Insulin-like growth factor-1 and insulin-like growth factor binding protein-1 in early human pregnancy.

Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) were measured in amniotic fluid, extraembryonic coelomic fluid and maternal serum from 23 women with apparently normal first trimester pregnancies prior to termination. The levels of IGF-1 and IGFBP-1 were significantly higher in coelomic fluid than amniotic fluid (IGF-1, P = 0.006; IGFBP-1, P = 0.0008 (paired t-test)). The levels of IGFBP-1 were lower in amniotic fluid than in maternal serum (P = 0.017), a finding in sharp contrast to the situation in the second and third trimesters of pregnancy. There was a significant relation between levels of IGF-1 and IGFBP-1 in amniotic fluid (r = 0.43; P = 0.04) and in coelomic fluid (r = 0.81; P less than 0.001) but not in maternal serum. The finding that both the absolute levels of IGFBP-1 and the ratio to IGF-1 were low in amniotic fluid implies that there is a very high level of unbound, biologically active IGF-1 in this compartment in the first trimester. Thus, the regulatory role of IGFBP-1 may change as pregnancy advances.     

Insulin-like growth factor binding protein-1 as glucose regulator in adolescent boys with type 1 diabetes

The aim of the present study was to investigate whether the diurnal variability of B-Glucose is dependent on GH, IGF-I and IGFBP-1 levels, apart from insulin, and if there is any difference between Tanner stages 3 and 5. Five boys in Tanner stage 3 and 6 boys in stage 5 with type 1 diabetes were included. Blood was continuously collected from a cubital vein for 24 h. S-Insulin, S-GH, S-IGF-I and S-IGFBP-1 were analysed. B-Glucose was analysed hourly at bedside. One week before and 1 wk after the 24-h study period the participants performed self-monitoring of blood glucose (SMBG) during normal physiologic conditions. In the 24-h profile of B-Glucose, insulin, IGFBP-1 and GH, we found a significant positive correlation between B-Glucose and log IGFBP-1 (r = 0.5, p = 0.005) and an inverse correlation to insulin (r = -0.5, p = 0.004) but no correlation to logGH (r = -0.04, p = 0.831). In multiple regression analysis, B-Glucose was still significantly correlated to log IGFBP-1, when adjusting for insulin and GH, in Tanner stage 5. We found a difference between Tanner stages 3 and 5 in the variability of B-Glucose over a longer period during normal daily activity (p = 0.02), but not over the 24-h study period. CONCLUSION: We have demonstrated in type 1 diabetes adolescent boys a relationship between simultaneously measured blood-glucose and IGFBP-1 levels independent of the insulin and GH levels, suggesting that the free fraction of IGF-I influences the glucose metabolism.     

Maternal insulin-like growth factor binding protein-1, body mass index, and fetal growth

AIM: To examine the hypothesis that the maternal insulin-like growth factor system may constrain fetal growth. METHODS: A prospective observational study of maternal serum insulin-like growth factor binding protein-1 (IGFBP-1) and fetal growth was undertaken in neonates with birthweights below the 5th centile. They had been classified either as having fetal growth restriction (FGR) due to placental dysfunction (increased umbilical artery Doppler pulsatility index (PI); n = 25) or as being small for gestational age (SGA; normal umbilical artery PI, growth velocity and amniotic fluid; n = 27). Eighty nine controls had normal birthweights (5th-95th centile), umbilical artery PI, growth velocity, and amniotic fluid. IGFBP-1 was measured by radioimmunoassay. RESULTS: Among the controls, there was no significant correlation between IGFBP-1 and birthweight after allowing for body mass index (BMI). Maternal BMI was high in FGR and after adjusting for this, IGFBP-1 was increased (109 ng/ml) compared with SGA babies (69 ng/ml) and controls (57 ng/ml) and correlated with the umbilical artery PI. CONCLUSIONS: Maternal IGFBP-1 is probably not part of normal placental function. Its increase in FGR could be the cause or consequence of impaired placental perfusion, but high IGFBP-1 concentrations might further reduce the availability of maternal IGF-I to the placenta. This could worsen placental function and so adversely affect fetal growth.     

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.     

Insulin-like growth factor-I and insulin-like growth factor binding protein-3 during maintenance chemotherapy of acute lymphoblastic leukemia in children.

PURPOSE: To assess the effect of maintenance chemotherapy (MT) on growth factors and growth in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-one children (10 girls, 11 boys) with standard risk pre-B ALL treated with chemotherapy had serum insulin-like growth factor-I (IGF-I), serum IGF binding protein-3 (IGFBP-3) levels, and linear growth and weight data measured every 3 months during MT. The levels of the cytotoxic metabolites of methotrexate (MTX) and 6-mercaptopurine (6MP) (i.e., erythrocyte MTX polyglutamates [E-MTX], and erythrocyte 6-thioguanine nucleotides [E-6TGN]), s-aminotransferases, and white blood counts (WBC) were measured at least monthly. RESULTS: At the beginning of MT, the median IGF-I standard deviation scores (SDS) and IGFBP-3 SDS were -0.52 and -0.09, respectively, which declined during MT to -1.67 (P < 0.001) and -1.82 (P < 0.001), respectively. At the time of diagnosis, the median height SDS was -0.4, which declined during MT to a median height SDS of -0.9 at cessation of therapy. No significant correlations were found between growth factor levels, growth and body mass index (BMI) versus the doses of MTX, and 6MP, E-MTX, E-6TGN, s-aminotransferases, or WBC. CONCLUSIONS: A significant decline in IGF-I, IGFBP-3, and growth retardation may not be directly related to the treatment intensity during MT.     

Insulin-like growth factor binding protein-3 proteolysis and growth of athyreotic infants in the first weeks of life

To gain a better understanding of the growth of athyreotic newborns in the first weeks of life, we evaluated auxological parameters and determined the serum levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and free IGF-I, and IGF-binding protein-3 (IGFBP-3) in 15 hypothyroid infants (10 females) at a mean age of 25 d of life, immediately before the beginning of L-thyroxine therapy, and at 3 and 6 mo of life. Fourteen normal infants (9 females) of the same age were studied as controls. IGFBP-3 proteolytic activity was evaluated in 8 patients and in 8 controls at 25 d and 6 mo of life. There was no significant difference concerning weight and length between the patients and controls at birth, 25 d, 3 and 6 mo of life. The blood GH, IGF-I and IGFBP-3 levels were significantly lower in patients at diagnosis than in controls of the same age (p < 0.01 for all parameters), as well as IGFBP-3 studied by Western blotting. At diagnosis, the patients' free IGF-I level was within the control range, but the free IGF-I percentage of total IGF-I was higher than in the controls (p < 0.01). IGFBP-3 proteolytic activity was found to be greater in the patients (p < 0.01). At 6 mo of life, after therapy, none of these parameters was different from those of the controls. CONCLUSION: Increased IGFBP-3 proteolytic activity in our patients at diagnosis, favouring IGF-I bioavailability, could account for normal free IGF-I levels and in turn for their normal growth pattern during the first weeks of life and before the start of treatment.     

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.

     

胰岛素样生长因子结合蛋白7与肿瘤

胰岛素样生长因子结合蛋白7(insulin-like growth factor binding protein 7,IGFBP7)通过与胰岛素样生长因子(insulin-like growth factor,IGF)、胰岛素相结合,延长IGF/胰岛素的半衰期,从而发挥IGF/胰岛素的生物学功能.与其他结合蛋白不同的是,IGFBP7能与胰岛素强有力的结合,从而能够不依赖IGF而发挥功能.IGFBP7在细胞生长、增殖和在肿瘤细胞的黏附、浸润、迁徙及肿瘤血管的形成等方面发挥作用,可能与某种信号传导通路有关.     

Insulin-like growth factor binding protein-3 induces insulin resistance in adipocytes in vitro and in rats in vivo

Insulin-like growth factor binding protein (IGFBP)-3 binds to IGF and modulates their actions and also possesses intrinsic activities. We investigated its effects on insulin action and found that when IGFBP-3 was added to fully differentiated 3T3-L1 adipocytes in culture, insulin-stimulated glucose transport was significantly inhibited to 60% of control in a time- and dose-dependent manner. Tumor necrosis factor (TNF)-alpha treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3 levels 3-fold. Co-treatment with TNF-alpha and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-alpha on glucose transport, indicating a role for IGFBP-3 in cytokine-induced insulin resistance. Insulin-stimulated phosphorylation of the insulin receptor was markedly decreased by IGFBP-3 treatment. IGFBP-3 treatment suppressed adiponectin expression in 3T3-L1 adipocytes. Infusion of IGFBP-3 to Sprague-Dawley rats for 3 h decreased peripheral glucose uptake by 15% compared with controls as well as inhibiting glycogen synthesis. Systemic administration of IGFBP-3 to rats for 7 d resulted in a dramatic 40% decrease in peripheral glucose utilization and glycogen synthesis. These in vitro and in vivo findings demonstrate that IGFBP-3 has potent insulin-antagonizing capability and suggest a role for IGFBP-3 in cytokine-induced insulin resistance and other mechanisms involved in the development of type-2 diabetes.     

Insulin-like growth factor 2 (IGF2) and IGF2 receptor gene variants are associated with fetal growth

AIM: Normal variation in size at birth is a result of the interaction between fetal genetic factors and the maternal uterine environment. It is, however, unclear how genetic factors contribute to fetal growth. The insulin-like growth factor (IGF) system regulates uterine, placental and fetal development, thereby partially controlling the rate of fetal growth. The aim of this study was to investigate the associations between the neonatal birth weight and the genotypes of polymorphic loci in the IGF2 and IGF2 receptor (IGF2R) genes. METHODS: We determined the genotypes of two polymorphic loci in the IGF2 gene and four loci in the IGF2R gene in 884 pairs of normal Japanese mothers and their neonates, and compared the genotypes with the birth weight converted into standard deviation scores (SDSs) according to sex, parity and gestational weeks at delivery. RESULTS: There was a significant difference in birth weight SDSs among the three neonatal +3123/ApaI genotypes of the IGF2 gene; AA, AG and GG. There was also a significant difference in birth weight among the three neonatal c.901C > G genotypes of the IGF2R gene; CC, CG and GG. Conclusion: These findings indicate that both IGF2 and IGF2R gene variants are associated with fetal growth.     

Power spectrum analysis of fetal heart rate variability at near term and post term gestation during active sleep and quiet sleep

Background

Spectral analysis of fetal heart rate variability is promising for assessing fetal condition. Before using spectral analysis for fetal monitoring it has to be determined whether there should be a correction for gestational age or behavioural state.

Aims

Compare spectral values of heart rate variability between near term and post term fetuses during active and quiet sleep.

Study design

Case-control. Cases had a gestational age of ≥ 42 weeks; controls were 36 to 37 weeks. Fetuses were matched for birth weight percentile.

Subjects

STAN^® registrations from healthy fetuses. For each fetus one 5-minute segment was selected during active and one during quiet sleep.

Outcome measures

Absolute and normalized low (0.04-0.15 Hz) and high frequency power (0.4-1.5 Hz) of heart rate variability.

Results

Twenty fetuses were included. No significant differences were found between cases and controls in absolute (481 and 429 respectively, P = 0.88) or normalized low (0.78 and 0.80 respectively, P = 0.50) or absolute (41 and 21 respectively, P = 0.23) or normalized high frequency power (0.08 and 0.07 respectively, P = 0.20) during active state. During rest, normalized low frequency power was lower (0.58 and 0.69 respectively, P = 0.03) and absolute (16 and 10 respectively, P = 0.04) and normalized high frequency power were higher (0.21 and 0.14 respectively, P = 0.01) in cases compared to controls. Absolute and normalized low frequency power were higher during active state compared to rest in both groups (all P values < 0.05).

Conclusions

We found sympathetic predominance during active state in fetuses around term. Post term parasympathetic modulation during rest was increased compared to near term.     

胰岛素样生长因子1及胰岛素样生长因子结合蛋白3与胎儿宫内生长发育的关系

目的　通过测定新生儿脐血中胰岛素样生长因子 1(IGF 1)和胰岛素样生长因子结合蛋白 3(IGF BP 3)水平 ,研究其与出生体质量、身长及胎盘质量等生长参数间的关系 ,探讨影响胎儿宫内生长发育的内分泌因素。方法　将新生儿根据出生体质量与胎龄的关系分为适于胎龄儿 (AGA)组与小于胎龄儿 (SGA)组 ,分别测定两组出生时身长、体质量和胎盘质量 ,同时取新生儿脐血用免疫放射法测定IGF 1和IGFBP 3含量。结果　1) 10 5例新生儿中 79例AGA和 2 6例SGA ,其出生时身长、体质量和胎盘质量 3个参数比较均存在显著差异(P <0 .0 0 1) ,AGA组显著高于SGA组 (P <0 .0 0 1) ;2 )两组脐血IGF 1和IGFBP 3比较 ,AGA组IGF 1和IGF BP 3水平均高于SGA组 (P <0 .0 1和P <0 .0 0 1) ;3)出生时身长、体质量和胎盘重质 3个生长参数均与IGF 1和IGFBP 3呈显著正相关 (P均 <0 .0 0 1)。结论　 1.出生时身长、体质量和胎盘质量可用来评价AGA和SGA的生长发育。 2 .AGA脐血中IGF 1和IGFBP 3明显高于SGA。 3.胎儿自身分泌IGF 1和IGFBP 3与上述生长参数密切相关 ,其对胎儿的生长发育起重要调节作用。IGF 1和IGFBP 3可作为胎儿宫内生长发育的指标     

Epidermal growth factor in human milk: daily production and diurnal variation during early lactation in mothers delivering at term and at premature gestation

Epidermal growth factor is a polypeptide that stimulates proliferation and differentiation of a variety of cell types, including the developing intestinal epithelium; it is the agent in human milk that induces mitosis in human fibroblast culture. We systematically evaluated the EGF content of milk from 20 women delivering prematurely and from 11 women delivering at term. In preterm mothers, the concentration of EGF was 70 +/- 5 ng/ml (mean +/- SEM), with no significant change during seven weeks of lactation. EGF concentration in milk of term mothers was 68 +/- 19 ng/ml (mean +/- SEM). No diurnal variation in the concentration was found. Total EGF content was closely correlated with the volume of milk expressed, suggesting a passive transport from the circulation. These observations confirm that a substantial amount of EGF is present in human milk and that EGF concentrations are not affected by duration of gestation, time of day, or duration of lactation.     

Relation between serum insulinlike growth factor-1, insulinlike growth factor binding protein-2, and insulinlike growth factor binding protein-3 and nutritional intake in premature infants with bronchopulmonary dysplasia.

BACKGROUND: The usefulness of serum insulinlike growth factor (IGF)-system-peptide measurement to assess the adequacy of nutritional intake in premature infants with chronic lung disease bronchopulmonary dysplasia (BPD) was assessed. METHODS: Twenty-nine premature infants had serial measurements taken of their serum IGF-1, insulinlike growth factor binding protein (IGFBP)-2, and IGFBP-3 concentrations between 2 and 6 weeks of age. Regression analyses were used to examine the relation between nutritional parameters and IGF-1, IGFBP-2, and IGFBP-3 concentrations in premature infants with and without BPD. RESULTS: The group of infants with BPD (n = 12) did not differ from infants without BPD (n = 17) in gestational age or weight at entry, but gained less weight during the study period. In infants without BPD, IGF-1 correlated positively with protein intake (r = 0.50) and caloric intake (r = 0.41) over the 3 days before sample collection and with weight change over the previous week (r = 0.46). In contrast, infants with BPD showed a significant correlation between IGF-1 and weight change (r = 0.54) only. There was a significant negative correlation between IGFBP-2 and protein intake in infants without BPD (r = -0.50) and in infants with BPD (r = -0.41). Negative correlations between IGFBP-2 and both weight change (r = -0.64) and caloric intake (r = -0.43) over the previous week were found only in the group of infants without BPD. IGFBP-3 correlated positively with weight changes and protein intake in both groups but correlated with caloric intake only in the group without BPD. Multiple regression analyses were used to determine significant independent variables associated with IGF-1, IGFBP-2, and IGFBP-3. In infants without BPD, significant independent predictors of IGFBP-2 were 7-day weight change and 2-day protein intake; 3-day caloric intake was the only significant independent predictor for IGFBP-3. For infants with BPD, 3-day weight gain was the only independent variable associated with serum IGF-1. Protein intake in the week before sample collection was an independent predictor of IGFBP-2 and 3-day weight change and 2-day protein intake were independent predictors of IGFBP-3. CONCLUSIONS: These results confirm that changes in serum IGF-1, IGFBP-2, and IGFBP-3 reflect the nutritional status of premature infants and demonstrate that the relation between these proteins and nutritional intake differs in premature infants with and without BPD. Refinement of these observations by future studies may permit a more accurate determination of the protein and caloric intake sufficient for growth and repair after injury in premature infants with lung disease.     

Sonographic markers of aneuploidies at 6-10 weeks of gestation

Objectives

To determine if sonographic features of live embryos at 6-10 weeks' gestation are altered in aneuploidies.

Methods

Embryonic crown rump length (CRL), embryonic heart rate, gestational sac diameter (GSD) and yolk sac diameter (YSD) were measured by transvaginal sonography in 5603 live embryos from singleton pregnancies at 6-10 weeks' gestation. The measurements were expressed as differences from the expected normal mean for CRL (delta values) and median delta values in the aneuploid cases were compared to the euploid group.

Results

5393 pregnancies resulted in the live birth of phenotypically normal neonates and these cases constituted the euploid group. In 55 cases there was subsequent prenatal diagnosis of aneuploidies (trisomy 21, n = 28; trisomy 18, n = 10; trisomy 13, n = 10; triploidy, n = 4; Turner syndrome, n = 3). The median and interquartile range (IQR) of delta embryonic heart rate in trisomy 18 was − 19.44 (− 23.77 to − 7.20) bpm and in trisomy 13 it was 11.12 (7.25 to 20.39) bpm, which were significantly lower and higher, respectively, than in euploid embryos (median − 0.05, IQR − 6.18 to 6.21 bpm). The median delta YSD in trisomy 21 was higher than in euploid fetuses (median 0.56, IQR 0.23 to 0.79 and median − 0.17, IQR − 3.11 to 2.82 mm). There were no other significant differences in measurements between the groups.

Conclusion

At 6-10 weeks' gestation there are sonographically detectable differences between euploid and trisomic embryos.     

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。     

Overexpression of human insulin-like growth factor binding protein-1 in the mouse leads to nephron deficit

IGFs and their binding proteins are important regulators of fetal development. We have previously reported that overexpression of the human IGF binding protein-1 in mice is associated with glomerulosclerosis. The aim of this study was to investigate whether, in that model, decreased bioavailability of IGFs also affected nephrogenesis. When the mothers expressed human IGF binding protein-1, pups were growth retarded and had a reduced number of nephrons. Even nontransgenic pups born to heterozygous mothers had a nephron reduction, indicating that renal hypoplasia was secondary to fetal growth retardation. When the transgene was expressed only in the fetus, pups had a normal birth weight and the kidney was normal at birth, as indicated by histologic studies. However, a significant reduction in the nephron number was observed at 3 mo of age. Because nephrogenesis continues for a few days after birth in the mouse, this indicated that human IGF binding protein-1 overexpression altered postnatal nephrogenesis. In addition, exogenously added IGF-II, but not IGF-I, was effective in stimulating in vitro nephrogenesis. Together these elements suggest that reduced amounts of circulating IGFs, presumably IGF-II, impair kidney development.