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Prepubertal children with obesity have high free IGF-1 levels and accelerated growth

despite reduced pappalysin levels

Authors:

Álvaro Martín-Rivada

1,2*

, Gabriel Á Martos-Moreno

1,2,3*

, Santiago Guerra-

Cantera

1,2,3

, Ana Campillo-Calatayud

, Claus Oxvig

, Jan Frystyk

Julie A Chowen

1,3,6

Vicente Barrios

1,3

, Jesús Argente

1,2,3,6#

Institutions:

Hospital Infantil Universitario Niño Jesús. Departments of Endocrinology. Research

Institute “La Princesa”, E-28009, Madrid, Spain

Department of Pediatrics. Universidad Autónoma de Madrid, E-28029, Madrid, Spain.

Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutriciόn

(CIBEROBN). Instituto de Salud Carlos III, E-28009, Madrid, Spain.

Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus,

Denmark.

Department of Clinical Research, University of Southern Denmark, 5230 Odense,

Denmark. Endocrine Research Unit, Department of Endocrinology, Odense University

Hospital, 5000 Odense, Denmark.

IMDEA. Food Institute, CEIUAM+CSI. Cantoblanco, E-28049, Madrid, Spain.

* Both authors contributed equally to the development of this study.

Short tittle:

Pappalysins and stanniocalcins in obesity.

Keywords:

Children obesity; growth; IGF-I; IGFBP; pappalysin; stanniocalcin.

Corresponding author:

Jesús Argente, M.D., Ph.D.

Hospital Infantil Universitario Niño Jesús

Department of Pediatrics & Pediatric Endocrinology

Avenida Menéndez Pelayo, 65

28009 Madrid, Spain

Phone #: +34 915035912

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FAX #: +34 915035939

E-mail: jesus.argente@uam.es

ORCID # http://orcid.org/0000-0001-5826-0276

Disclose summary:

The authors have nothing to disclose.

Abstract:

Background:

Prepubertal children with obesity frequently have enhanced growth,

accelerated skeletal maturation and changes in the GH-IGF axis. However, the involvement

of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF

bioavailability has not been studied in obesity.

Objective:

We aimed to determine the effects of childhood obesity and weight reduction

on serum levels of PAPP-A, PAPP-A2, STC1 and STC2 and their relationship with IGF

bioavailability, growth, and other components of the GH-IGF system.

Patients and methods:

Prepubertal children with severe obesity (150, 50% males/females,

age: 7.72 ± 2.05 years, BMI z-score: 4.95 ± 1.70, height z-score: 1.28 ± 1.04) were studied

at diagnosis and after a minimum of 0.5 BMI z-score reduction. Two hundred and six

healthy age- and sex-matched children were used as controls.

Results:

Children with obesity had decreased serum concentrations of PAPP-A, PAPP-A2

and STC2, but increased total and free IGF-I (fIGF-I), intact IGFBP-3, ALS, IGF-II and

insulin levels, with no difference in the free/total IGF-I ratio. Neither the standardized BMI

nor height correlated with any biochemical parameter analyzed. A decrease in IGF-II,

insulin, and ALS with an increase in IGFBP-2 and -5, STC2 and PAPP-A were observed

after weight loss.

Conclusion:

Increased circulating total and free IGF-I, insulin and IGF-II may all

contribute to the increased rate of prepubertal growth and bone maturation observed in

children with obesity, with STC2 possibly being involved.

Introduction

Over the past decades, obesity in children and adolescents has increased worldwide

(1) and is currently the most prevalent chronic disease during infancy in occidental

countries (2). It is well known that obesity during the first years of life can influence a

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child’s growth pattern, as growth is closely regulated by nutritional status (3). Several

studies have shown that, prior to pubertal development, children of both sexes with obesity

are frequently taller than expected according to their age and genetic background (4-7),

displaying an accelerated skeletal maturation and an earlier onset of puberty in females

(8,9). However, this acceleration in linear growth during the prepubertal period is followed

by a reduction in the pubertal growth spurt (10), which is reported to be negatively

correlated with the excess in body mass index (BMI) (11). Thus, in some studies of obese

adolescents, adult height is reported to be similar to (12) or slightly greater than the

genetically determined target height (13). Consequently, the rate of prepubertal growth and

skeletal maturation is suggested to correlate positively with the severity of obesity in

childhood. However, the pathophysiological basis and the underlying mechanisms and

effectors determining the influence of chronic overnutrition on growth in childhood remain

far from being fully understood (14-17).

Accelerated linear growth associated with singularities in the growth hormone

(GH)/insulin-like growth factor (IGF)-I axis have been described in prepubertal children

with obesity. Both spontaneous (18) and stimulated GH (19) release are reported to be

decreased, together with higher GH-binding protein (GHBP) levels (20,21). On the other

hand, total IGF-I levels are usually within the normal range (22,23) or even elevated (24) in

young children with obesity. Several studies have also demonstrated increased circulating

levels of free IGF-I, total IGF-II, IGF-binding protein (IGFBP)-3 and IGFBP-4 (22,25,26),

whereas serum IGFBP-2 levels have consistently been found to be reduced. These

observations support the hypothesis that elevated free IGF-I levels downregulate GH

secretion via feedback at the level of the pituitary while promoting growth in young

children with obesity.

The

pappalysin metalloproteinases (PAPP-A, PAPP-A2) were originally identified

pre-clinically as novel regulators of the GH-IGF axis, modulating IGF bioavailability by

proteolytic cleavage of IGFBPs, thus releasing IGF from the binary complexes (27,28).

Later studies in families with short stature due to homozygous loss of function of the

PAPP-A2

gene confirmed the importance of this protease as a physiological regulator of the

GH-IGF axis and linear growth (29,30). Moreover, the two stanniocalcins (STC1 and

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STC2) were shown to inhibit the proteolytic activity of PAPP-A and PAPP-A2,

consequently reducing the release of IGFs from the IGFBPs (31-33).

We have previously reported changes in IGFBP cleavage and IGF-I bioavailability

throughout childhood and during physiological pubertal development (34), as well as in

situations of undernutrition (35) and in Prader-Willi associated obesity compared to non-

syndromic obesity during adolescence (36). The observed changes could reflect underlying

modifications in PAPP-A and STC activity (37,38) and suggest that STCs and PAPP-As

might also influence the peripheral GH-IGF axis in childhood obesity. Therefore, here our

goal was to extend our knowledge regarding the STC-PAPPA-axis in childhood obesity.

Patients and methods

The study population included 150 prepubertal (Tanner stage I) Spanish children

(75 boys and 75 girls) with obesity [BMI z-score > 2, (39)], excluding any subjects with

identifiable underlying obesity causing disease, and 206 healthy age-matched prepubertal

controls (104 boys and 102 girls). The height and (BMI z-score for all controls was

between -1.5 and 1.5 for Spanish standards (39). The clinical and auxological

characteristics of the children at baseline are shown in Table 1.

All patients and their parents or guardians gave informed consent as required by the

local ethics committee (

Comité Ético y de Investigación con Medicamentos

[CEIM]), which

had previously approved the study in accordance with the “Ethical Principles for Medical

Research Involving Human Subjects” adopted in the Declaration of Helsinki by the World

Medical Association (64th WMA General Assembly, Fortaleza, Brazil, October 2013).

Weight status was evaluated after 6 months of follow-up in an outpatient regimen with

treatment based on behavioral, activity and nutritional recommendations, defining BMI z-

score reduction as significant when exceeding 0.5 SDS compared to the initial BMI

Blood samples were drawn from all subjects between 08:00 and 10:00 a.m. after

overnight fasting. Serum concentrations of total and free IGF-I, total IGF-II, total and intact

IGFBP-3, total and intact IGFBP-4, total IGFBP-5, PAPP-A and STC2 were determined by

enzyme-linked immunosorbent assays (ELISAs) from Ansh Laboratories (Webster, TX,

USA). Acid-labile subunit (ALS) and insulin ELISAs were manufactured by BioVendor

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(Brno, Czech Republic) and STC1 ELISA was purchased from R&D systems

(Minneapolis, Minnesota, USA). PAPP-A2 was measured by a chemiluminescent

immunoassay from Cloud Clone (Katy, TX, USA). All assays were performed according to

the manufacturers’ instructions and the intra- and inter-assay coefficients of variation were

lower than 10% in all cases, as previously reported (34-36). Research Resource Identifiers

of the immunoassays used in the study are provided in Table 2.

An X‐ray of the left wrist/hand was used to evaluate bone age in patients with

obesity using the Greulich and Pyle comparative method and their target height was

estimated as mid-parental height +6.5 / -6.5 cm for males and females, respectively.

Statistics

The one-sample Kolmogorov-Smirnov test was used to determine the normality of

the distribution for each variable. Demographic variables are reported as the mean ±

standard deviation whereas serum levels of IGF system components are shown as the

median and the interquartile range due to non-normal distribution of the latter. Inter- and

intragroup comparison of normal variables were performed using Student’s T and paired T

tests, respectively. The Mann-Whitney U test was used to compare serum parameter

concentrations between patients at baseline and controls, whereas the Wilcoxon signed -

rank test was used for the comparison within patients before and after weight loss.

Statistical data were performed by using Statview (Statview 5.01, SAS Institute, Cary, NC,

USA) software. The significance level was set at

<0.05.

Results

Baseline

Median and interquartile ranges and the statistical outcome of the biochemical

parameters in controls and patients with obesity are represented in Table 3. Total and free

IGF-I levels were increased in children with obesity (Fig. 1A and 1B, respectively), with no

differences in the free/total IGF-I ratio (Fig. 1C). Total IGFBP-3 (i.e., the concentration of

intact plus fragmented IGFBP-3) values were not different, but intact IGFBP-3 levels were

increased in children with obesity (Fig. 1D and 1E, respectively). However, there were no

significant differences found in the intact/total IGFBP-3 ratio (Fig. 1F). Total IGFBP-4

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concentrations were higher in children with obesity (Fig. 1G), but no changes were

observed in intact IGFBP-4 or the intact/total IGFBP-4 ratio (Fig. 1H and 1I, respectively).

Circulating concentrations of STC1 showed no differences between groups, whereas STC2

levels were reduced in children with obesity (Fig. 2A and 2B, respectively). Serum levels

of PAPP-A and PAPP-A2 were lower in children with obesity than in controls (Fig. 2C and

2D, respectively).

Serum levels of IGF-II, ALS and insulin were increased in children with obesity,

whereas IGFBP-2 levels were reduced. Levels of IGFBP-5 were not different between the

two groups.

In children with obesity, the degree of acceleration in skeletal maturation (expressed

in years of bone age over chronological age) was positively correlated with serum insulin

levels (ρ=+0.22, p<0.05). In contrast, neither standardized (SDS) BMI nor standardized

height correlated with any of the biochemical parameters studied.

Weight loss

A significant BMI z-score reduction (>0.5 SDS) was achieved by 30% of the

patients with obesity (n=45), with a mean standardized BMI z-score after weight loss of

2.81 ± 1.17 SDS, representing a mean BMI z-score reduction of 1.70 ± 0.98 SDS.

Compared to baseline, patients with weight loss showed an increase in PAPP-A and

STC2, as well as in IGFBP-2 and IGFBP-5 levels, in addition to a decrease in serum

concentrations of IGF-II, insulin, and ALS (Table 4).

Discussion:

This study provides evidence that in addition to the known influence of early onset

obesity on GH secretion (18,19,24), obesity also provokes changes in the peripheral

regulation of IGF-I levels and its bioavailability. Thus, chronic overnutrition is likely to

contribute to the frequently reported coexistence of increased height and acceleration of

skeletal maturation in childhood obesity. This scenario appears to be mainly driven by a

nutrition induced increase in IGF and insulin production (40, 41). Here we confirm the

reported changes in some of the classical components of the peripheral GH -IGF axis in

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children with obesity, such as increased free IGF-I levels (22,25) and include the novel

observation of reductions in serum PAPP-A, PAPP-A2 and STC2 levels.

Previous studies indicate unchanged or slightly elevated total IGF-I, IGFBP-3 and

ALS levels in young children with obesity (22,23,26,42). Our patients had an increase in

the circulating levels of the three main components of the ternary complex (IGF-I, IGFBP-

3, and ALS) possibly related to disease severity. They also had increased insulin and

decreased IGFBP-2 levels as reported in childhood obesity (23, 26, 42,43).

The observation that serum PAPP-A, PAPP-A2 and STC2 levels are reduced in

patients with early onset obesity provides novel information that could help understand the

interplay between nutritional status and the GH-IGF axis in the regulation of growth and

skeletal maturation in the presence of sustained overnutrition during the early stages of life.

Interestingly, these changes in the peripheral components of the GH-IGF-I axis are

different from those observed in adolescents with obesity (36), which could possibly be

associated with the differential growth velocities and/or sexual maturation of these subjects.

Serum ALS (45), total IGF-I and IGFBP-3 levels, are nutritional markers and show

strong correlation with nutritional status in healthy children (44), being decreased in

undernourishment (35) and increasing after refeeding (40) and in overnutrition and obesity

(22). This suggests that sustained overnutrition in our patients is, at least in part,

influencing the high circulating levels of the three components of the ternary complex.

Likewise, the severity of obesity is an important factor in determining the increase in

circulating insulin levels, a common finding preceding hyperglycemia (46, 47).

Hyperinsulinemia is suggested to play a major role in bone maturation in childhood obesity

(7) and this is supported by the correlation between insulinemia and the degree of

acceleration in bone maturation in our patients. The precise mechanism underlying the

effect of hyperinsulinemia on skeletal growth and maturation is not fully elucidated,

although there is evidence indicating that excess caloric intake mediates its effect on bone

growth through the insulin receptor (48).

Obesity during childhood can blunt GH secretion (18,19). Hyperinsulinemia has

been proposed as a possible mechanism underlying “

growth without growth hormone

phenomenon

”, probably due to insulin stimulating GH receptor production and thus GH

hypersensitivity,

observed in some children after hypothalamic tumor surgery or

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radiotherapy who develop hyperphagia with severe obesity and have an increased lineal

growth rate despite low circulating levels of total IGF-I and IGFBP-3 (49). This suggests

that in these patients, as in those in our cohort of children with severe obesity, the role of

overnutrition and increased insulin levels could play a major role in their lineal growth,

even overcoming the influence of GH. This could mimic that observed during the fetal

period and in the first months of extrauterine life, when total IGF-I and IGFBP-3

progressively become under the control of GH stimulus while maintaining a an important

influence of nutritional status (50,51,52).

IGF-II can activate IGF-I and insulin receptors and circulating IGF-II levels have

been reported to be higher in children and adults with obesity (22, 53) and to correlate with

the BMI z-score in young prepubertal children (54). The high IGF-II levels observed here

and their reduction after weight loss confirm these observations and would also support the

role of nutrition in lineal growth in these patients as IGF-II is not produced under GH

stimulus (55). Of note, adipose tissue secretes high amounts of IGF-II in vitro, which could

explain the association between adiposity and serum IGF-II (56). IGF-II is essential for

fetal growth and development (57,58). However, the precise physiological role of

circulating IGF-II in growth during the postnatal period remains to be elucidated. The fact

that impaired expression and overexpression of IGF-II are associated with either impaired

growth or overgrowth and obesity development in Silver Russell and Beckwith-

Wiedemann and other overgrowth syndromes, respectively (59-61), supports a role for

IGF-II in linear growth in postnatal life (62).

Changes in serum levels of IGFBPs have been partially characterized in patients

with nutritional alterations, with IGFBP-2 being the subtype most closely related to

nutritional status and insulin levels in obesity (42,63), as well as in other eating disorders

(35). Here we confirmed low IGFBP-2 levels in children with obesity (22-23), with a

significant increase after weight loss (64-66).

Free IGF-I levels were increased in our patients with obesity, confirming previous

observations (22,26). To date, it has been assumed that this is the main determinant of

increased linear growth rate in young children with obesity. A novel finding here is that

these patients have lower serum levels of pappalysins, especially PAPP-A2, whereas the

free to total IGF-I ratio and the intact to total IGFBP-3 and IGFBP-4 ratio were not

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different from control levels, with these ratios suggested to be indirect estimations of

pappalysin activity (67). Together these observations suggest that it is not an increase in

pappalysin levels that underlies the rise in free IGF-I levels in childhood obesity and again

emphasize the relevance of the nutritionally driven changes in ternary complex abundance.

Our study does not establish the mechanism underlying the reduction in PAPP-A

levels in young patients with obesity. However, it resembles previous observations in

newborns where both PAPP-A and PAPP-A2 levels in cord blood were inversely correlated

with the offspring’s birth length and weight z-scores, with the latter being strongly

correlated with cord blood total IGF-I levels (68). Both observations point towards the

possibility of a negative feed-back effect of growth and weight gain on circulating

pappalysin levels in early stages of life.

We are also unable to explain the mechanism underlying the coexistence of reduced

circulating pappalysin levels with normal free/total IGF-I and intact/total IGFBP-3 and

IGFBP-4 ratios in our patients. However, we speculate that a reduction in the STC2

mediated inhibition of pappalysin enzymatic activity could counteract the effects of low

endogenous pappalysin on growth. Indeed, lower STC2 levels were observed in our

patients, with correlations of this factor with body fat content being previously reported

(69). The fact that circulating STC1 levels were not altered in patients and remained

unchanged after weight loss reinforces the idea that STC1 acts mainly at the tissular level

and its influence on the ternary complex cleavage is less than that of STC2 (70).

The persistence of high circulating free and total IGF-I levels even after significant

weight loss is most probably because these children remained within the range of obesity.

Additionally, the time to achieve this weight loss was limited and possibly insufficient for

the peripheral IGF-I axis to totally adapt, although changes in insulin, IGFBP-2 and IGF-II,

known to be rapidly modified in response to nutrient restriction, were observed. However,

the increase in STC2 levels after weight loss could indicate an initial inhibitory change in

the peripheral IGF axis associated with caloric restriction.

Another relevant finding is that modifications of the peripheral GH-IGF axis differ

between young prepubertal children and adolescents with obesity. Here and previously (36)

we found that in both age ranges increased serum levels of insulin, total IGF-I, IGFBP-3,

ALS and IGF-II, and lower IGFBP-2 serum levels are observed, most likely related to their

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sustained overnutrition. However, in contrast to what was seen in young children,

adolescents with obesity exhibited a ten-fold increase in free IGF-I levels and a decrease in

the intact to total ratios of both IGFBP-3 and IGFBP-4, congruent with their increase in

serum levels of PAPPA and PAPPA-2 and decreased STC2 (36). The production of GH

during puberty is increased largely because of sex steroids (71). Thus, it is possible that

there is an influence of sex steroids on these components of the GH-IGF-I axis, although no

information on the direct effects of sex steroids on pappalysin or STC levels is available.

The serum levels and role of IGFBP-4 and -5 in patients with obesity have been

poorly studied. A previous study found higher total serum concentrations of IGFBP-4 in

children with obesity, as found here, and a positive correlation between IGFBP-4 and

insulin levels (26). This latter finding was not observed here possibly due to the difference

in age between the two cohorts with those studied here being younger. In addition, we

found no influence of overnutrition on IGFBP-5 levels. As severe undernourishment was

also not found to modify this parameter (35), nutritional state does not appear to be a major

regulator of IGFBP-5 production.

In summary, this study furthers our understanding regarding regulation of the

peripheral GH-IGF axis in prepubertal children with obesity. We report a parallel decrease

in circulating levels of pappalysins and STC2 and this could indicate that the decrease in

STC2 allows sufficient pappalysin proteolytic activity to ensure that even though ternary

complexes are increased, free IGF-I levels are also increased. This increase in free IGF-I in

addition to increased insulin and IGF-II levels, would then be the main determinants of the

acceleration in skeletal maturation and linear growth rate in these patients. However, it

remains necessary to delineate the molecular mechanisms involved in the changes in

pappalysin levels, as well as its proteolytic activity and the factors that modulate this

enzymatic activity, not only in obesity but in general. Likewise, how STCs are regulated

and the link between circulating levels of STCs and PAPP-As and their actions on specific

tissues deserves further investigation. It is plausible that as our understanding of the

interplay between these factors, as well as with growth, sexual development and nutrition,

advances specific clinical applications will emerge.

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Acknowledgments

The authors wish to thank the patients and their relatives for participating in this study.

Funding

This research was funded by the Spanish Ministry of Health (FIS-PI19/00166 to JA and

FIS PI22/01820 to VB and GÁ-MM), and by “ERDF A way of making Europe”, the

“European Union”, and Centro de Investigación Biomédica en Red Fisiopatología de

Obesidad y Nutrición (CIBEROBN), Instituto Carlos III (JA). AM-R received a Río

Hortega contract from the Instituto de Salud Carlos III (No. CD19/00008), SGC received a

PFIS contract from the Instituto de Salud Carlos III (No. FI17/00218), and A.C.C. received

a contract “Garantía Juvenil” from the Comunidad Autónoma de Madrid, Madrid, Spain.

The funder was not involved in the study design, collection, analysis, interpretation of data,

the writing of this article or the decision to submit it for publication.

Abbreviations

ELISA, enzyme-linked immunosorbent assay; fIGF, free insulin-like growth factor; GH,

growth hormone; IGF, insulin-like growth factor; IGFBP-2, insulin-like growth factor

binding protein-2; IGFBP-3, insulin-like growth factor binding protein-3; IGFBP-4,

insulin-like growth factor binding protein-4; IGFBP-5, insulin-like growth factor binding

protein-5; PAPP-A, pregnancy-associated plasma protein A; PAPP-A2, pregnancy-

associated plasma protein A2; STC1, stanniocalcin 1; STC2, stanniocalcin 2.

Author Contributions

Substantial contributions to study conception and design: V.B., A.M.-R., G.Á.M.-M, J.A.;

substantial contributions to analysis and interpretation of the data: V.B., A.M.-R., G.Á.M.-

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M, S.G.-C., A.C.-C, C.O., J.F., J.A.C., J.A.; drafting the article or revising it critically for

important intellectual content: V.B., A.M.-R., G.Á.M.-M, C.O., J.F., J.A.C., J.A.; final

approval of the version of the article to be published: A.M.-R., G.Á.M.-M, S.G.-C., A.C.-C,

C.O., J.F., J.A.C., V.B., J.A.

Disclosures

The authors have nothing to disclose.

Data Availability

Some or all data sets generated during and/or analyzed during the present study are not

publicly available but are available from the corresponding author on reasonable request.

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FIGURE LEGENDS

Figure 1.

Box plot showing serum concentrations of total IGF-I (A), free IGF-I (B),

free/total IGF-I ratio (C), total IGFBP-3 (D), intact IGFBP-3 (E), the intact/total IGFBP-3

ratio (F), total IGFBP-4 (G), intact IGFBP-4 (H), and the intact/total IGFBP-4 ratio (I) in

controls (C) and patients with obesity (OB).

The whiskers of the plots represent the 5 to 95 percentiles. The lower, middle and upper

lines of box represent the lower quartile, median and the upper quartile, respectively. The

points represent outliers. **

<0.01, ***

<0.001 by Mann–Whitney

test. Abbreviations:

IGFBP, IGF binding protein; NS, not significant.

Figure 2.

Box plot showing serum concentrations of STC1 (A), STC2 (B), PAPP-A (C),

and PAPP-A2 (D) in controls (C) and patients with obesity (OB).

The whiskers of the plots represent the 5 to 95 percentiles. The lower, middle, and upper

lines of box represent the lower quartile, median and the upper quartile, respectively. The

points represent outliers. *

<0.05, ***

<0.001 by Mann–Whitney

test. Abbreviations:

NS, nonsignificant; PAPP, pappalysin; STC, stanniocalcin.

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Table 1.

Clinical features of controls and patients with obesity included in the study.

* In patients with obesity: Patient´s height SDS: 1.15 ± 1,10

vs.

target height SDS -0.27

±1.12; p< 0.001.

** In patients with obesity: Bone age: 9.07 ± 2.65 years

vs.

chronological age 7.72 ± 2.05

years; p< 0.001.

Data expressed as mean ± standard deviation.

Abbreviations:

BMI

: body mass index;

na:

not available;

ns:

not significant;

: significance

level;

SDS

: standard deviation score (z-score).

Controls

Patients with obesity

Age (years)

7.46 ± 1.90

7.72 ± 2.05

BMI-SDS

-0.22 ± 0.85

4.95 ± 1.70

< 0.001

Height-SDS

0.24 ± 0.86

1.28 ± 1.04

< 0.001

Height (SDS) - target

height (SDS)

1.52 ± 1.22 SDS

Bone age

–

Chronological age

1.00 ± 1.30 SDS

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Table 2.

Research Resource Identifier (RRID) of the assays used.

Abbreviations:

ALS, acid-labile subunit; IGF, insulin-like growth factor; IGFBP-2, insulin-

like growth factor binding protein-2; IGFBP-3, insulin-like growth factor binding protein-3;

IGFBP-4, insulin-like growth factor binding protein-4; IGFBP-5, insulin-like growth factor

binding protein-5; PAPP-A, pregnancy-associated plasma protein A; PAPP-A2, pregnancy-

associated plasma protein A2; STC-1, stanniocalcin 1; STC-2, stanniocalcin 2.

Parameters

Commercial

source

Catalog #

RRID

Total IGF-I

Ansh Labs

AL-121

AB_2783672

Free IGF-I

Ansh Labs

AL-122

AB_2783673

IGF-II

Ansh Labs

AL-131

AB_2783680

IGFBP-2

Ansh Labs

AL-140

AB_2783686

Total IGFBP-3

Ansh Labs

AL-120

AB_2783671

Intact IGFBP-3

Ansh Labs

AL-149

AB_2783688

Total IGFBP-4

Ansh Labs

AL-126

AB_2783676

Intact IGFBP-4

Ansh Labs

AL-128

AB_2783678

IGFBP-5

Ansh Labs

AL-127

AB_2783677

ALS

Mediagnost

E35

AB_2813809

Insulin

BioVendor

RIS006R

AB_2893123

PAPP-A

Ansh Labs

AL-101

AB_2783656

PAPP-A2

Cloud Clone

SCD471Hu

AB_2893124

STC-1

R&D Systems

DY2958

AB_2893122

STC-2

Ansh Labs

AL-143

AB_2783687

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Table 3.

Serum levels of the insulin-like growth factor system components in controls and

patients with obesity.

Controls

Patients with obesity

Total IGF-I, ng/mL

306.5 (221.6-416.9)

341.0 (225.1-466.7)

< 0.01

Free IGF-I, ng/mL

2.83 (1.67-3.98)

3.42 (2.16-4.87)

< 0.001

IGF-II, ng/mL

153.6 (112.7-187.3)

172.1 (122.1-216)

< 0.05

IGFBP-2, ng/mL

47.7 (21.7-110.8)

31.1 (18.7-47.1)

< 0.001

Total IGFBP-3, ng/mL

4197 (3210-5637)

4081 (3063-5400)

Intact IGFBP-3, ng/mL

622 (368-909)

830 (665-1033)

< 0.001

Total IGFBP-4, ng/mL

20.7 (15.3-29.0)

28.7 (19.3-40.5)

< 0.001

Intact IGFBP-4, ng/mL

21.4 (13.0-33.9)

22.7 (16.1-34.8)

IGFBP-5, ng/mL

345.4 (299.6-445.6)

341.8 (273.2-428.3)

Insulin, µU/mL

4.83 (2.29-9.31)

17.14 (13.49-26.18)

< 0.001

ALS, ng/mL

8098 (6709-9181)

9139 (7933-6766)

< 0.001

STC1, pg/mL

481 (333-685)

536 (337-715)

STC2, ng/mL

28.2 (23.5-33.4)

24.9 (20.6-30.0)

< 0.05

PAPP-A, ng/mL

0.63 (0.41-0.82)

0.43 (0.31-0.62)

< 0.001

PAPP-A2, ng/mL

5.41 (4.24-6.82)

3.14 (2.22-4.40)

< 0.001

F/T IGF-I, %

0.88 (0.52-1.30)

0.95 (0.66-1.38)

I/T IGFBP-3, %

15.2 (7.9-24.6)

20.4 (14.4-28.7)

I/T IGFBP-4, %

106.5 (52.3-157.1)

86.4 (58.6-126.2)

Values are expressed as median and interquartile range.

Abbreviations:

ALS, acid-labile subunit; F/T, free/total; IGF, insulin-like growth factor;

IGFBP, insulin-like growth factor binding protein; I/T intact/total ratio; ns, Not significant; p:

significance level; PAPP, pregnancy-associated plasma protein; STC, stanniocalcin.

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Table 4.

Effect of weight loss on the serum levels of the insulin-like growth factor system

components in patients with obesity.

Baseline

Weight loss

Total IGF-I, ng/mL

467.4 (349.1-588.8)

487.1 (357.2-595.2)

Free IGF-I, ng/mL

3.74 (2.72-614)

3.36 (2.25-5.15)

IGF-II, ng/mL

277.6 (158.8-487.0)

182.4 (129.5-234.3)

< 0.01

IGFBP-2, ng/mL

18.3 (10.2-27.5)

26.2 (18.7-42.0)

< 0.05

Total IGFBP-3, ng/mL

5167 (4062-6567)

4700 (4033-5641)

Intact IGFBP-3, ng/mL

803 (718-976)

902 (669-1030)

Total IGFBP-4, ng/mL

23.7 (17.4-30.3)

24.2 (17.9-31.3)

Intact IGFBP-4, ng/mL

15.2 (11.9-18.7)

16.0 (14.2-18.7)

IGFBP-5, ng/mL

279.2 (239.7-331.6)

359.8 (300.9-437.2)

< 0.001

Insulin, µU/mL

16.5 (12.0-20.7)

12.3 (7.2-16.2)

< 0.001

ALS, ng/mL

12470 (8979-14423)

8656 (7985-10137)

< 0.001

STC1, pg/mL

319 (255-509)

298 (157-428)

STC2, ng/mL

22.4 (18.8-25.3)

26.0 (21.8-29.3)

< 0.001

PAPP-A, ng/mL

0.43 (0.33-0.50)

0.51 (0.39-0.76)

< 0.001

PAPP-A2, ng/mL

3.85 (2.67-4.62)

3.77 (3.23-4.60)

F/T IGF-I, %

0.75 (0.64-1.08)

0.75 (0.55-1.10)

I/T IGFBP-3, %

15.2 (12.3-22.0)

19.0 (14.2-22.1)

I/T IGFBP-4, %

67.7 (49.7-94.9)

74.0 (50.4-97.2)

Values are expressed as median and interquartile range.

Abbreviations:

ALS, acid-labile subunit; F/T, free/total; IGF, insulin-like growth factor;

IGFBP, insulin-like growth factor binding protein; I/T intact/total ratio; ns, Not significant; p:

significance level; PAPP, pregnancy-associated plasma protein; STC, stanniocalcin.

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