serum concentrations of insulin, insulin-like growth factor(igf)-i, igf binding protein (igfbp)-1...

Clinical Endocrinology (1998) 48, 487–492

487q 1998 Blackwell Science Ltd

Serum concentrations of insulin, insulin-like growthfactor(IGF)-I, IGF binding protein (IGFBP)-1 and -3 andgrowth hormone binding protein in obese children:fasting IGFBP-1 is suppressed in normoinsulinaemicobese children

Hisako Saitoh*, Tomohiro Kamoda*, SatokoNakahara†, Takeki Hirano‡ and Norimasa Nakamura**Department of Paediatrics, University of Tsukuba,Tsukuba, †Department of Paediatrics, Kensei GeneralHospital, Iwase and ‡Department of Paediatrics, IbarakiChildren’s Hospital, Ibaraki, Japan

(Received 16 September 1997; returned for revision 21November 1997; finally revised 15 December 1997; accepted 20January 1998)

Summary

OBJECTIVE Simple obesity is characterized bynormal or accelerated growth in the presence ofreduced serum levels of GH, whereas its detailedmechanism remains unknown. We, therefore, evalu-ated interrelationships among serum levels of insulin,IFG-I, IGF binding protein (IGFBP)-1 and -3 and growthhormone binding protein (GHBP) in prepubertalobese children.SUBJECTS Prepubertal 20 obese children and 20 age-matched control children were included in the study.RESULTS Serum levels of insulin, IGF-I and IGFBP-3in obese children did not differ from those in controls.The serum level of IGFBP-1 was significantly lower inobese children (22·1 6 18·4mg/l, P<0·001) than in con-trol children (76·0 6 62·9mg/l). No relationship wasfound between the serum levels of insulin and IGF-I,IGFBP-1, or IGFBP-3 in obese subjects. The serumlevel of GHBP in obese children was significantlyelevated as compared with that in controls and waspositively correlated with body mass index (BMI). Norelationship was found between the serum levels ofGHBP and IGF-I in obese subjects.CONCLUSIONS The present study showed for the firsttime that the fasting IGFBP-1 level was suppressed in

prepubertal obese children with fasting normoinsuli-naemia. We speculate that the hyperinsulinaemiawhich cannot be detected in the fasting state mayhave suppressed hepatic production of IGFBP-1.Alternatively, the reduced IGFBP-1 is likely to be acompensatory response to impaired insulin sensitiv-ity. Thus, the IGFBP-1 level may be a useful predictorfor the early identification in the development ofinsulin resistance in prepubertal obese children.

Introduction

Simple obesity is characterized by normal or acceleratedgrowth in the presence of reduced levels of GH and poor GHresponses to pharmacological stimuli (Vignoloet al., 1988;Vanderschueren-Lodeweyckx, 1993). To date, its detailedmechanism is unknown. The results of recent studies havesuggested that suppression of the level of IGFBP-1 due tohyperinsulinaemia increases the level of free IGF-I andpromotes the IGF-I action, resulting in normal growth withpoor GH secretion in obese children (Conoveret al., 1992;Frystyket al., 1995).

Prepubertal obese children do not always show thehyperinsulinism as found in adult obesity, because suchhyperinsulinism may not become manifest until a later age(Stunff & Bougneres, 1994). It is, therefore, unlikely that theincreased IGF-I action due to suppression of IGFBP-1 levels inthese children can be explained solely by the hyperinsulinism.Little is known about the relationship between insulin andcirculating IGFBP-1 levels in prepubertal obese children. Ourobjective was to evaluate the relationships among serum levelsof insulin, IGF-I, IGFBP-1 and -3 and GHBP in prepubertalobese children.

Subjects and methods

Subjects

Twenty Japanese obese children (12 males and 8 females, mean(6SD) age 8·86 2·2 years, range; 4·3–13·6 years) wereincluded in the study. They were selected among all children

Correspondence: Dr. Tomohiro Kamoda, Department of Paediatrics,Institute of Clinical Medicine, University of Tsukuba, 1-1-1Tennoudai, Tsukuba 305, Ibaraki, Japan. Fax:þ81 298 53 3039;E-mail: tkamoda @md.tsukuba.ac.jp

with newly diagnosed, simple obesity at the paediatric clinic,University of Tsukuba. The mean body mass index (BMI) was25·16 3·7 kg/m2, and the mean height SD score ((x¹X)/SD,where x is the observed height value, X is the mean height forsex and age, and SD is the standard deviation of the height forsex and age taken from reference tables of Japanese children;Suwa & Tachibana, 1993) was 1·06 1·2. Pubertal developmentwas Tanner stage 1 in all subjects. With growth curve chartsrecorded from the children’s birth, the onset of obesity wasdated when body weight exceeded 120% ideal body weight(IBW) for age, sex and height. The mean (6SD) duration ofobesity in the children studied was 4·76 3·0 years. All obesechildren had neither attempted to reduce their caloric intake,nor experienced any weight loss since the onset of obesity. Amedical examination that included previous history, physicalexamination and routine laboratory tests revealed no abnorm-alities other than obesity. None of them were receiving anymedication. A total of 20 age-matched prepubertal children (13males and 7 females) were studied as controls. They werechosen among the patients visiting the paediatric clinic byreason of non-endocrinological problems. None of them had afamily history of obesity or diabetes nor took any medication.Informed consent was obtained from parents of all the childrenand the study was approved by the local ethical committee.

Methods

Subjects were admitted to our hospital the evening before thestudy and were given a standard evening meal. Thereafter, onlywater was permitted. On the following morning, blood sampleswere collected from each subject. Serum was separatedimmediately by centrifugation and kept at¹208C until analysis.

Hormone assays

The serum insulin level was determined by use of a commercialradioimmunoassay kit (Eiken Chemical Co., Tokyo), with inter-and intraassay coefficients of variation of less than 10% and alower limit of detection of 6 pmol/l. After acid-ethanol extrac-tion, serum IGF-I concentration was assessed by use of acommercial radioimmunoassay kit (Medgenix Diagnostics Co.,Brussels). The sensitivity of this assay was 0.3mg/l. Inter- andintraassay coefficients of variation were 3·6 to 6·4% and 2·0 to6·4%, respectively. Serum IGFBP-1 was determined by use of acommercially available radioimmunoassay kit (DiagnosticSystem Laboratories, Inc., Webster, TX, USA) which is notaffected by the state of IGFBP-1 phosphorylation and quantifiestotal IGFBP-1 in serum. The lower limit of detection was0·33mg/l and inter- and intraassay coefficients of variation were3·5 to 6·0% and 2·7 to 5·2%, respectively. Serum IGFBP-3was measured by use of a commercial enzyme-linked

immunosorbent assay kit (Diagnostic System Laboratories).The lower limit of detection was 0·04mg/l and inter- andintraassay coefficients of variation were 8·2 to 11·4% and 7·3 to9·6%, respectively.

Serum GHBP was measured by an assay utilizing dextran-coated charcoal separation. This assay was performed asdescribed by Amitet al.(1990). [125I]hGH (1ng) was incubatedat 48C for 20 hours with 50ml of serum in the absence orpresence of excess unlabeled hGH. Thereafter, bound and free[125I]hGH were separated by the addition of dextran-coatedcharcoal. Specific binding of [125I]hGH to GHBP (total bindingminus nonspecific binding) obtained with 50ml of serum wasexpressed as a percentage of the total [125I]hGH incubated.Values were corrected to account for the effect of endogenousserum levels of GH measured by use of a commercialradioimmunoassay kit (Eiken Chemical Co.). The inter- andintra-assay coefficients of variation in the GHBP assay were 4·6and 1·5%, respectively.

Statistical methods

Results are expressed as mean6 SD. Student’s unpaired t testor the Mann-Whitney U test was used to determine statisticalsignificance. Relationships between parameters were evaluatedby linear regression analysis. All analyses were performedusing Stat View software (version 4.02; Abacus Concepts Inc,Berkeley, CA, USA). A level ofP< 0·05 was accepted asstatistically significant.

Results

The characteristics of the subjects are shown in Table 1. Theobese and control children were comparable regarding age andsex. The mean BMI, percentage IBW and height SD scores inobese children significantly exceeded those of controls(P<0·0001,P<0·0001, andP<0·01, respectively).

The levels of serum insulin, IGF-I and IGFBP-3 in obesechildren did not differ from those in controls (Table 2). Theserum level of IGFBP-1 was significantly lower in obese(22·16 18·4mg/l) than in control children (76·06 62·9mg/l,P< 0·001; Table 2). There was no significant differencebetween obese children and controls in the molar IGF-I/IGFBP-3 ratio (Table 2). No relationship was found betweenthe serum level of insulin and that of IGF-I, IGFBP-1, orIGFBP-3 in obese children. Since the IGFBP-1 data in bothgroups had the large standard deviations, further analyses wereperformed on log transformed IGFBP-1 values. However, norelationship was observed between insulin levels and logIGFBP-1 in obese subjects (r¼ 0·30,P¼ 0·08).

The serum level of GHBP was significantly elevated inobese children (19·06 5·6%), as compared with that in

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q 1998 Blackwell Science Ltd,Clinical Endocrinology, 48, 487–492

controls (10·36 3·3%,P< 0·0001; Table 2) and was positivelycorrelated with BMI (r¼ 0·81, P<0·0001; Fig. 1) andpercentage IBW (r¼ 0·82, P<0·0001). No relationship wasobserved between the serum levels of IGF-I and GHBP in obesesubjects (r¼ 0·13,P¼ 0·60).

The serum level of insulin in obese children was positivelycorrelated with age and duration of obesity (r¼ 0·57,P<0·01and r¼ 0·60,P<0·01; Fig. 2, respectively).

Discussion

Simple obesity is characterized by a normal or increased growthrate with an acceleration of bone age maturation (Vaderschueren-Lodeweyckx, 1993). The height SD scores in our obesechildren were also greater than those in controls. Somelongitudinal studies have shown that children with simpleobesity reach normal or subnormal heights as adults (Garn &Clark, 1975; Vignoloet al., 1988).

It is well known that obesity is associated with diminishedspontaneous 24-h secretion of GH (Meistaset al., 1982),blunted GH responses to a variety of pharmacological stimuli(Glasset al., 1981; Junget al., 1982; Kopelman & Noonan,1986), and accelerated GH clearance (Veldhuiset al., 1991).These changes have been considered secondary to obesity, but

the exact mechanism remains unknown. Based on the well-documented inverse relationship between obesity and GHsecretion, one would expect circulating IGF-I levels in obesesubjects to be subnormal. However, findings are conflicting,with serum concentrations of total IGF-I reported to be low(Copelandet al., 1990; Gamaet al., 1990; Collettiet al., 1991),unchanged (Cordidoet al., 1991; Slowinska Srzednickaet al.,1992), or increased (Van Vlietet al., 1986; Locheset al., 1987).

The majority of IGF-I in the circulation is bound to IGFBP-3,whereas the other circulating binding proteins (IGFBP-1, 2, and4) are believed to bind the remainder of IGF-I in serum. Thecomplex which consists of IGF-I, IGFBP-3 and an acid-labileprotein subunit cannot leave the circulation and probably servesas a reservoir of IGF-I (Leeet al., 1993). Only the free form ofIGF-I is considered to be biologically active and cross thecapillary boundaries to reach the target cells (Brismar & Holl,1993). Although the precise physiological function of IGFBP-1is not completely defined, several studies have demonstratedthat IGFBP-1 inhibits IGF-I binding to cell surface receptorsand thereby inhibits metabolic and mitogenic actions of IGF-I(Lee et al., 1993). Conoveret al., (1992). showed that serumIGFBP-1 levels were low and a significant inverse correlationexisted between serum levels of insulin and IGFBP-1 in adultobesity, suggesting that insulin was an important regulator of

IGF-I, IGFBP-1,3 and GHBP in obese children 489


Table 1 Characteristics of obese and controlchildren Obese Control

(n¼ 20) (n¼ 20) P-values

Age (year) 8.86 2.2 9.06 2.4 NS(4.3–13.6) (4.3–13.3)

Sex (M : F) 12 : 8 13 : 7BMI (kg/m2) 25.16 3.7 16.06 2.0 <0.0001

(20.3–34.4) (12.0–19.8)Ideal body weight (%) 152.36 19.9 99.16 11·5 <0.0001

(123.9–197.0) (78.3–118.4)Height SD score 1.06 1.2 ¹0.16 1.0 <0.01

Values are mean6 SD with the ranges in parentheses. NS, not significant.

Table 2 Mean serum concentrations ofinsulin, IGF-I, IGFBP-1 and 3, molar ratio ofIGF-I/IGFBP-3, and GHBP in obese andcontrol children

Obese Control(n¼ 20) (n¼ 20) P-values

Insulin (pmol/l) 37.26 22.8 40.16 23.4 NSIGF-I (mg/l) 215.66 124.5 193.56 125.6 NSIGFBP-1 (mg/l) 22.16 18.4 76.06 62.9 <0.001IGFBP-3 (mg/l) 6,0276 3,020 5,0636 1,585 NSIGF-I/IGFBP-3 0.166 0.09 0.146 0.06 NSGHBP (%) 19.06 5.6 10.36 3.3 <0.0001

Values are mean6 SD. NS, not significant.

hepatic production of IGFBP-1. Moreover, some investigatorsdemonstrated that the concentration of free IGF-I in fastingserum was increased by reducing the concentration of IGFBP-1in obese adults, whereas the level of total IGF-I was unalteredas compared with that in nonobese controls (Frystyket al.,1995; Namet al., 1997). On the other hand, it has been knownthat phosphorylation of IGFBP-1 may alter its molecularstructure, consequently affecting its affinity for IGF-I. West-wood et al. however demonstrated that the phosphorylationstatus of IGFBP-1 was not altered in response to exogenousinsulin in humans, suggesting that insulin has no effect onIFGBP-1 phosphorylation status (Westwoodet al., 1995). It is,therefore, likely that suppression of the IGFBP-1 level due tohyperinsulinaemia in obesity increases free IGF-I and promotes

the IGF-I action. In addition, insulin itself may act to increasefree IGF-I levels through a direct stimulation by portal insulinof hepatic IGF-I production (Russell-Joneset al., 1992).Consequently, it is thought that normal growth is maintainedin obese children despite the low GH level.

In agreement with previous reports on obese adults, we alsoobserved suppression of the serum concentration of IGFBP-1 inprepubertal obese children. However, fasting insulin levels inobese children did not differ from those in controls and noinverse correlation was found between fasting insulin andIGFBP-1 levels. Therefore, the low serum level of IGFBP-1observed in obese children could not be explained solely by thehyperinsulinemia found in obese adults. Brismaret al. (1991)reported that no correlation was found between basal levels ofinsulin and IGFBP-1 in nonobese healthy adults, during ahyperglycaemic clamp, but basal IGFBP-1 levels wereinversely correlated with the integrated 2-h insulin concentra-tions. In our study, the integrated 24-h insulin releasepreceeding the IGFBP-1 sampling is likely to be higher inobese children than in control subjects, which in turn may havesuppressed the IGFBP-1 production. Indeed, it has been wellknown that obese individuals with normal glucose toleranceand normoinsulinaemia in the fasting state have an exaggeratedinsulin response to an oral glucose challenge compared with thenonobese individuals (Reavenet al., 1983). On the other hand,Conoveret al.(1992) assessed the insulin regulation of IGFBP-1 under controlled hypoinsulinaemic conditions in obese andnonobese women, and showed that the response of IGFBP-1 toinsulin withdrawal was blunted and the level of IGFBP-1remained low in obese subjects, as compared with nonobesecontrols. This blunted IGFBP-1 response could not beattributed solely to differences between obese and lean subjects.Possible explanations they offered were an impairment of hepaticIGFBP-1 production induced by chronic hyperinsulinaemia, and adelayed rise in the IGFBP-1 level due to elevated portal insulinconcentration. We speculate that the hyperinsulinaemia whichcannot be detected in the fasting state may have suppressedhepatic production of IGFBP-1 in our prepubertal obese children.

An alternative possibility for our failure to document aninverse relationship between fasting insulin and IGFBP-1 levelsis that other factors apart from insulin have effects on IGFBP-1.Cortisol and somatostatin have been found to increase IGFBP-1levels in some studies (Conoveret al., 1993; Ezzatet al., 1991).Since plasma cortisol and peripheral somatostatin-like immu-noreactivity levels in simple obesity have been reported to besimilar to those in controls, respectively (Glasset al., 1981;Rosskampet al., 1987), no effects of these factors on IGFBP-1levels are suggested in obese subjects. In contrast, conflictingresults have been reported with regard to an effect of glucagonon IGFBP-1 independently of insulin in humans and plasmalevels of glucagon in simple obesity (Leeet al. 1993; Starke



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2010 30 40

Fig. 1 Relationship between BMI and serum GHBP levels in obesesubjects (r¼ 0·81;P< 0·0001).

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Fig. 2 Relationship of duration of obesity and fasting serum insulinlevels in obese children (r¼ 0·60;P<0·01).

et al., 1984). We therefore cannot exclude the possibility thatglucagon may modulate the level of IGFBP-1 in obesity.

Morris & Falcone (1996) have demonstrated that in womenwith polycystic ovary syndrome, both insulin sensitivity andIGFBP-1 levels are significantly lower than those in controlsand the IGFBP-1 levels are positively related to insulinsensitivity, suggesting that reduced levels of IGFBP-1 allowgreater fractions of IGF-I to be unbound and increase the tissueavailability of IGF-I, which in turn stimulates glucose uptake inpatients with impaired insulin sensitivity. Therefore, since lowIGFBP-1 levels may be a compensatory response to decreasedinsulin sensitivity without increasing insulin secretion, this maybe also responsible for our failure to describe a relationshipbetween fasting insulin and IGFBP-1 levels.

Serum levels of total IGF-I and IGFBP-3 in obese childrendid not differ from those in controls, nor did the molar IGF-I/IGFBP-3 ratio which was considered to be a marker of freeIGF-I (Juulet al., 1994), show a significant difference betweenobese children and controls. Since the serum level of free IGF-Iis very low, being approximately 0·4% of total IGF-I (Frystyket al., 1995), the molar IGF-IIGFBP-3 ratio may not reflect anactual level of free IGF-I. However, Wabitschet al. (1996)reported that a decrease in IGF-I/IGFBP-3 ratio was observedafter weight loss in obese adolescent girls. Since serum freeIGF-I was not measured directly in our study, we could notdetermine whether the serum level of free IGF-I wasmaintained in the normal range.

The serum level of GHBP in our obese subjects exceeded thatin controls and was positively correlated with BMI, aspreviously described by others (Hollet al., 1991; Hochberget al., 1992). Jørgensenet al. (1995) argued that circulatingGHBP reflected mainly hepatic GH receptor status, and thatelevated GHBP was considered to be due to an up-regulation ofGH receptors to compensate for the reduction in GH level. Onthe other hand, Mercadoet al. (1992) suggested that the portallevel of insulin stimulated hepatic production of GHBP. In oursubjects, no relationship was observed between serum levels ofGHBP and IGF-I, or insulin.

The fasting plasma level of insulin is well known to besignificantly higher in obese children than that in non-obesechildren (Waliul Islam et al., 1995). However, since theprevious studies regarding glucose metabolism in obesity wereperformed in patients who were already hyperinsulinaemic inthe fasting state, it remained to be determined whether fastinghyperinsulinaemia was the first event at the early phase ofobesity. Stunff & Bougne`res (1994) studied the development ofhyperinsulinaemia and insulin resistance in obese children witha recent onset of obesity, and showed that postprandialhypersecretion of insulin was one of the earliest metabolicalterations, followed by the fasting hyperinsulinaemia andinsulin resistance. In addition, Montiet al.(1995) demonstrated

that, in obese children with fasting normoinsulinaemia andobesity duration of no longer than 6 years, peripheral insulinresistance was the first alteration at the early stage of obesity,whereas permanent hyperinsulinaemia might develop at thelater stage. In our study, the fasting serum level of insulin waspositively correlated with age and duration of obesity, and themean duration of obesity was less than 6 years. Therefore, theresult that the fasting insulin levels in our obese children werecomparable with those in controls may be partly explainable byrelatively short duration of obesity.

In conclusion, the present study showed for the first time thatthe fasting IGFBP-1 level was suppressed in prepubertal obesechildren with fasting normoinsulinaemia. We speculate that thehyperinsulinaemia which cannot be detected in the fasting statemay have suppressed hepatic production of IGFBP-1. Alter-natively, the reduced IGFBP-1 is likely to be a compensatoryresponse to impaired insulin sensitivity. Thus, the IGFBP-1level may be an useful predictor in the early identification in thedevelopment of insulin resistance in prepubertal obese children.Further studies are required to elucidate a role of insulin in theregulation of IGFBP-1 in obese children.

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serum concentrations of insulin, insulin-like growth factor(igf)-i, igf binding protein (igfbp)-1...

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