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Size at Birth and Cord Blood Levels of Insulin, Insulin-Like Growth Factor I (IGF-I), IGF-II, IGF-Binding Protein-1 (IGFBP-1), IGFBP-3, and the Soluble IGF-II/Mannose-6-Phosphate Receptor in Term Human Infants¹

Department of Paediatrics, University of Cambridge, Addenbrookes Hospital (K.O., D.D.), Cambridge, United Kingdom CB2 2QQ; Universitätskinderklinik und Poliklinik, University of Leipzig (J.K., W.K.), Leipzig, 04317 Germany; Unit of Pediatric and Perinatal Epidemiology, University of Bristol (ALSPAC Study Team), Bristol, United Kingdom BS8 1TQ; and Kolling Institute for Medical Research, University of Sydney, Royal North Shore Hospital (M.C., C.S.), New South Wales 2006, Australia

Address all correspondence and requests for reprints to: Prof. David B. Dunger, Department of Paediatrics, Level 8, Addenbrookes Hospital, Box 116, Cambridge, United Kingdom CB2 2QQ. E-mail: dbd25{at}cam.ac.uk

	Abstract

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Experimental rodent studies demonstrate that insulin-like growth factor II (IGF-II) promotes fetal growth, whereas the nonsignaling IGF-II receptor (IGF2R) is inhibitory; in humans their influence is as yet unclear. A soluble, circulating form of IGF2R inhibits IGF-II mediated DNA synthesis and may therefore restrain fetal growth. We measured cord blood levels of IGF-II, soluble IGF2R, insulin, IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and examined their relationships to weight, length, head circumference, ponderal index, and placental weight at birth in 199 normal term singletons. IGF-II levels correlated with levels of IGF-I (r = 0.29; P < 0.0005), IGFBP-3 (r = 0.45; P < 0.0005), and soluble IGF2R (r = 0.20; P < 0.005). Insulin and IGF-I were positively related to all parameters of size at birth. IGF-II was weakly related to ponderal index (r = 0.18; P < 0.05) and placental weight (r = 0.18; P < 0.05), and the molar ratio of IGF-II to IGF2R was also related to birth weight (r = 0.15; P < 0.05). Correlations between the IGFs and size at birth were stronger in nonprimiparous pregnancies; in these, IGF-I (r = 0.52; P < 0.0005), IGFBP-3 (r = 0.41; P < 0.0005), and the IGF-II to IGF2R ratio (r = 0.40; P < 0.0005) were most closely related to placental weight, together accounting for 39% of its variance. We demonstrate for the first time relationships between circulating IGF-II and soluble IGF2R levels and size at birth, supporting their putative opposing roles in human fetal growth.

	Introduction

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IN RECENT YEARS the roles of the insulin-like growth factors (IGF-I and IGF-II) and their binding proteins in fetal growth has been demonstrated by a series of elegant gene knockout animal models (1). Birth weights in mice homozygous for null mutations in either IGF1 or IGF2 are reduced to approximately 60% compared with those of wild-type mice (2, 3), and knockout of the gene encoding the type 1 IGF receptor (IGF1R), which signals the anabolic actions of both IGF-I and IGF-II, results in even more severe fetal growth retardation, with birth weights 45% of normal (1). In contrast, knockout of IGF2R, which encodes the nonsignaling IGF-II/mannose-6-phosphate receptor (IGF2R), results in fetal overgrowth (4, 5).

In humans, severe intrauterine growth failure has been reported in a subject homozygous for a partial IGF1 deletion (6), and there is evidence of IGF2 overexpression in patients with the Beckwith-Wiedermann overgrowth syndrome (7). However, these are rare cases, and the roles of these growth factors within the normal range of human fetal growth and size at birth is less clear. Associations between size at birth and cord blood levels of insulin, IGF-I, and its binding proteins have been shown (8, 9, 10, 11, 12, 13). However, reported relationships with IGF-II are inconsistent (8, 10, 11, 13, 14), and there are no data on the role of IGF2R in human fetal growth.

A soluble circulating form of IGF2R results from proteolytic cleavage of the intact membrane-bound receptor and has been shown to inhibit IGF-II-mediated DNA synthesis (15, 16). In the rat and human fetus, levels of both forms of receptor are regulated in tandem, showing wide variations with gestational age in parallel with levels of IGF2R messenger ribonucleic acid (17, 18, 19). In the large representative Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) birth cohort, we now show that cord blood levels of IGF-II and soluble IGF2R interact with each other and with other maternal factors in their relationships with size at birth.

	Materials and Methods

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Subjects and data collection

The ALSPAC children-in-focus cohort (born in 1992) is a random selection of the larger geographically based ALSPAC birth cohort (20). Sufficient cord blood samples for assays were available for 199 term (37–42 weeks gestation) singleton births. Recruitment, measurements, and sample collection have previously been described (21). Briefly, birth weights were noted from hospital records at birth. Length and head circumference within 1 day of birth (median, 1 day; range, 1–15 days) and weight at 2 yr were measured by the study team. Placentas and cord blood samples were collected by midwives; blood samples were centrifuged, and plasma or serum was stored at -70 C.

Assays

Insulin assays were performed using an ultrasensitive human insulin RIA (Linco Research, Inc., St. Charles, MO); the limit of sensitivity was 0.2 mU/L, and intra- and interassay coefficients of variation (CVs) were less than 10%. IGF-I levels were measured after acid-ethanol extraction by a competitive solid phase immunoassay, modified from the method of Kratzsch et al. (22), by the use of biotin for labeling of IGF-I and streptavidin-europium (Wallac, Inc., Turku, Finland) for the detection of labeled molecules by time-resolved fluorescence. The limit of sensitivity was below 15 ng/mL, and intra- and interassay CVs were less than 10% (range, 100–500 ng/mL). IGF-II levels were measured by direct enzyme-linked immunosorbent assay (ELISA; Diagnostic Systems Laboratories, Inc., Sinsheim, Germany) after dissociation of the IGF-II/IGF-binding protein (IGFBP) complexes. The limit of sensitivity was below 40 ng/mL, and intra- and interassay CVs were less than 10% (range, 300-1200 ng/mL). IGFBP-1 levels were measured by ELISA (Diagnostic Systems Laboratories, Inc.). The limit of sensitivity was below 0.4 ng/mL, and intra- and interassay CVs were less than 9% (range, 8–100 ng/mL). IGFBP-3 assays were performed by an in-house RIA as previously described (23), and soluble IGF2R levels were assayed using a novel human-specific two-site sandwich ELISA developed by M.C. and C.S. (19); intraassay CVs ranged from 9–15%, and there was no cross-reactivity with IGF-II.

Calculations

Ponderal index (weight (kilograms)/length³ (cubic meters)] at birth was calculated as the appropriate weight for length index, as this was independent of length. Molar concentrations of IGF-I (7649 Da), IGF-II (7471 Da), IGFBP-1 (25.7 kDa), and soluble IGF2R (220 kDa) were determined. From these, molar ratios of IGF-I to IGFBP-1 and of IGF-II to IGF2R were calculated as indexes of the expected interactions between these factors.

Statistics

Levels of insulin, IGF-I, IGF-II, IGFBP-1, IGFBP-3, and IGF2R all showed positively skewed distributions, and log_e transformations were calculated to achieve normal distributions and allow the use of parametric tests. Pearson’s correlations were used to examine relationships among levels of hormones, binding proteins, and IGF2R and their relationships to size at birth. Multiple linear regression was used to examine these relationships, allowing for effects of gestation and parity (primiparous/multiparous), and analysis of covariance was used to examine the effects of different growth factors simultaneously on size at birth.

	Results

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Medians and interquartile ranges for cord blood levels of insulin, IGF-I, IGF-II, IGFBP-1, IGFBP-3, and soluble IGF2R are presented in Table 1. No significant sex differences were seen. Insulin levels in cord blood were positively related to IGF-I and IGFBP-3 levels and inversely related to IGFBP-1 levels (Table 2). IGF-I levels were also positively related to IGF-II and IGFBP-3 and inversely related to IGFBP-1. Levels of soluble IGF2R were positively related to levels of IGFBP-3 and IGF-II (Fig. 1).

View larger version (20K): [in this window] [in a new window]   Figure 1. Scattergraph of IGF-II against soluble IGF2R. The relationship is best described by the equation: loge IGF-II = 5.74 + (0.21 ± 0.07 x loge IGF2R) (P < 0.005). There were no significant differences between males (X and solid line) and females (O and broken line).

In all pregnancies, insulin, IGF-I, and IGFBP-3 levels were positively related to birth weight and in particular to ponderal index, a marker of adiposity at birth; weaker correlations were also seen with birth length and head circumference (Table 3a). IGFBP-1 levels were inversely related to size at birth, but these were only significant after adjustment for gestational age. IGF-II levels were weakly related to ponderal index and placental weight, whereas nonsignificant negative trends were seen between soluble IGF2R levels and all parameters of size at birth, and thus the molar ratio of IGF-II to IGF2R was significantly related to birth weight, ponderal index, and placental weight.

	Discussion

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Those models have also highlighted the role of IGF-II in fetal growth. However, in previous human studies, IGF-II levels at birth are at best only weakly related to size at birth (14, 25), and most recent studies have found no significant relationships (8, 10, 11, 13). Our novel data may help to explain these inconsistencies. Overall, IGF-II levels were only weakly related to ponderal index and placental weight. However, taking into account its interaction with the inhibitory soluble IGF2R improved these relationships, and a significant correlation was seen with birth weight.

IGF2R is a multifunctional glycoprotein that binds IGF-II and a number of mannose 6-phosphate containing ligands, including lysosomal enzymes and latent transforming growth factor-ß. The soluble form of IGF2R results from proteolytic cleavage of the transmembrane region of the intact receptor and is detectable in many different species (18, 19). Soluble IGF2R is developmentally regulated (17, 18, 19) and binds IGF-II, resulting in its degradation and inhibition of its mitotic actions (15, 16). Despite their opposite relationships with size at birth, levels of IGF-II and soluble IGF2R were positively related. It has been shown that overexpression of soluble IGF2R leads to an increase in IGF-II levels (26). The reason for this link is unknown, but may explain the difficulties in identifying the fetal growth effects of IGF-II in the absence of data on IGF2R levels (8, 10, 11, 13, 14).

Although association does not prove causality, our findings are strongly supported by animal experimental and human case report data that demonstrate the fetal growth-enhancing effects of IGF-II (1, 7) and the inhibitory effects of IGF2R (4, 5). Growth factor levels were determined in cord blood samples, and this may explain why associations with IGF-I, IGF-II, and soluble IGF2R were stronger with placental weight than with other parameters of birth size. Furthermore, these associations with growth factor levels at birth in term deliveries may be weakened by the inability to consider gestational stage-dependent effects on fetal growth and may also be confounded by peripartum variations in growth factor levels (27). Primiparity weakened the relationship between soluble IGF2R levels and size at birth, and the reason for this is unclear. Comparison of birth weights in siblings demonstrates that offspring size is smallest in the first pregnancy, and with greater maternal restraint of fetal growth the contributions of other biological factors may be reduced (28, 29). For example, primiparity also weakens the correlation between birth weights in parents and their offspring (30), suggesting that maternal restraint may have an overriding influence on birth weight in the primiparous mother.

The opposing influences of IGF-II and IGF2R on fetal growth complement the opposite effects of parental imprinting on their genes. In humans, IGF2 is exclusively paternally expressed (31), whereas at least in some subjects, IGF2R is only maternally expressed (32). IGF2R may therefore represent a further mechanism, separate from the effects of primiparity, by which the mother may restrain fetal growth.

Normal variation in size at birth results from interaction between fetal genetic factors and the maternal uterine environment. The complexity of this interaction is added to by possible competition between maternal and paternally derived imprinted fetal genes (33). Furthermore, as well as reflecting the mother’s health and nutrition, the maternal-uterine influence on fetal growth may be a maternally inherited trait (28, 34). Elucidation of these mechanisms may be aided by further understanding the roles of the growth factors that regulate fetal growth. Our data demonstrate for the first time the opposing relationships between circulating IGF-II and soluble IGF2R levels on size at birth in humans. These findings suggest that genetic or other factors that influence levels of IGF-II or IGF2R may contribute to the normal variation in human fetal growth.

	Acknowledgments

 
We thank Prof. Robert Baxter for performing the IGFBP-3 assays. We are also extremely grateful to all the children and parents who took part and to the midwives for their cooperation and help with recruitment. The entire ALSPAC Study Team comprises interviewers, computer technicians, laboratory technicians, clerical workers, research scientists, volunteers, managers, and the staff of the Children in Focus research clinics.

	Footnotes

 
¹ ALSPAC is supported by the Medical Research Council, the Wellcome Trust, the Department of Health, the Department of the Environment, and many others.

² Medical Research Council Clinical Training Fellow.

³ Supported by IZKF Leipzig, Germany (BMBF, Projects B11 and B15).

Received March 13, 2000.

Revised May 31, 2000.

Revised August 1, 2000.

Accepted August 4, 2000.

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