Leptin, insulin-like growth factor (IGF)-I and IGF binding protein-3 levels in children with constitutional delay of growth

This study was planned in order to investigate the role of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and leptin, the product of the ob gene synthesized by fat tissue cells, in constitutional delay of growth and puberty (CDGP) which is the most frequent cause of short stature in children. This study was conducted on 80 children with CDGP aged 6-15 years, and 60 healthy children served as controls. Serum IGF-I, IGFBP-3, insulin and plasma leptin levels were measured by immunoradiometric assay. Mean IGF-I and leptin levels were significantly lower in the CDGP group compared with the controls, but the mean IGFBP-3 level was not different in the two groups. Mean leptin levels were 3.72 +/- 2.29 in CDGP and 4.68 +/- 3.08 in the control group (p <0.05). There was a statistically significant relationship between leptin levels and height, weight, and body mass index. Leptin levels were also correlated with chronological age, bone age and height age. When evaluated according to pubertal status, a significant difference was found in IGF-I, leptin and IGFBP-3 levels between prepubertal and pubertal groups. Leptin levels were significantly different in the prepubertal CDGP group compared with controls but in the pubertal CDGP group only IGF-I levels were significantly different from controls. As the weight of children with CDGP was lower than in the control group, it is postulated that the reason for short stature and pubertal delay may be this decrease in weight which is also the cause of low levels of leptin and IGF-I.     

Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 in girls with premature thelarche

Premature thelarche (PT) is characterised by precocious breast development without any other sign of puberty, normal height velocity (HV) and normal bone maturation, while girls with central precocious puberty (CPP) show increased HV, bone maturation and increased serum IGF-I and IGFBP-3 levels. This prompted us to study serum IGF-I and IGFBP-3 concentrations in girls with PT. Thirty-nine girls with premature breast development were studied and classified as PT or CPP according to clinical and laboratory evaluation. Normal prepubertal and pubertal girls were studied as controls. Serum IGF-I and IGFBP-3 were determined in all girls by IRMA. IGF-I levels in PT (155 +/- 61 microg/l) were lower than in CPP (337 +/- 149 microg/l) or late-pubertal controls (355 +/- 84 microg/l) and similar to those found in prepubertal (113 +/- 72 microg/l) and early-pubertal (222 +/- 81 microg/l) girls. Considering the SDS of IGF-I for chronological age (CA), the values observed in PT were in an intermediate position between CPP and prepubertal controls and statistically similar to those observed in CPP and prepubertal girls. IGFBP-3 levels in PT (2.1 +/- 0.5 mg/l) were similar to those found in CPP (2.5 +/- 0.8 mg/l), but only the latter were higher than in prepubertal girls (1.9 +/- 0.9 mg/l). IGF-I/IGFBP-3 molar ratios in PT were in an intermediate position between CPP and prepubertal controls. In conclusion, IGF-I and IGF-I/IGFBP-3 values in PT are intermediate between those observed in prepubertal children and in CPP, suggesting that PT could be a very early stage of puberty with slight but real changes in the GH-IGF axis.     

The insulin-like growth factor I generation test in the investigation of short stature

Genotypic and phenotypic heterogeneity in patients with growth hormone (GH) insensitivity syndrome suggests that partial defects exist in the GH receptor. The insulin-like growth factor I (IGF-I) generation test was assessed as a means of identifying partial GH receptor defects in a heterogeneous group of 22 prepubertal children with short stature. In a subgroup of nine patients with peak GH levels of 63.7 ± 3.7 mU/l during a glucagon tolerance test, the response to the IGF-I generation test was no different from that for the group as a whole (peak GH, 43.3 ± 4.5 mU/l), despite the fact that this subgroup exhibited a negative relationship between height SDS and peak GH and a positive relationship between height SDS and IGF binding protein-3. This preliminary study therefore suggests that the IGF-I generation test in its present form will not be useful as a primary screening test for partial GH insensitivity. Despite this, the IGF-I generation test has been extremely useful in the confirmation of the diagnosis of GHIS and may therefore also prove useful in the confirmation of partial defects in the GH receptor. A subgroup of short children with peak GH levels above 40 mU/l had some characteristics of partial GH receptor deficiency. These children, to whom GH therapy would not normally be given, may respond better to recombinant human IGF-I.     

Diagnosis of idiopathic growth hormone deficiency: contributions of data on the acid-labile subunit, insulin-like growth factor (IGF)-I and-II, and IGF binding protein-3

The diagnosis of non-organic growth hormone (GH) deficiency (GHD) remains difficult. OBJECTIVE: To evaluate the value of measuring plasma insulin-like growth factor (IGF)-I and -II, IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) as criteria for diagnosing GHD. PATIENTS: 120 prepubertal patients having at least one of the main auxological criteria defined by the GH Research Society for initiating GH exploration were classified as (1) certain GHD (n = 40), (2) transient GHD (n = 18), (3) idiopathic short stature (n = 27), or (4) extreme short stature (n = 35). RESULTS: All the patients with certain GHD had low (< or = -2 z-score) plasma concentrations of IGF-I and ALS, but only 35.1% had low IGF-II, and 48.6% had low IGFBP-3. All the patients but three (83.3%) with transient GHD had low IGF-I, but only 44.4% had low ALS, and only one had low IGF-II or IGFBP-3. The data for patients with idiopathic and extreme short stature and normal GH peak were similar to each other and to those for patients with transient GHD, except that IGF-I was less frequently low (49.2%, p <0.05). CONCLUSIONS: All the patients with certain GHD had both IGF-I and ALS z-scores < or = -2, unlike those with transient GHD, and idiopathic or extreme short stature. Almost all the patients with short stature and normal GH peak had normal serum IGF-II and IGFBP-3 concentrations.     

Clinical utility of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 measurements in paediatric practice

Measurements of serum insulin-like growth factor-I (IGF-I) and its major binding protein, IGFBP-3, are utilised in the routine clinical management of short children. In this review, the value of such measurements in the diagnosis of primary and secondary IGF-I deficiency is presented. The achievement of optimal growth while maintaining IGF-I within the normal range is the goal of GH treatment schedules used in a range of growth disorders, and thus data on IGF-I monitoring during initiation and maintenance phases of GH treatment are discussed. Comment is also made on the relationship between levels of IGF-I and IGFBP-3 in the population with regard to risks for cancer and cardiovascular disease.IGF-I and IGFBP-3 are important parameters to measure as one part of the process of managing short children. It is proposed that improving the clinical value of IGF measurement may involve measurement of specific prohormones and E-peptides, to get closer to the pool of GH dependent IGF-I.     

Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3 and insulin in obese children.

In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.     

Developmental pattern of fetal growth hormone,insulin-like growth factor I,growth hormone binding protein and insulin-like growth factor binding protein-3

AIMS—To evaluate the developmental pattern of fetal growth hormone (GH), insulin-like growth factor I (IGF-I), GH binding protein (GHBP) and IGF binding protein-3 (IGF-3); to determine the implications for fetal growth.
METHODS—Serum GH, IGF-I, GHBP and IGFBP-3 were measured in 53 fetuses, 41 aged 20-26 weeks (group A) and 12 aged 31-38 weeks (group B). Fetal blood samples were obtained by direct puncture of the umbilical vein in utero. Fetal blood samples were taken to rule out β thalassaemia, chromosome alterations, mother to fetus transmissible infections, and for maternal rhesus factor. GHBP was determined by gel filtration chromatography of serum incubated overnight with ¹²⁵I-GH. GH, IGF-I and IGFBP-3 were determined by radioimmunoassay.
RESULTS—Fetal serum GH concentrations in group A (median 29 µg/l, range 11-92) were significantly higher (P<0.01) than those of group B (median 16.7 µg/l, range 4.5-29). IGF-I in group A (median 20 µg/l, range 4.1-53.3) was significantly lower (P<0.01) than in group B (median 75.2 µg/l, range 27.8-122.3). Similarly, IGFBP-3 concentrations in group A (median 950 µg/l, range 580-1260) were significantly lower than those of group B (median 1920 µg/l, range 1070-1770). There was no significant difference between GHBP values in group A (median 8.6%, range 6.6-12.6) and group B (median 8.3%, range 6-14.3). Gestational age correlated positively with IGF-I concentrations (P<0.0001) and IGFBP-3 (P<0.0001) and negatively with GH (P<0.0001). GHBP values did not correlate with gestational age. Multiple regression analysis showed a negative correlation between GH:IGF-I ratio and fetal growth indices
CONCLUSIONS—The simultaneous evaluation of fetal GH, IGF-I, IGFBP-3 and GHBP suggests that the GH-IGF-I axis might already be functional in utero. The progressive improvement in the efficiency of this axis in the last part of gestation does not seem to be due to an increase in GH receptors.

     

宫内发育迟缓与胰岛素样生长因子及其结合蛋白关系研究

为了解脐血中胰岛素样生长因子_I(IGF -I)、胰岛素样生长因子结合蛋白_3(IGFBP_3)的水平变化与胎儿期生长的关系 ,将86例新生儿脐血标本分为宫内发育迟缓 (IUGR ,即小于胎龄儿 )组 (22例 )及适于胎龄儿 (AGA)组 (64例 )两组 ,采用竞争性放射免疫分析法 (RIA)测定IGF_1水平、非竞争性免疫放射分析法 (IRMA)测定IGF BP_3水平。结果显示 ,与AGA组相比 ,IUGR组脐血中IGF_1和IGFBP_3水平显著降低 (P均<0.01) ;IGF_1、IGFBP_3水平均随胎龄及出生体重增加而增加 (P均<0.01) ;IGFBP_3与IGF_1呈正相关 (P<0.01)。提示IUGR与IGF_1及其结合蛋白降低密切相关 ;脐血中IGF_1、IGFBP_3水平与胎龄及出生体重呈正相关     

Molecular mechanisms underlying insulin-like growth factor action: How mutations in the GH: IGF axis lead to short stature

Insulin-like growth factors (IGFs) act via the Type 1 IGF receptor (IGF-1R) to promote growth and development. Recent structural and site-directed mutagenesis studies have provided detailed insight into the mechanism of interaction between the IGFs and the IGF-IR. Studies of the insulin: insulin receptor interaction have provided important additional understanding of the mechanisms underlying the IGF:IGF-1R interaction. The recent crystal structure of the insulin receptor ectodomain showed a folded over conformation accommodating two potential ligand binding pockets. The ligand interacts with the receptor at two different sites within a binding pocket to achieve high affinity binding and activation of the receptor. In this review the effect of mutations in the human IGF1 and IGF-1R genes so for reported are explained in terms of the effect on ligand binding and receptor activation. The severity of patient phenotype can generally be correlated to the effect of the mutation on protein structure and function.     

胰岛素样生长因子-1生成试验在身材矮小诊治中的应用

身材矮小在儿童内分泌疾病中占较大比例,其病因具有复杂性和交叉性,是儿童生理及心理问题的危险因素之一,需正确诊断并及时治疗。胰岛素样生长因子-1生成试验通过重组人生长激素刺激外周靶细胞分泌胰岛素样生长因子-1,根据胰岛素样生长因子-1的反应情况以评价重组人生长激素的刺激效应,从而进一步诊断身材矮小类型,及时评估重组人生长激素治疗疗效,实现个性化治疗。     

How to use insulin-like growth factor 1 (IGF1)

Insulin-like growth factor 1 (IGF1) is produced in the liver and peripheral tissues including the growth plate, in response to growth hormone (GH) and is commonly used as a diagnostic marker of growth hormone deficiency (GHD) and to monitor GH replacement therapy, as recommended by an international GH consensus.1 However, while it is a useful biochemical tool, there are limitations to its use and results should be interpreted with care.     

Serum zinc, insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in children with type 1 diabetes mellitus

BACKGROUND: Growth is impaired during the course of diabetes mellitus (DM). Derangement of the growth hormone/insulin-like growth factor (IGF) axis, insulinopenia and zinc deficiency are the possible causative factors of this impairment. Zn supplementation is proven to attenuate hyperglycemia in mice but its use to ameliorate impaired height is still a matter of discussion. OBJECTIVE: To investigate serum Zn, IGF-I and IGF binding protein-3 (IGFBP-3) levels and to emphasize the potential beneficial effects of Zn supplementation for the prevention of growth failure in children with type 1 DM (DM1). Patients and Methods: Twenty-eight patients with DM1 and 15 control children were included in the study. Zn levels were measured by flame atomic absorption spectrophotometry; IGF-I and IGFBP-3 levels were measured by immunoradiometric assay. RESULTS: Mean serum Zn levels were significantly lower in diabetic children taken as a whole and as their pubertal subgroup compared to the controls. Mean serum IGF-I and IGFBP-3 levels were significantly lower in both prepubertal and pubertal diabetic groups compared to those of control groups. CONCLUSION: From the results of our study, it can be hypothesized that serum Zn levels should be closely monitored during the course of DM1 and supplementation may be given to patients, especially at the time of puberty. This hypothesis needs to be confirmed by further studies.     

胰岛素样生长因子-1受体基因变异与矮身材的研究进展

胰岛素样生长因子-1受体(IGF-1 R)是下丘脑-垂体-生长激素轴IGF信号通路的受体级联效应分子.近年来,国外IGF-1R基因突变矮身材报道逐年增多,现将IGF-1R基因缺陷与矮身材的研究进展总结如下,以期引起临床医师的重视.     

Maternal and fetal serum insulin-like growth factor-I (IGF-I) IGF binding protein-3 (IGFBP-3), leptin levels and early postnatal growth in infants born asymmetrically small for gestational age

This study was planned to investigate the relationship between birth weight and insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), and leptin levels in neonates with normal growth (appropriate for gestational age: AGA) and retarded growth (small for gestational age: SGA); and to evaluate these growth factors' effects in early postnatal growth. All newborns were full-term: gestational age 3,841 weeks. Of 50 neonates, 25 were SGA. IGF-I, IGFBP-3 and leptin levels were measured in maternal serum and venous cord blood at birth and at 15 days of life of neonates using specific RIAs. Maternal serum leptin concentrations were significantly higher than cord blood leptin concentrations (p < 0.001). Maternal serum IGF-I, IGFBP-3 and leptin levels did not show correlations with birth weight. In contrast, there were significantly positive correlations between birth weight and venous cord blood IGF-I, IGFBP-3 and leptin levels (p < 0.001). In the SGA group, the newborns with a slow postnatal growth pattern had lower umbilical cord serum IGF-I levels compared with newborns with a normal growth pattern. A similar result was also found in the AGA group. Similar results were not found for serum leptin and IGFBP-3. In conclusion, cord blood IGF-I, IGFBP-3 and leptin levels play an important role in the regulation of fetal and neonatal growth. It is likely that IGF-I has a more important role than the other factors in early postnatal growth.     

儿童急性淋巴细胞白血病血清IGF-1和IGFBP-3表达变化及其意义

目的：探讨急性淋巴细胞白血病（ALL）患儿血清中胰岛素样生长因子-1（IGF-1）、胰岛素样生长因子结合蛋白-3（IGFBP-3）水平的表达变化及其临床意义。 方法：36例ALL患儿分别在治疗前和完全缓解后6个月留取血清, 对照组血清来自30例外科疾病患儿。应用放射免疫法（RIA）测定IGF-1和免疫放射法（IRMA）测定IGFBP-3水平。结果：ALL组治疗前血清IGF-1、IGFBP-3水平分别为19±4 ng/mL和1216±132 ng/mL,低于对照组的IGF-1、IGFBP-3水平（分别为32±3 ng/mL、2104±191 ng/mL）, 差异有统计学意义（P0.05）。结论：ALL患儿血清IGF-1和IGFBP-3水平降低,并随着病情缓解而升高。提示IGF-1和IGFBP-3可能可以作为儿童ALL诊断及疗效判断的有效指标。     

特发性矮小患儿胰岛素样生长因子受体基因单核苷酸多态性研究

目的：探讨胰岛素样生长因子-I受体（IGF-IR）基因单核苷酸多态性（SNP）与特发性矮小（ISS）的发病危险的相关性。方法：2008~2011年确诊为ISS患儿804例,正常对照组575例,用Snapshot法检测两组 IGF-IR基因相关位点SNP。结果：两组rs1976667基因型分布频率差异无统计学意义（P>0.05）;rs1976667 A等位基因分布频率较正常对照组高,差异有统计学意义（P<0.01)。结论：IGF-IR基因rs1976667位点等位基因A是ISS发病的危险因素。     

生长激素缺乏症患儿血清胰岛素样生长因子-1及其结合蛋白的变化

目的 研究血清胰岛素样生长因子1(IGF-1)、胰岛素样生长因子结合蛋白-3(IGFBP-3)浓度与生长激素缺乏症(GHD)患儿生长激素(GH)激发试验中血清GH峰值关系,为其代替GH激发试验提供依据。方法选择GHD患儿62例(男39例,女23例),为GHD组;60例健康儿童(男38例,女22例)为对照组。分别用放射免疫分析法(RIA)、免疫放射分析法(IRMA)检测两组血清IGF-1、IGFBP-3浓度,同时做GH激发试验,测定血清GH峰值,并比较其与IGF-1、IGFBP-3的关系。结果 GHD血清IGF-1、IGFBP-3均显著低于对照组(t=3.116、11.579 P均<0.01);GHD组血清IGF-1、IGFBP-3浓度与GH激发试验中GH峰值呈显著正相关(r=0.331、0.347 P均<0.01);GHD组血清IGF-1、IGFBP-3降低阳性率分别为97.58％、98.38％,与激发试验的阳性率(100％)比较无统计学意义(x~2=3.074、2.033 P均>0.05)。结论 血清IGF-1、IGFBP-3浓度的检测对诊断GHD有重要意义;检测血清IGF-1、IGFBP-3浓度可替代GH激发试验。     

Markers of collagen metabolism and insulin-like growth factor binding protein-1 in term infants

AIM: To study the relation between fetal growth and markers of collagen metabolism and insulin-like growth factor binding protein-1 (IGFBP-1) in term infants. METHODS: Cord vein plasma was obtained from 67 term infants of gestational age 37.1-41.7 weeks (39 appropriate for gestational age (AGA), 11 large for gestational age (LGA; relative birth weight >/= 2.0 SD), and 17 small for gestational age (SGA; relative birth weight 0.05). CONCLUSIONS: In the term fetus, collagen metabolism is primarily dependent on maturity and not on intrauterine growth status, whereas IGFBP-1 reflects intrauterine growth independently of maturity.