Growth in foetal life and infancy is associated with abdominal adiposity at the age of 2 years: The Generation R Study

Objective Early weight gain is associated with an increased risk of obesity. It is not known whether rapid weight gain in foetal life and infancy is also associated with increased abdominal adiposity. We examined the associations of foetal and postnatal growth characteristics with abdominal fat mass at the age of 2 years. Design This study was performed in 481 children participating in a prospective cohort study from early foetal life onward. Measurements Foetal and postnatal growth characteristics in second and third trimester, at birth and at the age of 2 years were related to abdominal fat mass (subcutaneous distance and area, preperitoneal distance and area) measured by ultrasound at the age of 2 years. Results Foetal and birth weight were not associated with abdominal subcutaneous fat mass. Estimated foetal weight in second trimester of pregnancy was inversely associated with preperitoneal fat area [?3·73% (95% confidence interval ?7·23, ?0·10)] per standard deviation score increase in weight. Weight gain from birth to the age of 2 years was positively associated with preperitoneal fat mass measures. These associations remained significant after adjustment for age, sex, breastfeeding and body mass index. Positive associations were found between catch‐up growth in weight and abdominal fat mass measures. Conclusions Our results suggest that rapid growth rates during foetal life and infancy are associated with increased abdominal subcutaneous and preperitoneal fat mass in healthy children. Further studies need to explore whether these associations persist in later life and are related to metabolic syndrome outcomes.     

Variation in the IGF-1 gene is associated with lymphocyte subset counts in neonates: The Generation R Study

Objective  IGF-1 stimulates growth, development and function of lymphocytes. The aim of this study was to examine whether functional variants of the IGF-1 gene are associated with absolute lymphocyte subset counts in neonates.
Study design and measurements  This study was embedded in the Generation R Study, a prospective cohort study from foetal life onwards. A polymorphism in the IGF-1 promoter region was genotyped in cord blood DNA. Lymphocytes (T, B and NK) and T lymphocyte subsets (helper, cytotoxic, naïve and memory) in cord blood were immunophenotyped in 380 neonates by six-colour flow cytometry.
Results  In total, 39% of the neonates were homozygous for the 192-bp allele (wild-type), 48% were heterozygous and 13% were noncarrier. No differences in absolute lymphocyte and T lymphocyte subset counts were observed between the 192-bp allele heterozygous and homozygous groups. In noncarriers, we found 15% lower T lymphocyte ( P =  0·03), 22% lower B lymphocyte ( P =  0·04) and 10% lower NK lymphocyte counts ( P =  0·36) than in the 192-bp allele homozygous group. Analyses of T lymphocyte subsets showed 16% lower helper T lymphocyte counts ( P =  0·01) in noncarriers. No significant differences were found for cytotoxic, naïve and memory T lymphocyte counts. All associations were adjusted for gravidity, mode of delivery, gestational age, birth weight, gender and 1- and 5- min Apgar scores.
Conclusions  Our study showed associations between this IGF-1 promoter region polymorphism and absolute lymphocyte subset counts in neonates. These results should be regarded as hypothesis generating until they have been replicated in other studies.     

Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation

Approximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.     

Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product.

Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema. The expression of the gene encoding insulin-like growth factor II (IGF-II) is often elevated in these tumors. Since many of the actions of IGF-II are mediated through activation of the IGF-I receptor (IGF-IR), we have measured the levels of IGF-IR mRNA in normal kidney and in Wilms tumor samples using solution hybridization/RNase protection assays. IGF-IR mRNA levels in the tumors were 5.8-fold higher than in adjacent normal kidney tissue. Among the tumors themselves, the levels of IGF-IR mRNA in those containing heterologous stromal elements were 2-fold higher (P < 0.01) than in tumors without these elements. IGF-IR gene (designated IGF1R) expression in the tumors was inversely correlated with the expression of the Wilms tumor suppressor gene WT1, whose inactivation appears to be a key step in the etiology of Wilms tumor. Cotransfection of Chinese hamster ovary cells with rat and human IGF-IR gene promoter constructs driving luciferase reporter genes and with WT1 expression vectors showed that the active WT1 gene product represses IGF-IR promoter activity in a dose-dependent manner. These results suggest that underexpression, deletion, or mutation of WT1 may result in increased expression of the IGF-IR, whose activation by IGF-II may be an important aspect of the biology of Wilms tumor.     

Protein intake during gestation affects postnatal bovine skeletal muscle growth and relative expression of IGF1, IGF1R, IGF2 and IGF2R

Expression of insulin-like growth factor (IGF)1 and IGF2 and their receptor (IGF1R and IGF2R) mRNA in fetal skeletal muscle are changed by variations in maternal nutrient intake. The persistence of these effects into postnatal life and their association with phenotype in beef cattle is unknown. Here we report that the cross-sectional areas of longissimus dorsi and semitendinosus (ST) muscles were greater for mature male progeny born to heifers fed low protein diets (70% vs. 240% of recommended) during the first trimester. In ST, this was accompanied by greater IGF1, IGF2 and IGF2R mRNA at 680 d. Females exposed to low protein diets during the first trimester had decreased IGF2 mRNA in ST at 680 d, however this did not result in an effect to phenotype. Exposure to low protein diets during the second trimester increased IGF1R mRNA in ST of all progeny at 680 d. Changes to expression of IGF genes in progeny skeletal muscle resulting from variations to maternal protein intake during gestation may have permanent and sex-specific effect on postnatal skeletal muscle growth.     

IGF1R在介导IGF1促糖代谢过程中的作用研究

目的 研究胰岛素样生长因子１受体（ＩＧＦ１Ｒ）在介导ＩＧＦ１促糖代谢过程中的作用。方法 建立胰岛素抗性细胞模型,ＩＧＦＩＲ封闭细胞模型和ＩＧＦＩＲ高表达细胞模型,对这３个细胞模型的促糖代谢作用。结果（１）ＩＧＦ１对胰岛素抗性细胞的促糖代谢效应没有被阻抑。（２）ＩＧＦ１对ＩＧＦ１Ｒ封闭细胞的降糖效应得到了明显的阻抑。（３）ＩＧＦＩＲ的表达,大大增强了ＩＧＦ１的促糖代谢效应。结论 ＩＧＦＩＲ在ＩＧＦ１     

Exhaled nitric oxide and the risk of wheezing in infancy: the Generation R Study

We assessed whether exhaled nitric oxide fraction (F(eNO)), a marker of eosinophilic airway inflammation, at 6 months was associated with the risk of wheezing during the first 2 yrs of life. In the Generation R birth cohort, pre- and post-natal risk factors for respiratory morbidity and respiratory symptoms were assessed by questionnaires at 6 and 24 months. In 428 infants, off-line mixed oral/nasal F(eNO) was successfully measured during tidal breathing at 6 months. Complete data on F(eNO) and respiratory symptoms within the first 6 months of life were available for 294 infants. F(eNO) was higher in males, was positively associated with age and was negatively associated with upper and lower respiratory symptoms within the first 6 months. Logistic regression analysis showed that for every ppb increase of F(eNO) measured at 6 months, infants had a 1.06 (95% confidence interval 1.01-1.11)-fold increased risk of wheezing in the second year of life. High F(eNO) (>17.5 ppb) showed a limited added value in predicting wheezing in the second year. We conclude that F(eNO) at 6 months is positively associated with the risk of wheezing, but has limited added value in predicting wheezing in the second year of life in individual children.     

Reduced foetal growth and growth hormone secretion in adult life

OBJECTIVES: Recent studies suggest that growth restriction or other adverse influences acting in utero or during early infancy lead to permanent alterations in growth hormone (GH) secretion. As GH secretion is known to predict cardiovascular risk, alterations in GH may contribute to the association between reduced foetal growth and cardiovascular disease. We have therefore assessed the relationship between birth size and GH secretion in a prospective study of young adults whose birth size was recorded and who have had their current blood pressure and glucose tolerance measured. DESIGN: Prospective cohort study PATIENTS: 153 healthy men and women, aged 20-21 years. MEASUREMENTS: Subjects carried out a timed overnight urinary collection for analysis of GH excretion. Insulin sensitivity and insulin secretion were measured using the intravenous glucose tolerance test with minimal model analysis. Blood pressure, height, weight, usual level of exercise, smoking habits, alcohol consumption, and socio-economic status were also recorded. RESULTS: GH excretion ranged from 0.01 to 41.8 microU per subject. It did not differ according to gender but was markedly reduced in obese subjects (P < 0.0001) Low birthweight was strongly associated with low GH excretion at age 20 years (P = 0.002). Low placental weight and short body length also predicted low GH (P = 0.02 and P = 0.04, respectively). These relationships were independent of other confounding factors including obesity. GH excretion was not independently related to current levels of blood pressure, insulin sensitivity or insulin secretion. CONCLUSIONS: Body size at birth predicts GH excretion in adult life. Low GH excretion in people who were small at birth may be one mechanism explaining their increased risk of cardiovascular disease.     

Insulin-like growth factors (IGF) 1 and 2 in human foetal plasma and relationship to gestational age and foetal size during midpregnancy

IGF-1 and IGF-2 were measured by specific radioimmunoassay after acid-ethanol extraction of plasma obtained by foetoscopy from 20 normal foetuses aged 15-23 weeks. IGF-1 and IGF-2 levels were 36 +/- 11 and 162 +/- 55 ng/ml, respectively. In comparison, levels in cord blood were 84 +/- 58 and 264 +/- 176 ng/ml, respectively, and in adult plasma were 410 +/- 106 and 818 +/- 272 ng/ml. Both IGF-1 and IGF-2 were in the normal foetal range in a further three foetuses with anencephaly and two foetuses with spina bifida. No sex difference was observed. IGF-1 was positively correlated with foetal body weight (P less than 0.001), placenta weight (P less than 0.02) and with body length measured crown-rump (P less than 0.01) or crown-heel (P less than 0.02). No correlation between IGF-2 and body weight, length, placenta weight or gestational age was found. Both IGF-1 and IGF-2 are present in the human foetal circulation earlier in gestation than has previously been demonstrated, the levels being low throughout this period of gestation in comparison with adult plasma.     

Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor i receptor (IGF1R) mutation: implications for a gene dosage effect of the human IGF1R

CONTEXT: Signaling via the IGF-I receptor (IGF-IR) is crucial for normal prenatal and postnatal growth. The heterozygous IGF-IR mutation Arg59Ter resulted in reduced IGF-IR expression and represents haploinsufficiency of the human IGF1R gene. OBJECTIVE: We studied clinical and in vitro aspects of a human IGF1R gene dosage effect. We provide detailed clinical data on the two half-brothers and their mother with the Arg59Ter mutation. Arg59Ter and control fibroblasts were examined for functionality of IGF-I and insulin-stimulated receptor phosphorylation and signal transduction. RESULTS: The two brothers presented with primary microcephaly, mild mental retardation, and intrauterine as well as postnatal growth deficits. After GH therapy (30 microg/kg.d) for 24 months, the growth deficit in the propositus decreased by +1.0 sd. There was no clinical evidence for impaired glucose tolerance or hypoglycemia in all Arg59Ter subjects. In vitro, IGF-IR-deficient Arg59Ter cells expressed less IGF-IR and unchanged insulin receptor (IR) protein. Receptor autophosphorylation and phosphorylation of downstream protein kinase B/Akt exhibited resistance to IGF-I but showed an augmented response to insulin in Arg59Ter cells. Decreased IGF-IR content was accompanied by a reduction of IGF-IR/IR receptor hybrids, and therefore, increased levels of IR/IR homodimers probably explain increased insulin-stimulated receptor autophosphorylation and Akt phosphorylation. CONCLUSIONS: In vivo and in vitro IGF-I resistance in Arg59Ter subjects and fibroblasts indicates a human IGF1R gene dosage effect involving not only the IGF-IR, but also IGF-IR/IR hybrids. The abundance of both the IGF-IR protein and IGF-IR/IR hybrid receptors may have an impact on human growth, organ function, and glucose metabolism.     

IGF1R signalling and its inhibition

The type 1 IGF receptor (IGF1R) is a transmembrane tyrosine kinase that is frequently overexpressed by tumours, and mediates proliferation and apoptosis protection. IGF signalling also influences hypoxia signalling, protease secretion, tumour cell motility and adhesion, and thus can affect the propensity for invasion and metastasis. Therefore, the IGF1R is now an attractive anti-cancer treatment target. This review outlines the effects of IGF1R activation in tumour cells, and will describe the strategies that are available to block IGF signalling, both as investigational tools and as novel anti-cancer therapeutics. Design of specific IGF1R inhibitors has been problematic due to close homology with the insulin receptor, but recently it has proved possible to design selective IGF1R inhibitors. These compounds and IGF1R antibodies are showing promise in preclinical models of human cancer, and several agents are now in early phase clinical trials. Both classes of agents affect insulin receptor signalling, either by direct kinase inhibition or antibody-induced insulin receptor downregulation. This effect may lead to clinical toxicity, but could be therapeutically beneficial in blocking signalling via variant insulin receptors capable of a mitogenic response to IGF-II. Specificity for IGF1R targeting can be achieved by antisense and siRNA-mediated IGF1R downregulation; these approaches have undoubted utility as research tools, and may in future generate nucleic-acid-based therapeutics. It will be important to use data from preclinical and early clinical trials to establish the molecular correlates of sensitivity to IGF1R blockade, and the optimum means of combining this new approach with standard treatment modalities.     

Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene

The type 1 IGF receptor (IGF1R) is required for normal embryonic and postnatal growth. The aim of this study was to determine whether we could detect abnormal IGF1R function in skin fibroblasts from children with an abnormal copy number of the IGF1R gene. We report two children with altered copy number of the IGF1R gene who presented with abnormal growth. Case 1 is a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal. Routine karyotype analysis identified a deletion on 15q26.2, and a fluorescence in situ hybridization study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and showed rapid early postnatal growth. He was found to have a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A fluorescence in situ hybridization study using the same probes showed three copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only one copy of IGF1R showed slower growth, whereas cells from the subject with three copies of IGF1R showed accelerated growth compared with controls. IGF1R phosphorylation, as assessed by Western blot, and IGF1R binding studies were decreased compared with controls in the child with one copy of the IGF1R and increased in the child with three copies of the gene. Our data are consistent with the concept that IGF1R gene copy number is of functional and clinical importance in humans.     

NSILA and foetal growth.

Employing a sensitive competitive protein binding assay for NSILA (non-suppressible insulin-like activity), circulating levels of this somatomedin (SM) have been measured throughout pregnancy, at parturition, and in foetal and newborn sera. Acid-dissociable serum NSILA (mean +/- SEM) in 57 women was significantly higher during pregnancy (1106 +/- 46 microunits/ml), than in 11 adult non-pregnant control subjects (844 +/- 22 microunits/ml), but not correlated with week of gestation or with serum growth hormone (GH) or cortisol levels. At parturition, the NSILA concentration in 28 cord sera (598 +/- 38 microunits/ml) was significantly less than in the corresponding maternal sera (1039 +/- 63 microunits/ml). The NSILA levels in 23 premature newborns (370 +/- 20 microunits/ml) and 8 small-for-gestational-age newborns (310 +/- 46 microunits/ml) were significantly less than in 33 term newborns (494 +/- 18 microunits/ml). Serum NSILA in 56 term and premature newborns exhibited a significant positive correlation both with gestational age and birth weight but not with serum GH or cortisol levels. These data suggest that the maternal-foetal growth-promoting system is a highly complex one in which NSILA levels both in maternal and foetal circulations appear to be under multifactorial control.     

Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes

Aims/hypothesis Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism. Materials and methods Variants in IGF1 were identified by direct resequencing of the exons, exon–intron boundaries and 5′ and 3′ regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent–child trios). We also genotyped a previously reported CA repeat in the region 5′ to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) ≥0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action. Results Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF ≥ 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5′ to IGF1 showed no association with any phenotype. Conclusions/interpretation Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. A. Vella and N. Bouatia-Naji contributed equally to this work.