFBP-3 (52 +/- 36%, and 38 +/- 14%, respectively) during the generation tests. S-thal and D-thal had significantly lower basal IGF-I and IGFBP-3 concentrations (85 +/- 42 and 101 +/- 36 ng/ml; and 1.60 +/- 0.49 and 1.79 +/- 0.52 mg/l, respectively) as compared to N-thal and C (P < 0.001 and P < 0.005, respectively), and a significantly higher percent increase of IGF-I and IGFBP-3 during the generation tests (249 +/- 43 and 161 +/- 76%; and 121 +/- 99 and 73 +/- 35%, respectively) as compared to N-thal and C (P < 0.0001 and P < 0.01, respectively). Twenty-five percent of the growth retarded patients had classic GH deficiency (GHD) and percent increases of IGF-I and IGFBP-3 in the generation tests (164 +/- 86% and 80 +/- 49%, respectively) which were similar to those of the remaining growth-retarded children. CONCLUSION: The greater percent increases of IGF-I and IGFBP-3 in the generation tests of the growth retarded beta-thal patients, both with and without GHD, strongly suggest impaired GH secretion rather than GHIS as the cause of their growth retardation. We conclude that the IGF-I and IGFBP-3 generation tests are useful tools for the study not only of GHIS but also of GH secretory disorders in patients with beta-thal and short stature that can easily be performed in an outpatient setting as an initial test to identify the patients that may benefit from GH therapy.     

Normal growth despite GH, IGF-I and IGF-II deficiency.

A 6.5-year-old male with normal linear growth, despite septo-optic dysplasia, panhypopituitarism and a deficient GH/IGF axis, is presented. In addition to measuring IGF-I, IGF-II and IGFBP-3, serum IGFBP-1, -2, -4 and -5 were measured. A human osteosarcoma cell line was used to assess growth-promoting activity in the patient's serum. The role of leptin in linear growth in this case was investigated. There was no evidence for hyperinsulinism or hyperandrogenism. GH was undetectable upon multiple stimulation. GHBP was elevated. Serum IGF-I (25 microg/l), IGF-II (194 microg/l), IGFBP-3 (0.4 mg/l), and IGFBP-5 (87 microg/l) levels were low compared to age-matched prepubertal children. Serum IGFBP-4 level was normal. Molecular size of IGF-II in the patient's serum was normal, suggesting normal IGF-II bioavailability. Human osteosarcoma cell proliferation in response to the patient's serum was similar to sera from age-matched normal controls. Leptin levels were markedly elevated. Osteoblast cell proliferation was not stimulated by leptin. The data demonstrate that normal growth and osteoblast cell proliferation in this patient is not mediated by GH, total IGFs, insulin, or leptin, and suggest the presence of a yet unidentified growth factor or mechanism. The case offers a detailed picture of binding proteins in a case of growth without GH. It introduces osteoblast cell proliferation as a method of assessing serum growth-promoting activity in such cases. It adds IGF-II and leptin to the list of excluded growth-promoting candidates in GH-independent growth, and further demonstrates our incomplete understanding of the phenomenon of growth.     

IGFs and binding proteins in short children with intrauterine growth retardation.

The aim of this study was to examine the relationship between the IGF-IGF binding protein (IGFBP) axis and insulin secretion in short intrauterine growth retardation (IUGR) children. Fifteen IUGR and 12 normal short prepubertal subjects had a 90-min frequently sampled iv glucose tolerance test performed to measure plasma glucose, insulin, IGF-I, IGF-II, IGFBP-3, and IGFBP-1. In addition, 29 nonobese prepubertal subjects of normal height had fasting plasma IGF-I and IGFBP-3 levels measured. In comparison to short normal subjects, IUGR subjects had higher plasma values for IGF-I (42 +/- 10 vs. 77 +/- 31 microg/liter; P < 0.0001), IGF-II (291 +/- 76 vs. 370 +/- 66 microg/liter; P < 0.008), IGFBP-3 (1.66 +/- 0.28 vs. 2.07 +/- 0.48 mg/liter; P < 0.0005), fasting insulin (2 +/- 1 vs. 4 +/- 2 mU/liter; P < 0.004), and acute insulin response (AIR; 215 +/- 36 vs. 504 +/- 90 mU/liter; P = 0.008). Nonobese subjects of normal height had higher plasma IGF-I (117 +/- 9 microg/liter; P < 0.0001) and IGFBP-3 (2.34 +/- 0.12 mg/liter) values than the IUGR group (P < 0.0005). During the frequently sampled iv glucose tolerance test, the magnitude of the AIR in short normal subjects was related to the fall in IGFBP-1 levels (P = 0.03); however, no relationship was seen between AIR and fall in IGFBP-1 in IUGR subjects (P = 0.24). In conclusion, short IUGR children have higher plasma IGF-I, IGF-II, and IGFBP-3, when compared with normal children matched for height, weight, and pubertal status. We speculate that hyperinsulinism secondary to insulin resistance may have led to these changes to the IGF-IGFBP axis in the IUGR group.     

Association of serum levels of IGF-I and IGFBP-1 with renal function in patients with type 2 diabetes mellitus.

OBJECTIVE: Our aim was to determine whether serum Insulin-like growth factor-I (IGF-I) and Insulin-like growth factor binding protein-1 (IGFBP-1) levels were different between type 2 diabetic patients and non-diabetic control group. We also aimed to establish any relationship that might exist between the serum IGF-I and IGFBP-1 levels with the urinary albumin excretion (UAE), creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion (as a marker of renal tubular dysfunction) and other parameters (such as age, duration of diabetes, treatment, etc.) in patients with type 2 diabetes mellitus (DM). DESIGN: Fifty-nine type 2 diabetic patients and thirty-one non-diabetic controls were included in this study. RESULTS: Mean serum IGF-I levels in diabetic patients were lower than the non-diabetic controls (158+/-12 vs. 287+/-26microg/l), (p<0.001). Serum IGFBP-1 levels were also higher in type 2 diabetic patients compared to the control group (67+/-5 vs. 35+/-4microg/l), (p<0.001). No relationship was obtained between IGF-I and IGFBP-1 levels with neither UAE nor urinary NAG excretion. A significant negative relationship was observed between creatinine clearance and serum IGFBP-1 level (r=-0.39, p=0.004). In multiple regression analysis IGF-I was independently and negatively associated with age and insulin treatment. On the other hand, IGFBP-1 was negatively related with creatinine clearance and positively related with the duration of diabetes. CONCLUSION: These results suggest that type 2 DM leads to a decrease in the IGF-I while elevating the IGFBP-1 levels. Further studies are needed to clarify a potential role of increased levels of IGFBP-1 in decreased creatinine clearance in type 2 DM.     

非霍奇金淋巴瘤患者血清胰岛素样生长因子-1及其结合蛋白-3表达水平的初步观察

目的:探讨非霍奇金淋巴瘤(NHL)患者血清胰岛素样生长因子-1(IGF-1)及其结合蛋白-3(IGFBP-3)表达水平及其临床意义.方法:选择28例诊断初发NHL患者(淋巴瘤组)及28例健康志愿者(对照组),化学发光法测定血清IGF-1及IGFBP-3水平并计算IGF- 1/IGFBP-3值,分析组间的差异.结果:血清IGF-1及IGFBP-3水平淋巴瘤组显著低于正常对照组(均P＜0.01);IGF-1/IGFBP-3淋巴瘤组与正常对照组差异无统计学意义(P＞0.05);不同亚型的淋巴瘤组的血清IGF-1、IGFBP-3水平及IGF-1/IGFBP-3比值的差异均未达到统计学意义(P＞0.05).结论:N HL患者血清IGF-I及IGFBP-3水平明显降低,可能与NHL相关.IGF-1/IGFBP-3比值与NHL无明显相关性,IGF-1及IGFBP-3水平与NHL的分型无明显相关.     

The growth hormone-insulin-like growth factor axis in adult patients with Prader Willi syndrome.

OBJECTIVE: Prader Willi syndrome (PWS) is a genetic disorder characterised by short stature, extreme obesity, body composition abnormalities and behavioural problems. Hypothalamic dysfunction with low growth hormone (GH) secretion and low levels of GH-related growth factors is common. However, the interpretation is difficult because of the concomitant obesity, which in itself has important effects on the GH-IGF-I-system. We therefore analysed free and total IGF-I, total IGF-II and their binding proteins in obese PWS adults before and during 12 months GH treatment. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-2.3 kg/m(2) participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin, Pharmacia) 0.8 IU (0.26 mg) for one month, and then 1.6 IU (0.53 mg) for 5 months. Subsequently GH doses were individually titrated to normal levels for age. Overnight fasting levels of free and total IGF-I, total IGF-II, GH-binding protein (GHBP) and IGF-binding proteins (IGFBP)-1, -2 and -3 were measured by RIA at baseline and after 6 and 12 months GH treatment. Mean levels+/-SEM of free IGF-I were 1.02+/-0.12 microg/L as compared to a reference value of 0.95+/-0.15 microg/L, while mean total IGF-I was 128+/-15 microg/L (212+/-14 microg/L) and total IGF-II was 704+/-45 microg/L (825+/-34 microg/L). Mean IGFBP-2 158+/-24 microg/L (764+/-72 microg/L) and GHBP 2.65 nmol/L (1.71+/-0.3 1nmol/L). IGFBP-1 and IGFBP-3 levels were normal. Both free and total IGF-I increased significantly during GH treatment, while IGF- and GH-binding proteins as well as total IGF-II remained unchanged. CONCLUSION: Low total IGF-I and, in relation to the obesity, low free IGF-I, low total IGF-II and non-suppressed IGFBP-1 are consistent with the concept that PWS patients have a partial GH deficiency, which can be corrected by GH replacement.     

Insulin-like growth factor binding protein-1 as a predictor of glucose-stimulated hyperinsulinemia in prepubertal obese children

OBJECTIVE: The present study was undertaken to examine the association of a glucose-stimulated insulin response with the fasting insulin-like growth factor-binding protein (IGFBP)-1 concentration in prepubertal obese children. SUBJECTS AND METHODS: The fasting levels of serum insulin and IGFBP-1 were measured in 17 obese and 16 control children. Furthermore, we performed an oral glucose tolerance test in obese children and examined the association of the area under the curve (AUC) for insulin with the fasting IGFBP-1 level. RESULTS: The mean serum level of IGFBP-1 was significantly lower in obese children (41.0 +/- 4.8 micrograms/l. P < 0.005) than in controls (91.2 +/- 9.9 micrograms/l). Although there was an inverse relationship between the fasting levels of serum insulin and IGFBP-1 in all subjects (r = -0.42, P < 0.05), no significant correlation between these two parameters was observed in the obese group alone. In obese children, the fasting IGFBP-1 level correlated inversely with AUC-insulin (r = -0.70, P < 0.005), whereas there was no significant relationship between the fasting insulin level and AUC-insulin. CONCLUSION: The present study suggests that the serum level of IGFBP-1 may be an early predictor of insulin resistance in prepubertal obesity.