role of visfatin, insulin-like growth factor-i and insulin in fetal growth

J. Perinat. Med. 35 (2007) 326–329 • Copyright � by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2007.071

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Role of visfatin, insulin-like growth factor-I and insulin infetal growth

Despina D. Briana1, Maria Boutsikou1, DimitriosGourgiotis2, Louiza Kontara1, Stavroula Baka1,Nicoletta Iacovidou1, Dimitrios Hassiakos1 andAriadne Malamitsi-Puchner1,*1 2nd Department of Obstetrics and Gynecology,

Neonatal Division, Athens University Medical School,Athens, Greece

2 2nd Department of Pediatrics, Research Laboratories,Athens University Medical School, Athens, Greece

Abstract

Objective: IGF-I and insulin are the main regulators ofintrauterine and postnatal growth. Adipose tissue secret-ed cytokines are implicated in intrauterine growth. Therelevant function of the adipocytokine visfatin isunknown.Materials and methods: Serum visfatin, IGF-I and insu-lin levels were measured by enzyme immunoassays in 40singleton full-term fetuses and neonates on postnataldays 1(N1) and 4 (N4).Results: No significant correlations exist between visfatinand IGF-I or insulin. N1 and N4 visfatin positively corre-lated with customized (adjusted) birth weight centiles(rs0.511, Ps0.021, and rs0.597, Ps0.005, respective-ly). Fetal and N1 IGF-I positively correlated with custom-ized centiles (rs0.608, P-0.001 and rs0.485, Ps0.006,respectively). Fetal insulin positively correlated with cus-tomized centiles (rs0.654, Ps0.021).Conclusions: Potential implication of visfatin in fetalgrowth is probably not mediated by IGF-I or insulin.Although a more active role cannot be excluded, visfatinmay simply represent a marker of fat accumulation.

Keywords: Fetus; IGF-I; insulin; intrauterine growthrestriction; neonate; visfatin.

Introduction

Intrauterine growth restriction (IUGR) results in significantperinatal and long-term complications, including, on the

*Corresponding author:Ariadne Malamitsi-Puchner, MD19, Soultani StreetGR-10682 AthensGreeceTel.: q30 6944443815Fax: q30 2107233330E-mail: [email protected]; [email protected]

one hand, increased neonatal mortality and morbidityw13x and on the other, higher risk for developing meta-bolic syndrome later in life w3, 8, 25x. For this reason,mechanisms controlling human fetal growth are currentlyextensively studied. The major regulator of growth, bothin fetal and postnatal life, is the insulin-like growth factor(IGF) axis w1x whereas insulin augments intrauterinegrowth by stimulating the production of IGF-I w9x. IGF-I,produced by numerous fetal tissues during gestation w9x,promotes cellular proliferation and differentiation w17x,and its levels correlate well with birth-weight w6, 26x. Inaddition, this pro-insulin-like polypeptide appears to bethe dominant growth-promoting factor during the rapidphase of somatic growth in late gestation w2x. Indepen-dently of the cause of poor growth, IUGR ultimatelyinvolves alterations in the IGF axis, which may perma-nently ‘‘program’’ the organism for future pathology w16,24x.

Adipocytokines (and particularly leptin) were implicatedin intrauterine growth w21x. Visfatin, which is a recentlydiscovered adipocytokine, is mainly produced by visceraladipose tissue, and shares metabolic properties withinsulin w10x. Preliminary studies suggest that circulatingvisfatin concentrations are increased in humans withabdominal obesity w10, 15x, type 2 diabetes, and insulinresistance w5x. Furthermore, insulin may regulate visfatinrelease in humans w14x, whereas growth hormone (GH)directly reduces visfatin expression in human adipocytesw18x.

Interestingly, visfatin, previously recognized as a pre-Bcell colony-enhancing factor (PBEF), is constitutivelyexpressed by the feto-placental unit during pregnancyw23x. Moreover, in our recent study comprising normalinfants (unpublished data), visfatin was present in cordand neonatal blood, and thus possibly associated withfetal growth. If the latter were the case, it is reasonableto hypothesize that either IGF-I, insulin, or both, couldmediate the possible effect of visfatin on intrauterinedevelopment, in a similar way as was proposed for theadipocytokines leptin w6x and adiponectin w20x. We,therefore, aimed to examine potential correlations of cir-culating visfatin concentrations with IGF-I and insulin –the main factors implicated in fetal and postnatal growthw1, 9, 22x.

Material and methods

The Ethics Committee of our teaching hospital approved thestudy protocol. Signed informed consent was obtained from

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Briana et al., Visfatin, IGF-I and insulin in fetal growth 327


Figure 1 Scatterplot demonstrating the positive correlationbetween day 1 (N1) visfatin concentrations and customized cen-tiles (adjusted birth weight) of the studied neonates.

Figure 2 Scatterplot demonstrating the positive correlationbetween day 4 (N4) visfatin concentrations and customized cen-tiles (adjusted birth weight) of the studied neonates.

mothers of participating infants. The study group comprised of40 full-term (38–40 weeks of gestation) singleton infants withcustomized centiles ranging from 1 to 85, calculated by applyingthe Gestation Related Optimal Weight (GROW) computer-gene-rated program w11, 12x. Significant determinants of birth weight(maternal height and booking weight, ethnic group, parity, ges-tational age and gender) were entered into the program to adjustthe normal birth-weight centile limits w11x.

None of the neonates presented symptoms of intrauterineinfection or signs of genetic syndromes. Twenty were deliveredvaginally and 20 by elective cesarean section. One- and five-minute Apgar scores were G8 in all cases. All infants werebreastfed.

Blood was drawn at delivery from the doubly clamped umbili-cal cord (UC) reflecting fetal state, and from the neonates ondays 1 (N1) and 4 (N4), representing the transition and stabili-zation to extrauterine life, respectively. Blood was collected inpyrogen-free tubes and was immediately centrifuged after clot-ting. The supernatant serum was kept frozen at y808C untilassay. The determination of visfatin levels was performed byenzyme immunoassay (Visfatin C-Terminal wHumanx, PhoenixPharmaceuticals Inc, Belmond, California 94002). The minimumdetectable concentration, intra- and interassay coefficients ofvariation (CV%) were 0.1 ng/mL, 5% and 12%, respectively.

IGF-I was measured by ELISA (Assay Designs Inc, 800 Tech-nology Drive, Ann Arbor, Michigan, USA). The minimum detect-able concentration, intra- and interassay CV% were 187 pg/mL,4.9% and 7.1%, respectively.

The determination of insulin levels was performed by Micro-particle Enzyme Immunoassay wAbbot Diagnostics (AxsymSystem), Wiesbaden, Germanyx. The minimum detectable con-centration, intra- and interassay CV% were -1 mU/mL, 4.1%and 5.3%, respectively.

Statistical analysis

Visfatin and IGF-I data presented normal distribution, in contrastto insulin (Kolmogorov-Smirnov test). Pearson or Spearman9scorrelation coefficient were used where appropriate to detectpositive or negative correlations. In order to examine possibleeffects of IGF-I, insulin and customized birth-weight centiles onvisfatin levels in each consecutive measurement (UC, N1, N4) alinear regression model was constructed, using visfatin as thedependent variable and IGF-I, insulin and customized centilesas the independent factors. P-0.05 was considered statisticallysignificant.

Results

No significant correlations were observed between vis-fatin and IGF-I or insulin levels. IGF-I, insulin and custom-ized birth-weight centiles did not significantly predictvisfatin levels in any of the measurements (UC, N1, N4).

N1 and N4 visfatin levels positively correlated with cus-tomized birth-weight centiles (rs0.511, Ps0.021, andrs0.597, Ps0.005, respectively) (Figures 1 and 2). Fetaland N1 IGF-I levels positively correlated with customizedbirth-weight centiles (rs0.608, P-0.001 and rs0.485,Ps0.006, respectively), as well as birth weight (rs0.707,P-0.001 and rs0.515, Ps0.003, respectively). Fetal

insulin levels positively correlated with customized birth-weight centiles (rs0.654, Ps0.021). N4 insulin levelspositively correlated with birth weight (rs0.637, Ps0.026).



328 Briana et al., Visfatin, IGF-I and insulin in fetal growth


Discussion

The role of visfatin in fetal growth is unknown. Accordingto our study, visfatin is positively associated with adjust-ed birth weight (customized centiles) but the mecha-nism(s) underlying this association have to be elucidated.The above association might be a direct relationshipbetween adipose tissue mass and circulating visfatinconcentrations w4x; however, the recognition of the pla-centa and fetal membranes as a source of PBEF/visfatinproduction w23x may suggest an active role for visfatin infetal growth as well. Thus, it would be important to doc-ument whether the primary established endocrine regu-lators of fetal growth, IGF-I and insulin w1, 9x, interactwith, or influence the production or tissue effects ofvisfatin.

The results of this study do not indicate an associationbetween visfatin and IGF-I or insulin in fetal and neonatalserum. Recent experimental data indicate that visfatinexpression is reduced after exposure of 3T3-L1 adipo-cytes to GH w18x, the effects of which are mediated byIGF-I w7x. Furthermore, it has been documented that therelease of visfatin is actually regulated by glucose andinsulin w14x. However, research failed to show any asso-ciation between visfatin and insulin in women with ges-tational diabetes mellitus w19x. Admittedly, clinical dataabout visfatin are limited. Previous studies investigatedwhether the role of other adipocytokines in fetal growthis mediated by IGF-I or insulin w6, 20x. In this respect,Christou et al. w6x found that the role of leptin in fetalgrowth is independent of both IGF-I and insulin. In con-trast, it was indicated that alterations of the IGF systemmediate the association between adiponectin and new-born length w20x. Thus, it has been suggested that adi-ponectin contributes to fetal growth by acting as aninsulin-sensitizing factor w20x.

In conclusion, our study indicates that the potentialimplication of visfatin in fetal growth is probably notmediated by IGF-I or insulin. Although a more active rolecannot be excluded, it is possible that visfatin simply rep-resents a marker of fat accumulation.

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Received November 30, 2006. Revised March 2, 2007. AcceptedApril 18, 2007. Published online on May 21, 2007.



role of visfatin, insulin-like growth factor-i and insulin in fetal growth

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