The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 12 4426-4430
Copyright © 1998 by The Endocrine Society
From the Clinical Research Centers |
Dual Regulation of Insulin-Like Growth Factor Binding Protein-1 Levels by Insulin and Cortisol during Fasting1
Lorraine E. Levitt Katz, M.D,,
Marta S. Satin-Smith,
Paulo Collett-Solberg,
Lester Baker,
Charles A. Stanley and
Pinchas Cohen, M.D.
Department of Pediatrics, Children’s Hospital of Philadelphia,
University of Pennsylvania, Philadelphia, Pennsylvania 19104
Address all correspondence to Lorraine Katz, M.D., Assistant Professor of Pediatrics, Children’s Hospital of Philadelphia, Division of Endocrinology, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: katzl{at}email.chop.edu
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Abstract
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Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) gene
transcription is known to be inhibited by insulin in
vivo and in vitro. Levels of IGFBP-1 typically
rise during fasting but also rise after acute hypoglycemia, including
that induced by insulin, through an unknown mechanism that may involve
counterregulatory hormones such as cortisol. To study the regulation of
IGFBP-1 secretion during fasting, we measured IGFBP-1, insulin,
cortisol, GH, and glucose during the course of standardized fasting
studies in a total of 21 children. The fasting studies lasted 13–32 h
and were terminated for a whole-blood glucose concentration of less
than 50 mg/dL (2.8 mmol). Of the children studied, 9 children had no
disorder, 8 had ketotic hypoglycemia, 2 had isolated GH deficiency, and
2 had fatty acid oxidation disorders. During fasting, IGFBP-1 rose
above the mean baseline levels of 28 ± 5 ng/mL to a mean
level ± SEM of 336 ± 59 ng/mL at the time of
hypoglycemia (P = 0.001). IGFBP-1 was strongly
associated with serum insulin and cortisol levels over the entire
course of fasting (P < 0.0001)). The interaction
of the 2 hormones across time was also strongly significant
(P < 0.0001). There was no statistically
significant association between IGFBP-1 and GH or glucose. At the time
of hypoglycemia, insulin levels were suppressed to 1.7 µU/mL or less,
and there was no correlation between IGFBP-1 levels at the end of
fasting and final insulin level. In contrast, cortisol levels
correlated with IGFBP-1 in the final hypoglycemic sample (r =
0.56, P < 0.01). Partial correlation analysis
revealed that the relationship between IGFBP-1 and cortisol was
unchanged when the data was controlled for insulin levels. These data
show that insulin and cortisol both regulate IGFBP-1 secretion during
fasting; the effects of insulin and cortisol are strong during the
course of fasting. Significant hypoglycemia stimulates a further rise
in IGFBP-1, which seems to be regulated, in part, by cortisol. The
cortisol-induced rise in IGFBP-1 during fasting and during hypoglycemia
potentially serves to prevent the hypoglycemic effects of free IGFs.
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Introduction
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INSULIN-LIKE growth factor (IGF) binding
protein-1 (IGFBP-1) is a 28-kDa protein that is produced by liver
and decidua and is found mainly in serum and amniotic fluid. It binds
the IGFs with high affinity and is able to either inhibit or enhance
IGF action in vitro (1, 2, 3). Its secretion by the liver into
serum is acutely suppressed by insulin, and that the inhibitory effects
of insulin are mediated at the level of transcription (4, 5). IGFBP-1
levels typically rise during fasting and exercise and are increased in
poorly controlled insulin-dependent diabetes mellitus, reflecting
deficiency of insulin (6, 7, 8, 9, 10, 11). Under conditions associated with
elevated insulin levels (including postprandial states,
hyperinsulinemic clamps, and insulinomas), decreased IGFBP-1 levels are
seen (11, 12). The inverse relationship between IGFBP-1 and insulin is
maintained diurnally, in relation to meals, with IGFBP-1 being the only
IGFBP whose serum levels fluctuate 10- to 20-fold during the course of
a day (13). It has been hypothesized that IGFBP-1 serves to block the
potential hypoglycemic actions of the IGFs (1, 2) and, therefore, is
secreted at times of hypoglycemia, such as fasting.
It has also been reported that hypoglycemia, including that induced by
insulin, stimulates a rise in IGFBP-1 levels 1–2 h after the glycemic
nadir, in a pattern which resembles glucose counterregulatory hormones
(14, 15, 16). Though this phenomenon is not well understood, it has been
suggested that adrenal factors may be involved (16). At the molecular
level, it has been demonstrated that IGFBP-1 gene transcription is
inhibited by insulin via an insulin responsive element and is
stimulated by cortisol via a cortisol-responsive element (17, 18). The
rise in IGFBP-1 may serve to inhibit the metabolic actions of IGF-I
during acute hypoglycemia, supporting a role for IGFBP-1 in glucose
counterregulation (3). To study the regulation of IGFBP-1 during
fasting, leading to hypoglycemia in children, we measured IGFBP-1
levels in combination with insulin and cortisol during the course of
standardized fasting studies in children admitted to the Generalized
Clinical Research Center.
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Materials and Methods
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Study design
The patient population consisted of 21 children (age, 1–7 yr)
with known or suspected hypoglycemic disorders. Two of these children
had previously been demonstrated to have isolated GH deficiency, by
provocative testing, with an intact cortisol response to cortrosyn.
Additionally, 3 patients who were undergoing fasts for a ketogenic diet
protocol were studied. After the families gave informed consent,
standardized fasting studies were conducted in the Clinical Research
Center at Children’s Hospital of Philadelphia under an Institutional
Review Board-approved protocol. A total of 21 patients were
studied. The fasting studies lasted 13–32 h and were terminated for a
whole-blood glucose concentration of less than 50 mg/dL (2.8 mmol).
Children who were not able to fast for 24 h, but whose hormonal
response to fasting was normal, in combination with appropriate
generation of ketones and free fatty acids, were diagnosed with ketotic
hypoglycemia. Patients with normal metabolic and hormonal profiles who
became hypoglycemic after 24 h of fasting were considered to have
no disorder. Of the total 21 patients studied, 9 were determined to
have no disorder, 8 had ketotic hypoglycemia, 2 had isolated GH
deficiency, and 2 had fatty acid oxidation disorders. Details of the
patients are provided in Table 1
. At
regular intervals during the fasting and at the time of hypoglycemia,
blood samples were drawn for IGFBP-1, insulin, GH, and cortisol. After
the final blood draw, patients then were given either oral carbohydrate
or iv glucose and were observed until they were back on a full oral
diet and had stable blood glucose levels.
Methods
IGFBP-1 levels were measured at Nichols Institute Diagnostics (San Juan Capistrano, CA) by a double-antibody RIA
using rabbit anti-IGFBP-1 and 125IGFBP-1. The assay
sensitivity was 0.4 ng/mL at 90% B/Bo. Insulin was measured by
the IMx0 insulin microparticle immunoassay (Abbott Laboratories, Abbot Park, IL). This assay had a
sensitivity 
1.0 µU/mL, with an intraassay variation of 3.1% and an
interassay variation of 3.8%. Left censored data were assigned the
value of 1 for the study analysis.
Cortisol was measured by the TDxFLx Fluorescence Polarization
Immunoassay method (Abbott Laboratories).
This assay has a sensitivity of 0.64 µg/dL.
GH was measured by the DELFIA fluoroimmunometric assay (Wallac, Inc. Turku, Finland). The sensitivity of this assay is 0.03
mU/L.
Statistical analysis. Measurements of IGFBP-1, insulin,
cortisol, glucose, and GH were taken at different time points after the
start of fasting condition. The effects of insulin, cortisol, glucose,
and GH on IGFBP-1 across time were analyzed based on a longitudinal
mixed-effects approach. This model extends the usual repeated-measures
approach in ANOVA by enabling us to associate linearly the
repeated-outcome variable with a continuous explanatory variable, such
as time of measurement, and to include in the analysis all observed
subjects, even when some subjects do not have a complete set of
measurements. The BMDP5V statistical package was used for the
analyses (19). Models were fit to IGFBP-1, to each of four potential
predictors (insulin, cortisol, glucose, and GH) separately, to test for
effects over time. Natural logarithm values were used. Time was
measured as: time since the start of the fasting condition. Models
explaining prospective relationships between changes in IGFBP and
changes in the other parameters (insulin, cortisol, glucose, and GH)
were fit. Those parameters with statistically significant main effects
were included together in a full model, allowing for interaction
terms.
Spearman correlation was performed to analyze the relationships between
IGFBP-1 levels and several fasting parameters in the final hypoglycemic
sample.
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Results
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IGFBP-1 levels rose during fasting, from mean
(±SE) baseline levels of 28 ± 5 ng/mL to a mean
level ± SEM of 336 ± 59 ng/mL at the time of
hypoglycemia, which occurred after 13–32 h in all of the children
studied. The rise in IGFBP-1 was statistically significant by paired
t test (P = 0.001). However, there was no
direct correlation between peak IGFBP-1 levels at the end of fasting
and total length of fast. IGFBP-1 levels rose over time and were
elevated in the final blood sample in all of the children studied.
There were no significant differences between patients in the different
diagnostic categories, with regard to their IGFBP-1 rise or
hormonal variations during fasting. Over the course of fasting, mean
insulin and C-peptide levels steadily declined, and cortisol levels
varied according to a diurnal pattern. At the point of hypoglycemia,
cortisol levels demonstrated a rise above baseline values at the start
of fasting, to a mean of 22 ± 2.3 µg/dL. GH levels were highly
variable and did not demonstrate a mean interval rise at the time of
hypoglycemia. Table 2 presents the select
hormonal parameters at the time of hypoglycemia for the entire
group.
The relationships between IGFBP-1 (across time) and insulin, cortisol,
glucose, and GH are presented in Table 3.
IGFBP-1 was strongly associated with serum insulin and cortisol levels
over the entire course of fasting [Table 3 (models 1 and 2), Figs. 1 and 2].
There was no statistically significant association between IGFBP-1 and
GH or glucose (Table 3, models 3 and 4). When the model was fit to
IGFBP-1 with both insulin and cortisol as predictors, the effect of
insulin drops out (P = 0.2734), whereas the effect of
cortisol remains strong (P = 0.0000) (Table 3, model
5). Furthermore, when the model was fit to IGFBP-1 and the
insulin/cortisol interaction, the interaction of the two hormones is
statistically significant (Table 3, model 6).
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Figure 1. Relationships between levels of IGFBP-1 and
insulin, over the course of fasting. Closed triangles,
ln(IGFBP-1) Rsq = 0.4486; closed circles,
ln(insulin+1) Rsq = 0.3609.
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Figure 2. Relationships between levels of IGFBP-1 and
cortisol, over the course of fasting. Closed triangles,
ln(IGFBP-1) Rsq = 0.4486; closed squares,
ln(cortisol) Rsq = 0.2055.
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Correlation analysis of the final hypoglycemic sample is shown in
Fig. 3. At the time of hypoglycemia, when
insulin levels were suppressed to measure 1.7 µU/mL, there was no
direct correlation between peak IGFBP-1 levels at the end of fasting
and final insulin level. In contrast to insulin, cortisol levels
strongly correlated with IGFBP-1 in the final hypoglycemic sample
(r = 0.56, P < 0.01) (Fig. 3). At the time of
hypoglycemia, there was no correlation between glucose level with
IGFBP-1 or with cortisol. Partial correlation analysis revealed that
the relationship between IGFBP-1 and cortisol was unchanged when the
data were controlled for insulin levels, indicating that the
correlation of IGFBP-1, as a function of cortisol, was independent of
its relationship to insulin.
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Figure 3. Relationship between plasma IGFBP-1 and
cortisol at the time of hypoglycemia. The correlation between the two
parameters is r = 0.56, P < 0.01 (y = 1033.448 ·
100.018x).
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Discussion
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It has previously been demonstrated that IGFBP-1 levels rise
during fasting (6, 7), but most of the studies performed were not
carried out to the point of hypoglycemia. Furthermore, before the
present study, there was little data correlating IGFBP-1 levels with
fasting parameters other than insulin and glucose. We have confirmed
that IGFBP-1 levels rise with fasting and are elevated in the final
blood sample of patients at the time of hypoglycemia, regardless of the
etiology of hypoglycemia.
In all of the conditions that have been studied, IGFBP-1 levels are
inversely correlated with plasma insulin levels (10, 11, 12, 20). Given the
exquisite sensitivity of IGFBP-1 to insulin, it has remained a paradox
that IGFBP-1 levels rise acutely in response to insulin-induced
hypoglycemia. Some have postulated that glucose, not insulin, regulates
IGFBP-1 during fasting and hypoglycemia. Other investigators postulated
that suppression of insulin secretion into the hepatic portal
circulation, as a result of hypoglycemia, may account for the acute
rise in IGFBP-1 levels (21). Our data would suggest that during fasting
hypoglycemia, a state of low endogenous insulin secretion, other
factors (particularly cortisol) may play a role in the stimulation of
IGFBP-1 secretion, as previously suggested by Lewitt et al.
(16).
In vitro data have demonstrated a stimulatory role for
glucocorticoids on IGFBP-1 gene transcription and IGFBP-1 secretion by
liver cells ((17, 18, 22, 23, 24). In rat H4IIe hepatoma cells, insulin and
glucocorticoids were shown to have opposite effects on IGFBP-1
secretion, with the effects of insulin dominating (25). In animals, the
administration of glucocorticoids has been shown to increase IGFBP-1
(26, 27). The latter study examined the effects of glucocorticoid
administration on adrenal intact and adrenalectomized diabetic rats.
The diabetic animals demonstrated elevated IGFBP-1 levels, as would be
predicted, because of their insulin deficiency; these effects were
prevented by adrenalectomy, and restored by glucocorticoid
administration, supporting a role for glucocorticoids on IGFBP-1
secretion in insulin-deficient states. The one human study that
examined this phenomenon demonstrated that, under a hypoinsulinemic
state induced by SRIF, an infusion of cortisol increased IGFBP-1
levels beyond the increase induced by hypoinsulinemia alone (28).
Together, these studies support a role for IGFBP-1 in glucose
counterregulation, and they suggest that glucocorticoid stimulation of
IGFBP-1 predominates during low-insulin states.
One of the postulated roles of IGFBPs is the prevention of the
potential hypoglycemia that could arise from high plasma levels of free
IGFs (1, 2, 3). IGFBP-1 is thought to be the primary IGF binding protein
involved in the acute regulation of serum glucose levels (29). The
elevated IGFBP-1 levels seen in poorly controlled diabetes mellitus may
contribute to hyperglycemia by the binding endogenous IGF-I and
preventing its insulin-like effects (9). Conversely, the elevated
IGFBP-1 levels seen under fasting conditions may prevent hypoglycemia
in normal individuals by the same mechanism. During acute hypoglycemia,
the rise in IGFBP-1 may also serve to inhibit the metabolic actions of
IGF-I.
Our data, during fasting hypoglycemia, show that IGFBP-1 secretion
is regulated by cortisol together with insulin. The effects of insulin
and cortisol are both strong during the course of fasting. The
development of significant hypoglycemia stimulates a rise in IGFBP-1
that is associated with serum cortisol concentration. A model of
IGFBP-1 regulation is depicted in Fig. 4.
The rise in IGFBP-1, during fasting and hypoglycemia, may be regulated,
in part, by cortisol; and this potentially serves to prevent the
additional hypoglycemic effects of free IGFs.
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Footnotes
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1 Supported, in part, by NIH Grant GCRC-MO1-RR-00240, an NIH
CAP Award (to L.K.), an NIH Child Health Research Center
Award (to L.K.), and FDA Grant FD-R-001181–01 (to P.C.). 
Presented, in part, at the 1996 International Congress of
Endocrinology, San Francisco, California.
Received July 31, 1997.
Revised January 29, 1998.
Accepted September 2, 1998.
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Top
Abstract
Introduction
