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The Journal of Clinical Endocrinology & Metabolism 90(2):1061–1067
Copyright © 2005 by The Endocrine Society
doi: 10.1210/jc.2004-0501
Insulin-Like Growth Factor-I Response to a Single Bolus
of Growth Hormone Is Increased in Obesity
Helena K. Gleeson, Catherine A. Lissett, and Stephen M. Shalet
Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom
Reduced GH levels are found in obesity; despite which IGF-I
levels are reported as low normal or normal. Previously peripheral responsiveness to GH has been investigated and reported to be increased in obese men and premenopausal women; however, the use of weight-based GH doses in these studies
made data interpretation difficult. GH binding protein
(GHBP) measurement constitutes an indirect estimate of GH
receptor number. GHBP has been reported to be elevated in
obesity; however, results from a recent study implied that this
was only in men and premenopausal but not postmenopausal
women. Therefore, we pursued this question further by challenging a cohort of healthy normal-weight and obese subjects
with a non-weight-based dose of GH and examined the relationship of GHBP with the IGF-I response in the context of
their body composition.
Ninety-eight (40 male) healthy subjects with a wide range of
ages and body mass index (BMI) were studied. Ninety-one (34
male) of these subjects were divided into groups of similar age:
men and women with a BMI less than 30 [normal-weight men
(NM), BMI 26 (22–29) kg/m2 (n ⴝ 19) and women (NW), BMI 24
(19 –29) kg/m2 (n ⴝ 23) and with a BMI > 30 (obese men (OM),
41 (30 –72) kg/m2 (n ⴝ 15) and women (OW), 43 (30 – 68) kg/m2
(n ⴝ 34)]. Fat mass and percentage fat were measured by a
bioelectrical impedance analyzer. An IGF-I generation test,
O
BESITY IS ASSOCIATED with decreased GH secretion
(1– 4) and increased GH clearance (1, 5), resulting in
low 24-h spontaneous GH levels, despite which IGF-I levels,
a measure of GH bioactivity (6, 7), are reported as low normal
or normal (8 –11). To explain the discordancy between GH
and IGF-I status in obese subjects, an increase in peripheral
(hepatic) responsiveness to GH activity has been hypothesized (12).
Recently the IGF-I generation test has been employed in
adults to determine whether peripheral (hepatic) responsiveness varies with age and estrogen status in the female
(13–16). Previous studies employing this test in obese subjects demonstrated increased peripheral responsiveness to
GH in men and premenopausal women (17, 18) but not in
postmenopausal women (19); however, the use of weight-
First Published Online November 2, 2004
Abbreviations: AUC, Area under the curve; BIA, bioimpedance analyzer; BMI, body mass index; F%, percentage fat; FM, fat mass; GHBP,
GH binding protein; IGFBP, IGF binding protein; NM, normal-weight
men; NPo, normal-weight postmenopausal women; NPr, normalweight premenopausal women; NW, normal-weight women; OM, obese
men; OPo, obese postmenopausal women; OPr, obese premenopausal
women; OW, obese women.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
which involved a sc injection of 21 IU (7 mg) GH, was performed. At baseline serum samples were assayed for GHBP;
serum IGF-I and IGFBP3 levels were measured both at baseline and 24 h after GH administration.
There was a higher increment IGF-I in obese men and
women, compared with the equivalent normal-weight subjects [NM vs. OM: 245 (33–342) vs. 291 (192– 427) ng/ml (P < 0.05);
NW vs. OW: 220 (103– 435) vs. 315 (144 – 450) ng/ml (P < 0.0005)].
Increment IGF-I was negatively correlated with baseline
IGF-I (F ⴝ 12.1) and positively correlated with GHBP (F ⴝ 18.2)
(R2 ⴝ 0.29). GHBP levels were significantly higher in OM and
OW (pre- and postmenopausal) than in the equivalent normalweight groups [NM vs. OM: 2175 (995– 4190) vs. 3030 (1540 –
5470) pmol/liter (P < 0.05); NW vs. OW: 2131 (1010 –5040) vs. 3585
(1540 –5740) pmol/liter (P < 0.0005)]. GHBP levels correlated
highly with BMI, percentage fat, and fat mass (R > 0.6, P <
0.0001). Baseline IGF-I was not affected by body composition.
In conclusion, in obese compared with normal-weight
healthy subjects, there is a larger increment IGF-I to a single
bolus of GH in men, and irrespective of menopausal status,
women. Increment IGF-I is associated positively with GHBP
level, which in turn is associated with markers of increasing
obesity in men and women. GH responsiveness is increased in
obesity. (J Clin Endocrinol Metab 90: 1061–1067, 2005)
based GH doses in these studies, thereby making the GH
dose a confounding factor, made data interpretation difficult.
One hypothesis for the mismatch in GH and IGF-I status
is that the number of GH receptors is up-regulated to compensate for decreased GH levels. GH binding protein
(GHBP) corresponds to the extracellular domain of the GH
receptor (20) and has been used as an indirect measure of GH
receptor number. A positive correlation between the circulating GHBP level and estimates of body fat have been described (21). A recent study in women observed this finding
in pre- but not postmenopausal women (22). No association
has been found between IGF-I response to GH and GHBP
levels (13, 17).
Therefore, we pursued this question further by challenging a cohort of healthy normal-weight and obese subjects
with a non-weight-based dose of GH. The relationship between GHBP and the IGF-I response to GH in the context of
body composition has also been studied.
Subjects and Methods
Ninety-eight (40 male) healthy subjects were studied. Ethical approval was obtained from the local ethical committee, and all subjects
gave informed written consent. No subject had either a condition (e.g.
diabetes, liver disease, or pituitary disease) or was taking any medication (e.g. estrogen replacement or opioids) known to affect the GH-IGF-I
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Gleeson et al. • IGF-I Response to GH in Obesity
axis. All screening baseline blood tests (e.g. liver function tests, random
glucose, hemoglobin A1c, and thyroid function tests) were normal.
Ninety-one of the 98 subjects were divided into groups: men and
women with a body mass index (BMI) less than 30 [normal-weight men
(NM) (n ⫽ 19) and women (NW) (n ⫽ 23)] and those with a BMI of
greater than 30 [obese men (OM) (n ⫽ 15) and women (OW) (n ⫽ 34)].
The women were further subdivided by menopausal status: premenopausal and postmenopausal women with a BMI of less than 30 [normalweight premenopausal women (NPr) (n ⫽ 11) and postmenopausal
women (NPo) (n ⫽ 12)] and those with a BMI of greater than 30 [obese
premenopausal women (OPr) (n ⫽ 20) and postmenopausal women
(OPo) (n ⫽ 14)]. The seven youngest subjects (six male) were excluded
from the division into groups so that the groups were of equivalent
median ages.
Seventy-eight (29 male) of the 98 subjects had a more prolonged IGF-I
generation test and were divided into groups similar in age for the
assessment of the IGF-I and IGF binding protein (IGFBP)3 response to
GH; NM (n ⫽ 14) and NW (n ⫽ 15) with a BMI less than 30 and those
with a BMI greater than 30 [OM (n ⫽ 15) and OW (n ⫽ 34)].
Characteristics of the groups are presented in Tables 1–3.
Body composition
Height and weight were measured and BMI was calculated. Bioimpedance analyzer (BIA) (Tanita, Tokyo, Japan) was used to estimate
body composition, percentage fat (F%), and fat mass (FM). BIA has been
used in a previous study performed in this unit and has demonstrated
a high degree of correlation with dual-energy x-ray absorptiometryderived fat measurements (R ⫽ 0.9; P ⬍ 0.0001) (23).
IGF-I generation test
An IGF-I generation test was performed in each subject. Seven milligrams of recombinant GH (Pfizer, Genotropin 1 mg ⫽ 3 IU) was given
sc. This dose of GH was chosen to study near maximal IGF-I production.
It is also the largest dose of GH to have been used in previous studies
without side effects (13, 14).
All subjects had blood samples taken before and 24 h after the injection of GH; serum GHBP levels were estimated at baseline only,
whereas serum IGF-I and IGFBP3 levels were measured at baseline and
at 24 h. This timing for blood sampling was chosen because it is established that IGF-I levels peak 18 –24 h after a sc injection of GH (14). This
was confirmed in 78 of the 98 subjects who also had blood samples taken
at 18, 48, and 72 h. Peak IGF-I occurred at a median time of 24 h after
sc injection irrespective of BMI. This prolonged IGF-I generation test also
enabled assessment of area under the curve (AUC) IGF-I response and
evaluation of maximal IGFBP3 peak after a GH injection that occurs at
a median time of 48 h (14).
Assays
Serum IGF-I. Serum IGF-I was measured by an immunoradiometric
assay (Diagnostic Systems Laboratories, Webster, TX) with acid/ethanol
extraction. The sensitivity of the assay was 0.8 ng/ml. The intraassay
coefficients of variation for mean IGF-I concentrations of 9.3, 55, and 263
ng/ml were 3.4, 3.0, and 1.5%, respectively. The interassay coefficients
of variation for mean IGF-I concentrations of 10.4, 53, and 256 ng/ml
were 8.2, 1.5, and 3.7%, respectively. The value is multiplied by 0.13 to
convert nanograms per milliliter into nanomoles per liter for calculating
molar ratios.
Serum IGFBP3. Serum IGFBP3 was measured by an immunoradiometric
assay (Diagnostic Systems Laboratories). The sensitivity of the assay was
0.5 ␮g/liter. The intraassay coefficients of variation for mean IGFBP3
concentrations of 1.0, 2.2, and 9.8 mg/liter were 6.1, 4.1, and 4.4%,
respectively. The interassay coefficients of variation for mean IGFBP3
concentrations of 0.9, 3.5, and 11.0 mg/liter were 9.0, 4.6, and 3.8%,
respectively.
Serum GHBP. Serum GHBP was measured by an ELISA (Diagnostic
Systems Laboratories). The sensitivity of the assay was 1.6 pmol/liter.
The intraassay coefficients of variation for mean GHBP concentrations
of 20.2, 93.4, and 198.2 pmol/liter were 5.5, 3.1, and 4.7%, respectively.
The interassay coefficients of variation for mean GHBP concentrations
of 19.9, 93.8, and 195.7 pmol/liter were 8.3, 6.2, and 5.1%, respectively.
Analysis and statistics
Data are presented as median (range). The rank sum test was used to
compare the different groups. Forward stepwise regression analysis was
used to identify dependent variables (e.g. gender, age, height, and F%
as well as baseline IGF-I or IGFBP3 and GHBP in some analyses) in the
whole cohort (98 subjects). Because the three indices of obesity, BMI, F%,
and FM were closely correlated, F%, a more accurate marker of obesity,
was selected for use in regression analyses. F% and GHBP were also
closely correlated; consequently, the strongest dependent variable was
included in the regression analyses. Statistical significance was assumed
for P ⬍ 0.05.
Increment IGF-I or IGFBP3 was calculated by subtracting baseline
from peak levels. AUC IGF-I was calculated using the trapezoidal method; AUC IGF-I minus baseline IGF-I was calculated accordingly.
GHBP corresponds to the extracellular domain of the GH receptor
(20) and provides an indirect measure of GH receptor number. Therefore, as a marker of GH responsiveness in the context of estimated GH
receptor number, the molar ratio of IGF-I to GHBP was calculated for
baseline, peak, and increment. For forward stepwise regression analysis,
it was necessary to convert the molar ratio of IGF-I to GHBP into natural
logs because the values were not normally distributed.
Results
GHBP
GHBP levels were significantly greater in the groups of
OM, OPr, and OPo than in the equivalent normal-weight
groups (Tables 4 and 5). GHBP levels correlated with BMI,
F%, and FM (R ⬎ 0.6, P ⬍ 0.0001); F% correlated the most
strongly and was therefore included in the forward stepwise
regression analysis. GHBP was dependent on F% (F ⫽ 47.12)
and gender (F ⫽ 4.97), i.e. GHBP increased with increasing
F% but also for equivalent F%, GHBP was slightly lower in
females (R2 ⫽ 0.38) (Fig. 1); serum IGFBP3 at baseline (F ⫽
9.29) was also a dependent variable when included in the
regression analysis (R2 ⫽ 0.44).
There was no difference in GHBP levels between males
and females or pre- and postmenopausal women of equivalent BMI.
TABLE 1. Characteristics of normal weight and obese male and female groups
NM
Age (yr)
Height (cm)
BMI (kg/m2)
F%
FM (kg)
42 (30 – 82)
175 (163–183)
25.7 (21.6 –29.4)
19 (13–30)
14.0 (9.0 –26.4)
OM
53 (28 –77)
179 (169 –188)
41.0 (30.3–71.7)a
45 (28 – 60)a
61.2 (25.8 –102.6)a
Data are presented as median (range).
a
P ⬍ 0.0005, compared with equivalent normal-weight group.
b
P ⬍ 0.005, c P ⬍ 0.0005, compared with equivalent male group.
NW
OW
43 (20 –72)
163 (148 –178)c
24.0 (18.8 –28.9)
34 (24 – 42)c
21.5 (12.2–31.2)b
46 (32–70)
159 (142–188)c
43.1 (30.1– 67.6)a
57 (43–72)a,b
50.6 (34.0 –99.6)a
Gleeson et al. • IGF-I Response to GH in Obesity
J Clin Endocrinol Metab, February 2005, 90(2):1061–1067
1063
TABLE 2. Characteristics of normal weight and obese females by menopausal status
Age (yr)
Height (cm)
BMI (kg/m2)
F%
FM (kg)
NPr
OPr
NPo
OPo
37 (21– 48)
163 (151–169)
25.3 (18.8 –28.9)
34 (24 – 42)
24.0 (12.2–31.2)
40 (32–51)
161 (142–188)
42.3 (30.1– 67.6)a
51 (44 – 69)a
50.4 (35.0 –77.4)a
55 (38 –72)b
164 (148 –178)
23.7 (19.5–26)
34 (24 –39)
21.5 (13.0 –25.8)
55 (49 –70)b
157 (152–167)
43.3 (32.1– 61.3)a
61 (43–72)a
68 (34.0 –99.6)a
Data are presented as median (range).
a
P ⬍ 0.0005, compared with equivalent normal-weight group.
b
P ⬍ 0.0005, compared with equivalent premenopausal group.
IGF-I
There was no gender difference in baseline, increment, or
AUC IGF-I.
There was a greater increment IGF-I in OM, OPr, and OPo
(Tables 3–5), compared with the equivalent normal-weight
subjects (Fig. 2). Increment IGF-I was negatively correlated
with baseline IGF-I (F ⫽ 12.1) and positively correlated with
GHBP (F ⫽ 18.2) (R2 ⫽ 0.29). If GHBP was excluded from the
analysis, baseline IGF-I and F% were dependent variables (R2
⫽ 0.22). If baseline IGF-I was excluded from the analysis, age
and GHBP were dependent variables (R2 ⫽ 0.23). Therefore,
the lower the baseline, the greater the increment IGF-I, and
in addition increasing levels of GHBP or increasing obesity
was associated with a larger increment IGF-I.
Baseline IGF-I level was not significantly affected by body
composition in males or females (pre- or postmenopausal).
However, in females but not in the males, the median baseline IGF-I level was lower in the obese compared with the
normal-weight group; this difference almost reached significance in the premenopausal (P ⫽ 0.06) but not in the postmenopausal (P ⫽ 0.4) women. There was an age (F ⫽ 42.8)related decline in baseline IGF-I as well as an additional effect
of height (F ⫽ 12.4), with taller subjects having a higher
baseline IGF-I (R2 ⫽ 0.43).
In both males and females, the peak IGF-I level was nonsignificantly (P ⫽ 0.6) higher in the obese compared with the
normal-weight groups. However, AUC IGF-I and the calculation, AUC IGF-I minus baseline IGF-I (ng/ml ⫻ h), was
increased in OM and OW, compared with the equivalent
normal-weight subjects (P ⬍ 0.02) (Fig. 3, A and B).
IGF-I/GHBP ratio
Baseline IGF-I/GHBP was higher in NM, NPr, and NPo
groups than in the equivalent obese groups (Tables 4 and 5).
Baseline IGF-I/GHBP levels were significantly higher in
NPr, compared with NPo, and almost reached significance
between the same subdivisions within the obese groups.
Baseline IGF-I/GHBP was dependent on the variable F%
(F ⫽ 32.3) and age (F ⫽ 16.1), i.e. older and more obese
subjects produced less IGF-I per nanomole per liter of GHBP
(R2 ⫽ 0.44) (Fig. 4).
Peak IGF-I/GHBP was higher in NM, NPr, and NPo
groups than in the equivalent obese groups. Consequently,
F% was also a dependent variable for peak IGF-I/GHBP (F ⫽
38.3) (R2 ⫽ 0.32).
Only in postmenopausal women was the increment IGFI/GHBP greater in the normal-weight group, compared with
the obese group. The increment IGF-I to GHBP ratio was
negatively correlated with F% (F ⫽ 9.59) in females (R2 ⫽
0.13) but not males.
There was no gender difference in basal, peak, or increment IGF-I/GHBP levels.
IGFBP3
No differences in IGFBP3 were seen between NM and OM
(Tables 3–5).
TABLE 3. Subjects who underwent prolonged IGF-I generation tests: characteristics, baseline IGFBP3, and response to GH in normalweight and obese male and female groups
NM (L)
Group characteristics
Age (yr)
Height (cm)
BMI (kg/m2)
F%
FM (kg)
IGFBP3 (mg/liter)
Baseline
Peak
Increment
IGF-I (ng/ml 䡠 h)
Baseline (ng/ml)
AUC IGF-I
AUC minus baseline
IGF-I
47 (21– 82)
175 (163–183)
23.8 (20.0 –28.7)
18 (10 –30)
13.2 (6.4 –26.4)
3.27 (2.51–3.94)
4.17 (3.07– 8.66)
0.91 (0.35–5.06)
211 (89 – 477)
29,934
10,170
OM
53 (28 –77)
179 (169 –188)
41.0 (30.3–71.7)c
45 (28 – 60)c
61.2 (25.8 –102.6)c
NW (L)
52 (21–72)
164 (148 –178)f
23.4 (18.8 –28.9)
34 (24 – 40)f
21.4 (12.2–31.2)d
3.98 (1.35– 4.66)a
4.43 (2.43–5.63)
0.63 (0.03–1.15)
312 (86 – 484)
36,600a
15,024a
3.56 (2.39 – 4.27)
4.52 (3.34 –5.57)
0.79 (0.13–2.83)
254 (85–521)
29,592
10,128
L, Prolonged IGF-I generation test.
Data are presented as median (range).
a
P ⬍ 0.05, b P ⬍ 0.005, c P ⬍ 0.0005, compared with equivalent normal-weight group.
d
P ⬍ 0.05, e P ⬍ 0.005, f P ⬍ 0.0005, compared with equivalent male group.
OW
46 (32–70)
159.5 (142–188)f
43.1 (30.1– 67.6)c
57 (43–72)c,e
50.6 (34.0 –99.6)c
4.21 (3.33–5.12)c
4.79 (3.76 –5.63)
0.40 (0 –1.20)b
267 (108 – 485)
34,608a
16,092c
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Gleeson et al. • IGF-I Response to GH in Obesity
TABLE 4. Baseline GHBP, IGF-I, IGF-I/GHBP, and IGFBP3 and response to GH in healthy weight and obese male and female groups
NM
GHBP (pmol/liter)
Baseline
IGF-I (ng/ml)
Baseline
Peak
Increment
IGF-I/GHBP molar ratio
Baseline
Peak
Increment
IGFBP3 (mg/liter)
Baseline
Peak
Increment
OM
NW
OW
2175 (995– 4190)
3030 (1540 –5470)a
2131 (1010 –5040)
3585 (1540 –5740)c
290 (89 –523)
524 (207–756)
245 (33–342)
312 (86 – 484)
602 (366 – 685)
291 (192– 427)a
293 (85–521)
540 (267–732)
220 (103– 435)
267 (108 – 485)
594 (252– 683)
315.5 (144 – 450)c
16.5 (6.77–50.4)
33.2 (18.8 –75.7)
13.0 (2.31–35.7)
3.60 (2.51–5.67)
4.10 (3.03– 8.66)
0.48 (⫺0.12–5.06)
11.3 (3.73–26.3)a
23.0 (15.8 – 47.9)a
12.3 (8.51–21.5)
17.4 (7.01– 47.6)
32.0 (18.9 – 69.2)
14.7 (5.29 –30.0)
3.98 (1.35– 4.66)
4.01 (2.06 –5.18)
0.29 (0 – 0.72)
3.71 (2.39 – 4.90)
4.45 (3.27–5.11)
0.51 (⫺0.01–2.30)
9.21 (3.03–25.1)c
22.2 (9.0 –54.4)c
10.9 (5.17–29.3)a
4.21 (3.33–5.12)a
4.50 (3.60 –5.34)d
0.33 (0 – 0.85)b
Data are presented as median (range).
a
P ⬍ 0.05, b P ⬍ 0.005, c P ⬍ 0.0005, compared with equivalent normal-weight group.
d
P ⬍ 0.05, compared with equivalent male group.
Baseline IGFBP3 was significantly greater in OW than NW
(postmenopausal only). The expected age-related decline in
baseline IGFBP3 was seen only in NW but not OW. Baseline
IGFBP3 was dependent on GHBP (F ⫽ 20.2) and age (F ⫽ 9.2)
(R2 ⫽ 0.26). If GHBP was excluded from the analysis, the
dependent variables were age and F% (R2 ⫽ 0.25). Therefore,
like baseline IGF-I, baseline IGFBP3 declines with age, but
unlike IGF-I it rises with increasing obesity.
The peak IGFBP3 occurred at a median of 48 h after the
acute GH bolus in those subjects who underwent a prolonged IGF-I generation test. The increment IGFBP3, whether
it is calculated from the 24-h level in all subjects or at the
actual peak in those who had the prolonged IGF-I generation
test, showed similar results. The increment IGFBP3 was
greater in NW than OW (effect seen in postmenopausal
only). NPo also had a significantly greater increment IGFBP3
than NPr. Increment IGFBP3 negatively correlated with baseline IGFBP3 and, also but less strongly, GHBP and F%.
There was no gender difference for baseline or increment
IGFBP3.
Discussion
Decreased GH secretion (1– 4) and increased GH clearance
(1, 5) contribute to low GH levels found in obesity, despite
which IGF-I levels, a measure of GH bioactivity (6, 7), are
reported as low-normal or normal (8 –11). To explain the
discordancy between GH and IGF-I status in obese subjects,
an increase in peripheral (hepatic) responsiveness to GH
activity has been hypothesized (12). Previously peripheral
responsiveness to GH in obesity has been investigated and
reported to be increased in men and premenopausal women
(17, 18) and unchanged in postmenopausal women (19);
however, the use of weight-based GH doses (17–19) and also
the suboptimal timing of blood sampling (17–19) makes interpretation of the results from these studies difficult. Our
study using a non-weight-based fixed dose of GH in a larger
number of subjects confirms that obese subjects, men, and
pre- or postmenopausal women, have a greater IGF-I response to a single bolus of GH and therefore show increased
peripheral GH responsiveness. Increment IGF-I was also associated with the GHBP level. GHBP levels were found to be
TABLE 5. Baseline GHBP, IGF-I, IGF-I/GHBP, and IGFBP3 and response to GH in healthy weight and obese females by menopausal
status
NPr
GHBP (pmol/liter)
Baseline
IGF-I (ng/ml)
Baseline
Peak
Increment
IGF-I/GHBP molar ratio
Baseline
Peak
Increment
IGFBP3 (mg/liter)
Baseline
Peak
Increment
OPr
NPo
OPo
2260 (1010 –5040)
3540 (1540 –5540)a
1928 (1576 –2950)
3660 (2220 –5740)c
364 (212–521)
577 (374 –732)
212 (103– 435)
280 (145– 485)
618 (407– 683)
305 (194 – 450)b
245.5 (85– 427)d
526 (267– 630)
254 (182–397)
212 (108 –392)d
565 (252– 671)
322 (144 – 419)a
20.1 (7.66 –27.6)
32.4 (18.9 – 69.2)
12.9 (5.29 –21.7)
4.08 (3.52– 4.90)
4.58 (4.05– 4.98)
0.37 (⫺0.01– 0.64)
10.3 (5.07–25.1)b
22.5 (13.6 –54.4)b
11.1 (7.55–29.3)
4.17 (3.37– 4.88)
4.51 (3.68 –5.19)
0.37 (0 – 0.85)
Data are presented as median (range).
a
P ⬍ 0.05, b P ⬍ 0.005, c P ⬍ 0.0005, compared with equivalent normal-weight group.
d
P ⬍ 0.05, e P ⬍ 0.005, f P ⬍ 0.0005, compared with equivalent premenopausal group.
13.9 (7.01–33.3)d
29.9 (21.8 – 49.1)
15.8 (10.6 –30.0)
3.39 (2.39 – 4.27)e
4.37 (3.27–5.11)
0.75 (0.30 –2.30)f
6.89 (3.03–23.0)a
18.7 (9.05–36.0)b
10.9 (5.17–16.1)b
4.23 (3.33–5.12)b
4.49 (3.64 –5.34)
0.28 (0 – 0.58)c
Gleeson et al. • IGF-I Response to GH in Obesity
J Clin Endocrinol Metab, February 2005, 90(2):1061–1067
1065
FIG. 1. Correlation of GHBP and F% stratified by gender; regression
lines for males (R ⫽ 0.5; P ⬍ 0.005) (upper line) and females (R ⫽ 0.7;
P ⬍ 0.005) (lower line).
elevated in obesity, as has been previously reported (11, 24,
25). GHBP was elevated not only in obese men and premenopausal women but also in postmenopausal women,
demonstrating, contrary to the findings of a recent study (22),
that estrogen status is not the sole factor responsible for the
increase in GHBP levels found in obesity.
In the past, the justification for using a weight-based dose
FIG. 3. A and B, IGF-I levels before and after a sc injection of GH in
male (A) and female (B) normal-weight (f) and obese subjects (F).
Symbol represents median, whiskers fifth (below) and 95th (above)
centile.
FIG. 2. Increment of IGF-I in NM vs. OM, NPr vs. OPr, and NPo vs.
OPo (column represents median, whisker 95th centile).
of GH for the assessment of IGF-I response was presumably
based on the knowledge that there is increased metabolic
clearance of GH in obesity (1, 5). There is, however, no
evidence that this affects the extent of the IGF-I response after
a single bolus of GH. The use of weight-based doses in
previous studies (17, 18) has resulted in the obese individuals
receiving a dose of GH close to double that of the normalweight individuals; therefore, the conclusion that the results
demonstrate an increased sensitivity to GH in obese individuals are unfounded.
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J Clin Endocrinol Metab, February 2005, 90(2):1061–1067
FIG. 4. Relationship between molar ratio or IGF-1 to GHBP and F%.
Previous studies that examined the effect of obesity on
IGF-I generation in men and premenopausal women used
only BMI and waist to hip ratio measurements; the latter are
indirect measures of body composition (17, 18). In the current
study, BIA has been employed to provide a better estimate
of fatness of an individual. A previous study at this unit
showed a high correlation between fat mass estimates obtained using dual-energy x-ray absorptiometry and BIA (23).
There are several possible explanations for increased peripheral responsiveness to GH in obesity. The low levels of
GH observed in obesity may result in up-regulation of the
GH receptors and/or sensitivity as tends to occur in physiological systems to compensate for diminished ligand availability. GHBP corresponds to the extracellular domain of the
GH receptor (12, 20). It has been proposed that serum GHBP
activity may provide an indirect measure of GH receptor
status (26) and an index of tissue responsivity to GH (12).
Although the exact biological role of GHBP has not yet been
determined, it has been shown to protect GH from degradation and elimination and increase the half-life of GH in the
circulation. This suggests that GHBP may potentiate GH
action by prolonging the availability of GH to target tissues.
The liver is the primary source of GHBP (27), but the
observation of a strong correlation between GHBP levels and
visceral adipose tissue mass (11, 24, 25) indirectly suggests
that adipose tissue also plays a significant role in the generation of GHBP. Plasma GHBP concentrations are reported
to increase in obese subjects and return to normal after dietinduced weight loss (11). In this study, as noted by others (11,
12, 24), an elevated GHBP level was observed in all the obese
groups. In contrast with the findings of a recent study, which
found an effect of body composition on GHBP in premenopausal but not postmenopausal women, a phenomenon hypothesized to be related to estrogen status (22), our results
Gleeson et al. • IGF-I Response to GH in Obesity
indicate that the effect of FM on GHBP levels persists into the
postmenopausal years. The previous study did, however,
include women with a narrower range of BMI (22). Although
within-group comparisons revealed no gender difference in
GHBP levels, gender was an additional dependent variable
to F% for GHBP. For a similar F%, GHBP was lower in
females; the results in previous studies reporting that GHBP
was higher in females (28, 29) may simply reflect the greater
F% in females, compared with males. GHBP did not alter
with age, consistent with the findings of some (12, 22) but not
all studies (30, 31).
In agreement with the belief that levels of GHBP provide
an indirect measure of GH receptor status (26) and an index
of tissue responsivity to GH (12), increasing GHBP levels
were associated with an increasing peak and increment
IGF-I. GHBP has not previously been shown to be associated
with IGF-I response to both high- and low-dose GH in adults
of normal weight and with obesity (13, 17). There was, however, no association between GHBP and baseline IGF-I,
whereas previous studies have reported this association in
younger (32) but not older subjects (29).
Despite increased levels of GHBP, the peak IGF-I was not
as elevated as might have been predicted, and this is reflected
in the reduced peak IGF-I to GHBP molar ratio seen in the
obese groups. The interpretation was that GHBP does not
accurately reflect GH receptor status of the liver and the
increase in GHBP may relate to the GH receptor status of
adipose tissue (33, 34); that the dose of 7 mg GH was not large
enough to saturate the GH receptors; or that there is reduced
responsiveness of the GH receptor due to other factors.
As previously stated, GHBP is closely associated with
markers of obesity and therefore has also been shown to be
closely associated both with insulin secretion and sensitivity
and leptin (35, 36). It is therefore not possible to determine
whether the increased IGF-I response is due to elevated
GHBP and/or other factors associated with increasing obesity (29, 35–39). For instance, insulin acutely increases the
availability of GH receptors in liver cells (40). Insulin also by
itself stimulates IGF-I synthesis in hepatocytes, but a synergistic effect is seen when insulin is administered in combination with GH (41). Therefore, high levels of insulin could
increase hepatic GH responsiveness.
Although serum IGFBP3 is partly regulated by GH, it does
not reflect the 24-h GH secretion as accurately as IGF-I. In this
study IGFBP3 at baseline and after an acute bolus of GH was
only minimally affected by body composition in postmenopausal women. The IGFBP3 data differed from the IGF-I data
because IGFBP3 levels were higher at baseline in obese subjects, in keeping with a previous study (37), but at variance
from another, which found no difference in IGFBP3 levels at
baseline or after GH administration (18).
In summary, the apparent GH deficiency with IGF-I sufficiency seen in obesity can at least in part be explained by
an increase in responsiveness to GH. This effect is seen independent of gender, age, or menopausal state.
Acknowledgments
Received March 15, 2004. Accepted October 27, 2004.
Gleeson et al. • IGF-I Response to GH in Obesity
J Clin Endocrinol Metab, February 2005, 90(2):1061–1067
Address all correspondence and requests for reprints to: Professor
S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow
Road, Withington, Manchester M20 4BX, United Kingdom. E-mail:
[email protected].
21.
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