The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 167-171
Copyright © 2001 by The Endocrine Society
Effects of Recombinant Human Insulin-Like Growth Factor I Administration on the Growth Hormone (GH) Response to GH-Releasing Hormone in Obesity1
M. Maccario,
F. Tassone,
L. Gianotti,
F. Lanfranco,
S. Grottoli,
E. Arvat,
E. E. Muller and
E. Ghigo
Division of Endocrinology and Metabolism, Department of Internal
Medicine, University of Turin, Turin; and Department of Pharmacology,
University of Milan, Milan, Italy
Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it
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Abstract
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Circulating GH levels are reduced in obesity due to true reduction of
the 24-h GH production rate. GH insufficiency in obesity might reflect
neuroendocrine abnormalities and/or alterations in peripheral hormones
and metabolic factors. The somatotroph response to provocative stimuli
including GHRH is markedly blunted in obese patients. However, the
somatotroph responsiveness to GHRH in obesity shows also peculiar
refractoriness to the inhibitory effect of glucose load. In this
present study we aimed at verifying the effect of low dose rhIGF-I (20
µg/kg, sc, at 0 min) on the GH response to GHRH (1 µg/kg, iv, at
180 min) in obesity. With this goal in mind, six obese women with
abdominal adiposity [OB; age (mean ± SEM), 32.3
± 4.4 yr; body mass index, 32.8 ± 2.3 kg/m2] were
studied. The effects of recombinant human insulin-like growth factor I
(rhIGF-I) administration on circulating total IGF-I, insulin, and
glucose levels were also evaluated. The results in OB were compared
with those recorded in age-matched lean women (NW; age, 28.3 ±
1.2 yr; body mass index, 20.1 ± 0.5 kg/m2), in whom
the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I
levels in OB were similar to those in NW (199.7 ± 33.3
vs. 274.4 ± 25.3 µg/L). The mean GH
concentration over 3 h (from 0–180 min) in OB was lower than that
in NW (0.9 ± 0.4 vs. 2.6 ± 0.8 µg/L;
P = NS). Administration of GHRH induced a GH
response in OB lower than that in NW (area under the curve from
180–270 min, 576.5 ± 137.5 vs. 1315.9 ±
189.9 µg/L·min; P < 0.02). Administration of
rhIGF-I increased circulating IGF-I levels in both groups to the same
percent extent (326.8 ± 28.3 and 420.3 ± 26.5 µg/L in OB
and NW, respectively). rhIGF-I administration inhibited the GH response
to GHRH in OB (240.1 ± 99.6 µg/L; P <
0.05) as well as in NW (730.2 ± 288.1 µg/L;
P < 0.05), although it failed to lower the mean GH
concentration over 3 h in either OB or NW. After rhIGF-I the GH
response to GHRH in OB was slight and was still lower
(P < 0.05) than that in NW; in fact, the percent
decreases were similar in both groups (44.21 ± 14.06 and
48.21 ± 13.95 µg/L, in OB and NW, respectively). The mean
insulin (107.1 ± 21.9 and 36.8 ± 7.2 pmol/L), but not
glucose (4.0 ± 0.3 and 4.1 ± 0.1 mmol/L), levels calculated
over 270 min, were higher (P = 0.005) in OB than in
NW; rhIGF-I administration did not modify insulin and glucose levels in
either group. Our study shows that the sc administration of a low
rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese
as well as in normal subjects, indicating that somatotroph sensitivity
to the inhibitory effect of rhIGF-I is preserved in obesity.
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Introduction
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CIRCULATING GH levels are reduced in
obesity as a reflection of true reduction of the 24-h GH production
rate (1). GH insufficiency in obesity could denote
neuroendocrine abnormalities, including a hyperactive somatostatinergic
tone and/or, more likely, a state of GHRH hypoactivity
(2, 3, 4). On the other hand, recent evidence favors the view
that alterations in peripheral hormones and metabolic factors could
also play a major role; they include enhanced negative free
insulin-like growth factor I (IGF-I) feedback, hyperinsulinism,
alterations in leptin activity and elevated free fatty acids
(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15).
In obesity, not only spontaneous GH secretion, but also the somatotroph
response to provocative stimuli, including GHRH and GH-releasing
peptide, is markedly blunted (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27), sometimes to
levels similar to those recorded in patients with GH deficiency
(28). Interestingly, in the obese subjects, the low
somatotroph responsiveness to either GHRH or arginine shows a peculiar
refractoriness to the inhibitory effect of glucose load
(29), whereas the GH response to the same stimuli is
normally inhibited by pirenzepine, a muscarinic antagonist, which is
likely to act via somatostatin release as well as by exogenous
somatostatin (30).
It is well known that IGF-I exerts an inhibitory feedback action on
somatotroph secretion, being capable of inhibiting the GH responses to
GHRH, arginine and GH-releasing peptides in normal subjects
(31, 32, 33) and also in conditions of peripheral GH
resistance, which are generally refractory to the inhibitory effect of
glucose load (34, 35, 36, 37).
The inhibitory action of IGF-I on somatotroph secretion may occur
directly at the pituitary level through activation of IGF-I receptors
and lead to inhibition of GH synthesis and release
(39, 40, 41, 42, 43, 44, 45, 46). On the other hand, indirect central nervous
system-mediated actions of recombinant human IGF-I (rhIGF-I) have been
clearly demonstrated, which include enhancement of hypothalamic
somatostatin release (40, 42, 44) and/or inhibition of
GHRH release (39, 47, 48).
Based on the foregoing, we sought in the present study to verify the
effect of a low rhIGF-I dose on the GH response to GHRH in obesity. The
effects of rhIGF-I administration on circulating total IGF-I, insulin,
and glucose levels were also evaluated. The results in obese patients
were compared with those recorded in age-matched lean women, in whom
the inhibitory effect of rhIGF-I had been previously demonstrated
(31).
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Subjects and Methods
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Drugs
Vials containing 1000 µg lyophilized rhIGF-I were provided by
Pharmacia & Upjohn, Inc. (Stockholm, Sweden). Vials
containing 50 µg GHRH-29 were provided by Serono (Rome, Italy).
Study protocols
Six obese women with abdominal adiposity [OB; age (mean ±
SEM), 32.3 ± 4.4 yr; body mass index, 32.8 ±
2.3 kg/m2] took part in the study. Eight normal
young women (NW; age, 28.3 ± 1.2 yr; body mass index, 20.1
± 0.5 kg/m2) were studied as controls. The
results obtained in these subjects have been published
(31). All women had regular menses and were studied in the
early follicular phase (between days 2 and 6 of the same follicular
phase). All subjects gave their written informed consent to participate
in the study, which had been approved by an independent ethical
committee. All subjects underwent the following test sessions at least
3 days apart: 1) placebo (sc at 0 min) plus GHRH (1 µg/kg, iv, at 180
min), and 2) rhIGF-I (20 µg/kg, sc, at 0 min) plus GHRH. The order of
the sessions was randomized. The tests were begun in the morning at
0830–0900 h after an overnight fast and 30 min after an indwelling
catheter had been inserted into an antecubital vein of the forearm kept
patent by slow infusion of isotonic saline. Blood samples were drawn
basally at 0 min, then every 30 min up to 180 min, and then every 15
min up to 270 min. Serum GH levels were measured at each time point in
all sessions. Serum IGF-I, serum insulin, and plasma glucose levels
were measured under baseline conditions and then every 30 min up to 270
min in all sessions. Serum GH levels (micrograms per L) were measured
in duplicate by immunoradiometric assay (hGH-CTK IRMA, SORIN, Saluggia,
Italy). The sensitivity of the assay was 0.15 µg/L. The inter- and
intraassay coefficients of variation were 2.9–4.5% and 2.4–4.0%,
respectively. Serum IGF-I levels (micrograms per L) were measured in
duplicate by RIA (Nichols Institute Diagnostics, San Juan
Capistrano, CA). All samples were extracted with acid-ethanol to avoid
interference by binding proteins. The sensitivity of the assay was 0.1
µg/L. The inter- and intraassay coefficients of variation were
10.1–15.7% and 7.6–15.5%, respectively. Serum insulin levels
(picomoles per L) were measured in duplicate by immunoradiometric
assays (Sorin Biomedica, Saluggia, Italy). The sensitivity of the assay
was 17.9 ± 2.2 mU/L. Inter- and intraassay coefficients of
variation were between 6.2–10.8% and between 5.5–10.6%,
respectively. Plasma glucose levels (millimoles per L) were measured by
a glucose-oxidase colorimetric method (GLUCOFIX, Menarini Diagnostics,
Firenze, Italy). All samples from an individual subject were analyzed
in a single batch.
The hormonal responses are expressed as absolute values as well as
areas under the curve calculated by trapezoidal integration.
Statistical analysis was carried out using nonparametric ANOVA
(Mann-Whitney ANOVA, Wilcoxon signed rank test). The results are
expressed as the mean ± SEM.
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Results
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Basal IGF-I levels in OB were similar to those in NW (199.7
± 33.3 vs. 274.4 ± 25.3 µg/L). The mean GH
concentration over 3 h (from 0–180 min) in OB was lower than that
in NW (mGHc, 0.9 ± 0.4 vs. 2.6 ± 0.8 µg/L),
but this difference did not attain statistical significance.
Administration of GHRH induced a GH response in OB lower than that in
NW (area under the curve from 180–270 min, 576.5 ± 137.5
vs. 1315.9 ± 189.9 µg/L·min; P <
0.02; Fig. 1
). Administration of rhIGF-I
increased circulating IGF-I levels in both groups to the same percent
extent (326.8 ± 28.3 and 420.3 ± 26.5 µg/L in OB and NW,
respectively; Fig. 2). After rhIGF-I
administration the mGHc over 3 h was not significantly reduced in
either OB or NW (1.0 ± 0.5 and 3.2 ± 1.0 µg/L,
respectively). rhIGF-I administration inhibited the GH response to GHRH
in OB (240.1 ± 99.6 µg/L; P < 0.05) as well as
in NW (730.2 ± 288.1 µg/L; P < 0.05; Fig. 1).
After rhIGF-I the GH response to GHRH in OB was slight and still lower
(P < 0.05) than that in NW; in fact, the percent
decrease was similar in both groups (44.21 ± 14.06 and 48.21
± 13.95 in OB and NS, respectively; Fig. 1). Mean insulin (107.1
± 21.9 and 36.8 ± 7.2 pmol/L), but not glucose, levels (4.0
± 0.3 and 4.1 ± 0.1 mmol/L) calculated over 270 min were higher
(P = 0.005) in OB than in NW. Administration of rhIGF-I
did not modify mean insulin and glucose levels in either OB or
NW (Fig. 2).
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Figure 1. Mean (±SEM) serum GH levels
after GHRH (2 µg/kg, iv, at 180 min) alone or preceded by rhIGF-I (20
µg/kg, sc, at 0 min) in obese patients and normal subjects.
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Figure 2. Mean (±SEM) serum IGF-I,
insulin, and plasma glucose levels after placebo or rhIGF-I (20
µg/kg, sc, at 0 min) in obese patients.
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Side effects
All subjects experienced transient discomfort at the injection
site after rhIGF-I administration, but no systemic side effects were
observed. Five normal subjects and two OB patients had transient facial
flushes after GHRH administration.
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Discussion
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Our study shows that the sc administration of a low rhIGF-I dose
inhibits the somatotroph responsiveness to GHRH in both obese and
normal subjects. The low IGF-I dose that elicited an increase in
circulating IGF-I levels within the normal range did not modify insulin
and glucose levels in either obese or normal subjects.
The inhibitory feedback action of rhIGF-I administration on GH
secretion has been widely demonstrated in humans after iv and sc
administration (31, 32, 34, 35, 36, 37). The inhibition of
spontaneous GH secretion has been shown in normal fasted humans as well
as in pathophysiological conditions such as Laron’s syndrome,
insulin-dependent diabetes mellitus, malnutrition, and anorexia nervosa
(34, 35, 36, 37, 49). Moreover, the inhibitory effect of rhIGF-I
on the somatotroph response to GHRH has been shown in normal and
anorectic subjects (49), although this effect may depend
on the timing of rhIGF-I pretreatment (50). It is
noteworthy that the inhibitory effect of rhIGF-I in humans takes place
even after the administration of a low dose, after which, as in the
present study, circulating IGF-I levels do not exceed the normal range
(31).
Although IGF-I may exert its inhibitory feedback action directly at the
pituitary level (39, 40, 41, 42), there is evidence that it
generally modulates somatotroph secretion mainly via central nervous
system-mediated actions, which include concomitant inhibition of the
activity of GHRH-secreting neurons and stimulation of hypothalamic
somatostatin release (40, 47, 48, 51). Accordingly, it has
been demonstrated that in humans rhIGF-I is capable of inhibiting the
GH response to GHRH alone or to arginine alone (31, 33), which is
likely to act via inhibition of hypothalamic somatostatin release.
However, it does not inhibit the secretory effects of either the
combined administration of GHRH and arginine (52) or of
hypoglycemia (34, 53), a multifactorial stimulus that
triggers GHRH-secreting neurons and inhibits somatostatin release
(54).
The marked insufficiency of both spontaneous and stimulated GH
secretion in obesity might reflect neuroendocrine abnormalities,
including a hyperactive somatostatinergic tone and/or GHRH hypoactivity
(2, 3, 4), although abnormalities in peripheral hormones and
metabolic factors could play a major role. The latter abnormalities
could include enhanced negative free IGF-I feedback, hyperinsulinism,
alterations in leptin activity, and elevated free fatty acids
(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15).
Paradoxically, in obesity the low somatotroph responsiveness to
provocative stimuli is coupled with a peculiar refractoriness to the
inhibitory effect of hyperglycemia (29). In fact, the low
GH response to GHRH is not inhibited by previous glucose load, although
it is normally abolished by pirenzepine, a muscarinic antagonist, as
well as exogenous somatostatin (30).
Taking also into account the hypothesis that the GH hyposecretory state
in obese patients would reflect an exaggerated negative feedback of
high circulating free IGF-I levels (5), we aimed at
verifying whether a low rhIGF-I dose could inhibit the GH response to
GHRH in obese patients. Our present data show that the sensitivity to
the inhibitory effect of IGF-I is preserved in obesity. In fact, in
obese patients after rhIGF-I administration the GH response to GHRH was
lower than that in normal subjects, but the percent inhibitory effect
was similar in the two groups.
In obese as well as normal subjects no significant inhibitory effect of
rhIGF-I on spontaneous GH secretion before GHRH administration was
recorded. However, this finding should be examined with caution,
because we did not use an ultrasensitive GH assay that might better
investigate some inhibitory effect of rhIGF-I on low spontaneous GH
levels (55). On the other hand, our study of spontaneous
GH secretion was probably too short, and thus we might have missed
recording a significant number of GH peaks that could have been
inhibited by rhIGF-I (56). The clear inhibitory effect of
a low rhIGF-I dose, which raised circulating IGF-I levels within the
normal range, on the somatotroph responsiveness to GHRH may challenge
the hypothesis that GH insufficiency in obesity reflects an enhanced
negative feedback by high free IGF-I levels (5). However,
this hypothesis cannot be definitively ruled out, as we did not measure
free IGF-I levels. On the other hand, as the GH response to GHRH in
obese patients was inhibited by rhIGF-I in the present study as well as
by pirenzepine or exogenous somatostatin in previous studies
(30), the present results indirectly strengthen the
peculiar refractoriness of somatotroph secretion to the inhibitory
effect of a glucose load.
It has been shown that a high rhIGF-I dose inhibits insulin
secretion in normal subjects (57), whereas the
insulin-sensitizing effect of IGF-I has also been demonstrated
(58). Although we used a rhIGF-I dose that had been
previously shown to be devoid of any inhibitory effect on insulin and
glucose levels in normal and anorectic subjects (31, 49),
an inhibitory effect on the insulin hypersecretion that connotes
obesity could be foreseen. Our results show that 20 µg/kg rhIGF-I,
sc, does not modify insulin hypersecretion and glucose levels in obese
patients, at least after acute administration.
In conclusion, the present study shows that the inhibitory effect of
rhIGF-I on the GH response to GHRH is preserved in obese patients in
whom somatotroph hyporesponsiveness to all provocative stimuli known to
date as well as peculiar refractoriness to the inhibitory effect of
glucose load have been demonstrated. This would make it less likely
that the GH hyposecretion of obesity is due to a greater somatotroph
inhibition by circulating IGF-I levels.
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Footnotes
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1 This work was supported by Pharmacia & Upjohn, Inc.,
CNR (Grant 98.03040.CT04, Rome, Italy), Ministero
Universitá e Ricerca Scientifica e Technologica (Grant
9706151106, Rome, Italy), and the SMEM Foundation. 
Received June 15, 2000.
Revised September 18, 2000.
Accepted September 21, 2000.
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Abstract
Introduction
