International Journal of Obesity (1997) 21, 355359

1997 Stockton Press All rights reserved 03070565/97 $12.00

Effect of obesity on total and free insulin-like

growth factor (IGF)-1, and their relationship to
IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3,
insulin, and growth hormone
SY Nam, EJ Lee, KR Kim, BS Cha, YD Song, SK Lim, HC Lee and KB Huh
Division of Endocrinology, Department of Internal Medicine, Yong Dong Severance Hospital, Yonsei University, College of Medicine,
Seoul, Korea

OBJECTIVES: We investigated the effect of obesity on the serum levels of total and free IGF-1 and their relationship to
the circulating levels of insulin and IGF binding proteins (IGFBPs) in age and sex-matched groups.
SUBJECTS: The study included 43 obese subjects (ideal body weight; IBW > 120%) and 45 controls (IBW < 100%). All of
the subjects were male.
MEASUREMENT: Total IGF-1, free IGF-1, IGFBP-1, IGFBP-2, IGFBP-3, and insulin were measured in obese subjects and
normal control subjects.
RESULTS: No signicant differences in the circulating levels of total and IGFBP-3 were observed between the obese
and control groups. In contrast to total IGF-1, free IGF-1 in obese subjects was signicantly increased compared to
normal controls (P < 0.05). Serum total and free IGF-1 were inversely correlated with age (r 0.42, P 0.001, and
0.44, P 0.001). Fasting serum insulin concentrations were elevated in all the obese subjects (P < 0.05) and positively
correlated with IBW (r 0.57, P 0.001). The levels of serum GH and IGFBP-1 were suppressed in all the obese subjects
(P < 0.05). IGFBP-1 was inversely correlated with IBW (r 0.51, P 0.001) and serum insulin concentrations
(r 0.48, P 0.001). The IGFBP-2 concentrations were also suppressed in obese subjects and inversely related to
free IGF-1 (r 0.48, P 0.001). Using multiple linear regression analysis, total IGF-1 and insulin concentrations were
positively correlated (r 0.58, P 0.001) and free IGF-1 and IGFBP-1 concentrations were negatively correlated
(r 0.57, P 0.001).
CONCLUSION: We conrmed that total IGF-1 and IGFBP-3 concentrations were not signicantly different between the
obese and control groups, despite GH hyposecretion in obesity. We also found that free IGF-1 concentrations were
higher in obese subjects than in normal controls. It seems likely that overnutrition and chronic hyperinsulinaemia in
obesity may alter this regulated growth response by insulin stimulation of IGF-1 production and suppression of
hepatic IGFBP-1 and IGFBP-2 production, which may inhibit IGF-1 bioactivity.
Keywords: obesity; total IGF-1; free IGF-1; IGFBPs

Introduction
Obesity is associated with the impairment of normal
GH (growth hormone) secretion and blunted
responses to all stimuli such as GH-releasing hormone
(GHRH), hypoglycaemia, L-dopa, arginine, glucagon,
physical exercise, and sleep.14 Based on the well
known GH hyposecretion in obesity, `GH-dependent'
insulin-like growth factor (IGF)-1 concentrations
would be expected to be subnormal in obesity. However, the results have been conicting,57 due to
clinical differences in age, sex and degree and type
of obesity.
Circulating IGF-1 is predominantly bound in a
Correspondence: Dr SY Nam, Division of Endocrinology,
Department of Internal Medicine, Yong Dong Severance
Hospital, Young Dong PO Box 1217, Seoul, Korea.
Received 21 August 1996; revised 3 January 1997; accepted 16
January 1997

ternary 150 kDa complex, consisting of IGF-1, IGFbinding protein (IGFBP)-3, and an acid-labile subunit.8,9 Thus IGFBP-3 and IGF-1 have relatively long
half-lives in the circulation,10 and since they are GH
dependent they represent a stable index of long-term
changes in GH availability and action.11 IGFBP-2 is
the second most abundant IGF-binding protein in
serum. The serum concentration of IGFBP-2 is
known to be inversely related to GH secretion,
being high in states of GH deciency and low in
states of GH excess.12 These reports have suggested
that measurement of IGFBP-2 might be useful in
detecting GH deciency. In contrast, the serum concentrations of IGFBP-1 are lower than those of
IGFBP-3 and IGFBP-2, and acutely regulated by
food intake and uctuations in serum insulin and
glucose concentrations.1315 Because of this unique
property, IGFBP-1 is thought to play an important role
in acute regulation of IGF-1 availability.16,17 In previous reports, IGFBP-1 sequestered free IGF-1 and

IGF-1 and IGFBPs in obesity

SY Nam et al

356

inhibited its metabolic actions.18,19 A small portion of

circulating IGF-1 is detected in the free or readily
dissociable state, which is thought to be the metabolically active form. The amount of free/dissociable
IGF-1 in serum is dependent on a complex interplay
between the production rate and concentrations of
IGF-1 and IGFBPs.10
In this study, we investigated the effect of obesity
on the serum concentrations of total and free IGF-1
and their relationship to the concentrations of IGFbinding proteins and insulin in age and sex-matched
groups.

Subjects and methods

Subjects and protocol

Forty-three obese Korean males aged 2049 y (mean  s.e.m., 34.9  7.9) and 45 normal Korean male
subjects aged 2049 y (33.9  8.3) were studied. The
normal control subjects were within 10% of their ideal
body weight (IBW), and the obese subjects weighed
more than 120% of ideal body weight, as determined
by the Fogarty Center Conference on Obesity. All
subjects were recruited from subjects attending the
medical-checkup programs at the health-care centre of
Yong Dong Severance Hospital.
An oral glucose tolerance test was performed on
each subject to screen out impaired glucose tolerance
or diabetes mellitus. Apart from obesity, no abnormalities were detected. No subjects had used any
hormonal preparations or drugs within the 60 d prior
to the study.
The study was approved by the Hospital Ethics
Committee, and informed consent was obtained from
each subject.
Blood samples were obtained from each subject by
venepuncture between 08:00 am and 10:00 am after an
overnight fast. Serum was separated by centrifugation,
and stored at 20 C until analysis.
Analytical methods

Serum glucose level was measured by the glucoseoxidase method and insulin level by enzyme-linked
immunoadsorbent assay (ELISA). This ELISA uses
two monoclonal antibodies (Novo Nordisk A/S, Denmark) directed against human insulin and does not
cross-react with human proinsulin. Serum triglyceride
and cholesterol concentrations were determined in the
overnight fasting state with semi-automated methods
(Boehringer, Mannheim, Germany). Serum GH was
measured by an immunoradiometric assay (IRMA)
from Daiichi (Tokyo, Japan); the sensitivity was
0.1 mg/L and its intra and interassay coefcients of
variations were 1.3 and 1.4%, respectively. Serum
IGFBP-1, IGFBP-2, and IGFBP-3 were measured by
an immunoradiometric assay (IRMA) kit (Diagnostic
System Laboratories, Inc. Webster, TX); the sensitiv-

ities were 0.01 ng/mL, 0.5 ng/mL, 0.5 ng/mL, respectively and their intra and inter-assay coefcients of
variations were less than 10%. Serum total IGF-1 was
measured by an IRMA kit (Diagnostic System
Laboratories, Inc. Webster, TX); the sensitivity was
0.3 mg/L and its intra and interassay coefcients of
variations were less than 10%. Free/dissociable IGF-1
concentrations were measured by a highly sensitive
two-site IRMA kit (Diagnostic System Laboratories,
Inc. Webster, TX) according to the manufacturer's
suggestions. Assay characteristics have been reported
previously.20 This is a direct detection assay in which
100 mL of serum sample are added to tubes containing
a dense coating of high afnity anti-IGF-1 antibody,
which binds IGF-1 that is not bound to or is easily
dissociable from IGFBPs. Samples were then incubated for two hours at 28 C, washed, and incubated
with an 125I-labeled anti-IGF-1 antibody directed to a
second epitope of IGF-1 for two hours at room
temperature. After decanting and washing 3 times,
the tubes were counted in a g-counter. Assay standards
were recombinant human (rh)IGF1 (0.1320 mg/L).
The minimal detection limit was 0.05 mg/L or 5 pg/
tube. According to the manufacturer's specications
and previous characterization of the assay, there was
no cross-reactivity with IGF-II, and no residual
IGFBP-1 or IGFBP-3 was detectable in the assay
tube after the rst wash.20 The interassay coefcients
of variations were 7.7, 3.6 and 10.7% at 0.26, 5.52 and
13.87 ng/mL, and the intraassay coefcients of variations were 10.3, 5.1, and 3.3% at 0.29, 6.26, and
14.20 ng/mL. All samples from each subject were
analyzed in duplicate at the same time.
Statistical analysis

The results were expressed as the mean  s.e.m.

Statistical comparisons were made using the Student's
unpaired t-Test between obese and control groups.
Correlation between different parameters was calculated by linear regression analysis. Factors related to
total and free IGF-1 were analyzed using stepwise
multiple regression. P < 0.05 was accepted as the
signicance level.

Results
Percentage of ideal body weight (138.2  11.7%,
mean  s.e.m.), BMI (30.0  2.5 kg/m2), and waist to
hip ratio (0.93  0.2) in obese subjects were signicantly (P < 0.001) higher than those of normal controls (97.6  6.4%, 21.3  1.4 kg/m2, and 0.84  0.0).
Fasting serum glucose (FSG), total cholesterol, triglyceride, insulin and GH concentrations are summarized
in Table 1.
The FSG, triglyceride and insulin concentrations in
obese subjects were signicantly greater than those of
normal controls. In all obese subjects, fasting GH

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SY Nam et al

357

Table 1 Metabolic and hormonal data in control and obese

groups

Fasting serum glucose (mmol/L)

Total cholesterol (mg/dL)
Triglyceride (mg/dL)
Insulin (pmol/L)
GH (ng/mL)

Control

Obesity

5.0  0.5
185.8  34.5
114.8  49.3
23.5  12.0
2.0  0.8

5.3  0.6*
191.8  39.1
176.3  38.1*
49.2  23.8*
0.8  1.1*

* P < 0.05 control vs obesity.

concentrations were suppressed as compared with

control subjects (P < 0.05).
No signicant differences in the circulating concentrations of the total IGF-1 and IGFBP-3 were
observed between the control and obese subjects
(Figure 1). Serum total IGF-1 was weakly correlated
with IGFBP-3 (r 0.28, P 0.05). The free IGF-1
concentrations were signicantly elevated in obese
subjects (1.46  1.1 mg/L vs 0.91  0.9 mg/L, P < 0.05;
Figure 1). The ratio of free to total IGF-1 also was
higher in obese subjects (0.63% vs 0.39%, P < 0.05;
Figure 1).
The IGFBP-1 concentrations were signicantly
lower in the obese subjects (Figure 1) and negatively
correlated with percent of IBW (r 0.51, P 0.001)
and serum insulin (r 0.48, P 0.001).
The IGFBP-2 concentrations were also suppressed
in obese subjects (P < 0.05; Figure 1) and inversely
related to free IGF-1 (r 0.48, P 0.001). Additionally, the ratio of IGFBP-2 to IGF-1 was decreased
(1.6  0.5 vs 2.2  1.4, P < 0.005) in obese subjects.
Using multiple linear regression analysis, the total
IGF-1 and free IGF-1 were analyzed by age, IBW,
WHR, fasting serum insulin, GH, IGFBP-1, IGFBP-2,
and IGFBP-3 in all subjects. Of all variables, age and
serum insulin concentrations were associated with
serum total IGF-1. The total IGF-1 was inversely
correlated with age (r 0.42, P < 0.001) and positively correlated with serum insulin (r 0.58,
P < 0.001). The free IGF-1 was negatively correlated
with age (r 0.44, P < 0.001) and IGFBP-1
(r 0.57, P < 0.001).

Discussion
Using age and sex matched subjects, we conrmed
that GH levels were reduced in the obese while `GHdependent' total IGF-1 levels were not signicantly
different between obese and control subjects. Similar
results have been reported previously,2123 but the
contradictory ndings of increased or decreased
IGF-1 levels found by others, although due in part
to important clinical differences in age, sex and
degree of obesity in the different studies, could be
profoundly inuenced by nutritional factors.24,25 In
addition, the discordant relationship between GH and
IGF-1 in obesity may be also explained by the

Figure 1 Levels of total IGF-1, free IGF-1, ratio of free to total

IGF-1, IGFBP-1, IGFBP-2, and IGFBP-3 in control (u) and obese
subjects (j). * P < 0.05 control vs obesity.

hyperinsulinaemia present in obesity:26 insulin may

increase hepatic IGF-1 production.27 We found a
positive correlation between the serum total IGF-1
and insulin concentrations.
A small portion of circulating IGF-1 is detected in
the free or readily dissociable state, which is thought
to be the metabolically active form.28,29 In the present
study, free/dissociable IGF-1 was assessed by a twosite immunoradiometric assay. The absolute values for
free/dissociable IGF-1 in both obese and control
groups were higher than those reported by Frystyk
et al30 using RIA after separation by centrifugal
ultraltration. The difference between our results
and theirs are mostly likely due to the ages of
subjects; older subjects have lower total and free
IGF-1.30 However, the ratios of free to total IGF-1
in both groups are similar between the two assay
systems.
The amount of free/dissociable IGF-1 in serum is
dependent on a complex interplay between the production rate and the concentrations of IGF-1 and
IGFBPs. IGFBP-3 serves as major stabilizer of the
circulating IGF pool. Circulating IGFBP-3 might
undergo limited proteolysis, which results in smaller

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SY Nam et al

358

molecular weight IGFBP-3 fragments that have lower

afnity for IGF-1 than the intact binding protein.
Consequently, the levels of free/dissociable IGF-1
are elevated in situations where IGFBP-3 proteolysis
is increased.31 Bereket et al32 showed that acute mealrelated hyperinsulinaemia did not increase IGFBP-3
proteolysis. However, it is not known whether IGFBP3 proteolysis increases in obese subjects.
In contrast, IGFBP-1 exhibits marked diurnal variation in relation to meals.32 Insulin is the principal
regulator of IGFBP-1 and is reported to inhibit hepatic
IGFBP-1 synthesis.33 Because of this property,
IGFBP-1 is thought to play an important role in the
regulation of IGF bioactivity. Therefore, the obesityrelated hyperinsulinaemia may decrease circulating
concentrations of IGFBP-1, which can result in elevated free IGF-1 in obesity. In our study, circulating
IGFBP-1 concentrations in obese subjects were lower
than normal controls. There were also negative correlations between free IGF-1 and IGFBP-1.
IGFBP-2 is the second most abundant IGF-binding
protein in serum.34 Several reports have shown that
IGFBP-2 is differentially regulated by GH and IGF1.12,34 Administration of GH causes a reduction in
IGFBP-2, while the serum concentration of IGFBP-2
is high in states of GH deciency.34 In normal adults,
the infusion of IGF-1 results in suppression of GH and
an increase in IGFBP-2.38 The dissociation of the
effect of GH and IGF-1 in regulating IGFBP-2 suggests that IGFBP-2 and the ratio of IGFBP-2 to IGF-1
may be useful in detecting GH deciency. Thus, based
on the well-known GH hyposecretion in obesity, the
levels of IGFBP-2 and the ratio of IGFBP-2 to IGF-1
would be expected to be high. However, we found that
IGFBP-2 concentrations and the ratios of IGFBP-2 to
IGF-1 were suppressed in obese subjects. These ndings indicate that factors other than GH may be
regulating serum IGFBP-2 in obesity. Clemmons et
al34 showed that acute stimulation of insulin did not
suppress IGFBP-2, but IGFBP-2 concentrations were
elevated after prolonged fasting. This suggests that
prolonged changes in insulin secretion may result in a
signicant change of IGFBP-2. It appears, therefore,
that the obesity-related chronic hyperinsulinaemia
may result in suppression of IGFBP-2 in obesity.
We also found a negative correlation between
IGFBP-2 and free IGF-1 concentrations. This indicates that IGFBP-2 can quantitatively inuence IGF-1
transport and may have some role in regulating IGF-1
bioavailability in obesity, because serum IGFBP-2 are
more abundant than IGFBP-1 in adults.34

Conclusions
We conrmed that `GH-dependent' IGF-1 and
IGFBP-3 concentrations were not signicantly different between obese and control groups, despite the GH

hyposecretion in obesity. We also found that free IGF1 concentrations were increased in obesity compared
to normal controls. It seems likely that overnutrition
and chronic hyperinsulinaemia in obesity may alter
this regulated growth response: insulin may stimulate
production of IGF-1 and suppress production of
IGFBP-1 and IGFBP-2, which are thought to be
inhibitory IGFBPs.
Acknowledgement

We thank the Ewon Reference Laboratory for the

measurement of serum IGF-1, IGFBPs, GH and insulin. This paper was presented at the 15th annual
meeting of the Korean Association of Endocrinology
held in Seoul 1011th May, 1996.
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