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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2445-2449
Copyright © 1998 by The Endocrine Society

Original Studies

Differential Changes in Free and Total Insulin-Like Growth Factor I after Major, Elective Abdominal Surgery: The Possible Role of Insulin-Like Growth Factor-Binding Protein-3 Proteolysis1

Christian Skjærbæk, Jan Frystyk, Hans Ørskov, Peter Kissmeyer-Nielsen, Martin Bach Jensen, Søren Laurberg, Niels Møller and Allan Flyvbjerg

Medical Research Laboratories, Institute of Experimental Clinical Research, Aarhus University (C.S., J.F., H.Ø., N.M., A.F.), and the Surgical Research Unit, Department of Surgery L, University Hospital of Aarhus (P.K.-N., M.B.J., S.L.), DK-8000 Aarhus C, Denmark

Address all correspondence and requests for reprints to: Dr. Christian Skjærbæk, Medical Research Laboratories, Aarhus Kommune Hospital, Building 3, DK-8000 Aarhus C, Denmark. E-mail: cs{at}afdm.aau.dk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Major surgery is accompanied by extensive proteolysis of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3). Proteolysis of IGFBP-3 is generally believed to increase IGF bioavailability due to a diminished affinity of the IGFBP-3 fragments for IGFs. We have investigated 18 patients undergoing elective ileo-anal J-pouch surgery. Patients were randomized to treatment with GH (12 IU/day; n = 9) or placebo (n = 9) from 2 days before to 7 days after operation. Free IGF-I and IGF-II were measured by ultrafiltration of serum, and IGFBP-3 proteolytic activity was determined by a [125I]recombinant human IGFBP-3 degradation assay. In the GH-treated group, total IGF-I increased preoperatively by 99%. Postoperatively, total IGF-I decreased by 48% (placebo) and 52% (GH). Immunoassayable IGFBP-3 decreased by 27% (placebo) and 26% (GH). In the placebo-treated group, free IGF-I was unchanged throughout the study. In the GH-treated group, free IGF-I increased by 277% preoperatively and remained elevated after operation. IGFBP-3 proteolytic activity increased by 63–73% after operation. The relative elevations of free IGF-I levels despite decreased total IGF-I levels could thus relate to augmented IGFBP-3 proteolysis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INSULIN-LIKE growth factors (IGFs) are present in serum in three molecular mass (Mr) forms. A 150,000 Mr ternary complex composed of IGF-I or IGF-II, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit contain 80–90% of the circulating IGF-I (1). The 40,000–50,000 Mr forms contain IGFs in binary complexes with either IGFBP-3 or any of the other IGFBPs. Finally, a small portion of IGFs (~0.5%) are present in the free, 7,500 Mr form (2). The IGFBPs act to prolong the half-life of the circulating IGFs and possibly modulate the action of IGF by competing with type I and type II IGF receptors for binding of IGFs. The IGFBPs, in turn, are modulated by specific, but yet unidentified, proteases present in serum. Numerous conditions have been described in which this proteolysis is induced, many of them characterized by an acute or chronic catabolic status (3, 4). It is generally assumed that IGFBP proteolysis weakens the binding affinity of the IGFBPs for IGF-I and IGF-II, thereby increasing the availability of IGF for the receptors. This concept is mainly based on the lost ability of the IGFBP fragments to bind radiolabeled IGF in Western ligand blotting and binding assays (5, 6, 7). However, the matter is disputed, as other studies have indicated that proteolysed IGFBP may be functionally normal (8, 9). An increased in vitro IGF bioactivity in serum with increased IGFBP proteolysis has been reported (10); however, no studies have been undertaken to specifically investigate the effect of IGFBP proteases on serum levels of free IGF-I in vivo. In this study we have, consequently, simultaneously measured IGFBP-3 protease activity and serum free IGF-I and IGF-II levels in patients undergoing elective ileo-anal J-pouch surgery.

The study was performed as part of a placebo-controlled clinical trial investigating the effect of GH administration on postoperative fluid balance, muscle strength, and body composition. We, therefore, also had the opportunity to study the effects of GH on the above-mentioned parameters.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and design

Twenty-four patients with ulcerative colitis scheduled for elective ileo-anal J-pouch surgery entered the study and were randomly allocated to treatment with GH (12 IU/day; Norditropin. Novo Nordisk, Gentofte, Denmark; n = 12) or placebo (n = 12). Treatment was given as two daily sc injections from 2 days before to 7 days after operation. Nineteen patients completed the study (9 GH and 10 placebo). However, due to limitations in assay capacity, the number of patients investigated for this part of the study was reduced to 18. The patient to be left out was chosen randomly from among all 19 patients and was treated with placebo. Data for the 18 patients included in this part of the study are given in Table 1Go. The study was conducted in a double blinded fashion. Fasting serum samples were obtained on day -2 before operation, day 0 (day of operation), and days 2 and 7 after operation. The study was conducted in accordance with the Helsinki Declaration and was approved by the regional ethics committee; patients were enrolled after giving their informed consents.


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  		Table 1. Male/female ratio, age, and body mass index for all patients

 
Assays

IGFBP-1 was measured by enzyme-linked immunosorbent assay (Medix Biochemica, Kainainen, Finland). IGFBP-2 was measured by RIA (Diagnostic System Laboratories, Webster, TX). IGFBP-3 was measured by immunoradiometric assay (IRMA; Diagnostic System Laboratories) calibrated against recombinant nonglycosylated human IGFBP-3 (Mr, ~29,000). The same polyclonal antibody was used as catching antibody and detection antibody. Insulin was measured by RIA (Novo Nordisk, Bagsvaerd, Denmark). Total IGF-I and IGF-II were determined by two in-house, noncompetitive, time-resolved immunofluorometric assays after acid-ethanol extraction of serum as previously described (11). Free IGF-I and IGF-II were separated from bound IGFs by ultrafiltration (2); serum samples were diluted 1:11 in Krebs-Ringer bicarbonate buffer containing 5% human serum albumin (pH 7.4), and 600 µL of the dilution were applied to a YMT-30 ultrafiltration membrane mounted in a MPS-1 supporting device (both from Amicon Division, W. R. Grace Co., Beverly, MA) and centrifuged at 300 x g at 37 C in triplicate. We have previously demonstrated that dilution of serum from normal subjects and subjects with GH deficiency and acromegaly before centrifugation can be performed without altering the concentrations of free IGFs (2). After appropriate dilution of the filtrate, the concentrations of free IGF-I and IGF-II were measured directly in the time-resolved immunofluorometric assays. All samples from one subject were run in the same assay. The detection limit in serum was 27.5 ng/L for free IGF-I and 55 ng/L for free IGF-II. The average intra- and interassay coefficients of variation were 14% and 17%, respectively.

Western ligand blotting (WLB) for serum IGFBP-3

SDS-PAGE and ligand blot analyses were performed according to the method of Hossenlopp et al. (12). Two microliters of serum were subjected to SDS-PAGE (10% polyacrylamide) under nonreducing conditions. All samples from one patient were analyzed in the same gel. Autoradiograms of WLBs were quantified by densitometry using a Shimadzu CS-9001 PC dual wavelength flying spot scanner (Shimadzu Europe, Duisburg, Germany). The relative densities of the bands were measured as arbitrary absorbance units per mm2.

IGFBP-3 protease assays

The IGFBP-3 protease assay was performed as previously described (13), using human recombinant [125I]IGFBP-3 obtained from Diagnostic System Laboratories. [125I]IGFBP-3 (~30,000 cpm) was incubated for 18 h at 37 C with 2 µL serum from patients and subjected to SDS-PAGE as described above. On each gel, internal control sera from healthy, nonpregnant subjects and term pregnant women were included. Electrophoresed gels were fixed in a 7% acetic acid solution, dried, and autoradiographed. The amount of proteolysis was calculated as a ratio of the absorbance of fragmented [125I]IGFBP-3 over the sum of all [125I]IGFBP-3-related optical densities in that lane and expressed as a percentage (in vitro proteolysis).

Statistics

Data following normal distribution were analyzed using one-way repeated measures ANOVA; otherwise, data were analyzed using Friedman’s test for repeated measures ANOVA on ranks, followed by Student-Newman-Keuls method for pairwise multiple comparisons. To detect differences between treatments, Student’s t test was used for data following normal distribution. For data not following normal distribution, Mann-Whitney’s rank sum test was used. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Total IGF-I (Fig. 1aGo) increased significantly by 99% from day -2 to day 0 in the GH-treated group. After operation, total IGF-I decreased significantly from day 0 to day 2 by 48% (placebo) and 52% (GH). From day 2 to day 7, total IGF-I increased significantly in the GH-treated group towards preoperation levels, whereas there was only a slight and insignificant increase in total IGF-I in the placebo-treated group. Levels of total IGF-I were significantly higher in the GH-treated group compared to those in the placebo-treated group on days 0, 2, and 7.



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  		Figure 1. a, Total IGF-I; b, IGF-I; c, IGFBP-3; d, free over total IGF-I. {circ}, Placebo; •, GH. *, P < 0.05 vs. previous day (GH); +, P < 0.05 vs. previous day (placebo); #, P < 0.05, placebo vs. GH. All data are the mean ± SE.

 
IGFBP-3 (Fig. 1cGo), measured by IRMA, increased by 31% from day -2 to day 0 in the GH-treated group. After operation, IGFBP-3 decreased significantly from day 0 to day 2 by 27% (placebo) and 26% (GH). From day 2 to day 7, IGFBP-3 increased again by 12% (placebo) and 25% (GH). Levels of IGFBP-3 were significantly higher in the GH-treated group compared to those in the placebo-treated group on days 0, 2, and 7.

Free IGF-I (Fig. 1bGo) increased by 277% from day -2 to day 0 in the GH-treated group and remained increased for the rest of the study. In the placebo-treated group there were no changes in free IGF-I throughout the study. The relative amount of free IGF-I to total IGF-I (Fig. 1dGo) increased by 104% from day -2 to day 0 in the GH-treated group. From day 0 to day 2 after operation, the relative amount of free IGF-I to total IGF-I increased in both groups by 115% (placebo) and 54% (GH). From day 2 to day 7, the relative amount of free IGF-I returned to preoperation levels in both groups.

Total IGF-II (Fig. 2aGo) decreased by 26% from day 0 to day 2 in the placebo-treated group and increased again by 20% from day 2 to day 7. In the GH-treated group, total IGF-II was also decreased on day 2; however, this was only significant when compared to the day -2 value. In contrast to total IGF-II, free IGF-II (Fig. 2bGo) did not change significantly during the study, and there was no difference between the GH- and placebo-treated groups. Also, there were no significant changes in the relative amount of free IGF-II (data not shown).



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  		Figure 2. a, Total IGF-II; b, free IGF-II; c, IGFBP-1; d, IGFBP-2. {circ}, Placebo; •, GH. *, P < 0.05 vs. previous day (GH); +, P < 0.05 vs. previous day (placebo); #, P < 0.05, placebo vs. GH. All data are the mean ± SE.

 
IGFBP-1 (Fig. 2cGo) increased from day 0 to day 2 and decreased again from day 2 to day 7 in both groups. There were no differences in IGFBP-1 between the two groups at any time. IGFBP-2 (Fig. 2dGo) increased by 51% from day 0 to day 2 in the placebo-treated group and increased again by 36% from day 2 through day 7. In the GH-treated group, IGFBP-2 was also increased on day 7 compared to levels on days -2 and 0. There were no significant differences in IGFBP-2 between the two groups throughout the study.

In addition to IRMA, IGFBP-3 was also analyzed by WLB (Fig. 3Go), and the results of the densitometric scanning are shown in Fig. 5aGo. This analysis showed the same pattern as the immunoassay, except that the IGFBP-3 band in the placebo-treated group was increased on day 0 compared to that in the GH group, and the IGFBP-3 band in both groups was almost undetectable by WLB on day 2. The latter finding suggests that intensive IGFBP-3 proteolysis had taken place. To investigate this further, a specific IGFBP-3 protease assay was performed (Figs. 4Go and 5bGo). As suggested by WLB, we found 63% (placebo) and 73% (GH) increases in in vitro IGFBP-3 proteolytic activity in both groups on day 2 after operation, with no statistical difference in the IGFBP-3 proteolytic activity between the two groups. In both groups IGFBP-3 proteolytic activity was fully normalized on day 7.



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  		Figure 3. Representative WLB autoradiograph of serum samples from one patient treated with placebo (lanes 1–4) and one patient treated with GH (lanes 5–8). IGFBP-3 appear as a 38/42-kDa doublet.

 


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  		Figure 5. a, IGFBP-3 in WLB; b, IGFBP-3 proteolytic activity. {circ}, Placebo; •, GH. *, P < 0.05 vs. previous day (GH); +, P < 0.05 vs. previous day (placebo); #, P < 0.05, placebo vs. GH. All data are the mean ± SE.

 


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  		Figure 4. A representative [125I]IGFBP-3 degradation assay was performed with internal standard serum from a normal control subject (C), term pregnant serum (TP), serum from one patient treated with placebo (lanes 3–6), and serum from one patient treated with GH (lanes 7–10). Intact IGFBP-3 appears as a 38/42-kDa doublet, and IGFBP-3 fragments appeared as three smaller Mr bands with sizes of 30, 20, and 16 kDa.

 
No statistically significant correlations were found between the absolute or relative concentrations of free IGF-I and IGFBP-3 proteolysis (data no shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Major surgery is followed by acute changes in the IGF-IGFBP system, including rapid decreases in total IGF-I, total IGF-II, and IGFBP-3 (14, 15, 16) and an increase in IGFBP-1 (16); the latter is regarded an important inhibitor of IGF-I bioactivity in vivo (17, 18, 19). This apparent suppression of the IGF-I system could seem inappropriate in view of the catabolic status following major surgery. Thus, interest has recently focused on reversing the catabolic status and preventing the loss of protein by the administration of GH (14, 20, 21, 22) or IGF-I (15, 23). However, in addition to the above-mentioned changes, major surgery, like other catabolic challenges, is followed by the induction of IGFBP-3 proteolysis (4, 16, 24). The significance of IGFBP-3 proteolysis is still disputed, but it has been hypothesized that it leads to an increased IGF bioavailability by decreasing the affinity of IGFBP-3 for IGF-I and IGF-II. In the present study we have, therefore, measured free IGF-I and free IGF-II simultaneously with the induction of IGFBP-3 proteolysis after surgery and found differential changes in free and total IGF-I and IGF-II during both placebo and GH administration. In the placebo-treated group, free IGF-I was unchanged throughout the study despite a dramatic decrease in total IGF-I postoperatively. In the GH-treated patients, free and total IGF-I increased in parallel during the first 2 days of GH administration, in accordance with our previous findings in healthy subjects (25). However, in the GH-treated group surgery was also followed by nonparallel changes in free and total IGF-I. Total IGF-I decreased to pretreatment levels on day 2, but then, in contrast to the placebo group, returned to preoperative levels on day 7. Free IGF-I was insignificantly decreased on day 2, but remained at a relatively high level compared to both pretreatment levels and levels in the placebo-group, and had returned to preoperative levels by day 7. Previously, we presented evidence that besides total IGF-I, the most important determinant of free IGF-I is IGFBP-1 (2, 26, 27). In this study, however, the increased levels of IGFBP-1 on day 2 were apparently insufficient to detectably decrease free IGF-I. The paradoxical observation that free IGF-I remains constant despite decreasing levels of total IGF-I and increasing levels of IGFBP-1 could be explained by the observed stimulation of IGFBP-3 proteolysis. As IGF-I in the free, noncomplexed form has a substantially shorter half-life (~10–12 min) than IGF-I in binary (~20–30 min) or ternary (~12–15 h) complexes (28), it is likely that a shift of IGF-I from the binary and ternary complexes toward the free form would increase IGF-I clearance, resulting in a decease in levels of total IGF-I. Miell et al. (23) found an IGF-I elimination half-life of 10.8 ± 5.3 h in postoperative patients. This is much shorter than the IGF-I elimination half-life of 18.4 ± 7.6 h in healthy subjects (29) and supports the concept of increased IGF-I clearance postoperatively.

The degree of IGFBP-3 proteolysis was not influenced by GH administration, confirming previous findings in healthy subjects and GH-deficient patients (30). However, in the GH-treated group, total IGF-I returned to preoperative levels on day 7, indicating that de novo synthesis of IGF-I after exogenous GH administration is capable of counterbalancing the suggested increase in IGF-I clearance.

IGF-II is not as directly regulated by GH as IGF-I, and in the present study, there were no differences in free or total IGF-II between the GH-treated and the placebo-treated group, in accordance with previous findings in healthy subjects (25). The postoperative changes in IGF-II were similar in both groups and were grossly similar to the changes in IGF-I; total IGF-II decreased from day 0 to day 2 and increased again from day 2 to day 7, whereas there were no changes in free IGF-II. In cross-sectional studies of healthy and obese subjects and patients with insulin-dependent and noninsulin-dependent diabetes mellitus free, IGF-II is inversely correlated to IGFBP-2, and the most important IGFBP for determination of levels of free IGF-II is IGFBP-2 (our data submitted for publication). In the present study IGFBP-2 increased postoperatively in both groups, and therefore, it was surprising that free IGF-II remained constant in view of the decreased levels of total IGF-II. The physiological role and regulation of IGF-II in postnatal life remain largely unclear, but biochemically IGF-II shares many of the properties of IGF-I, including binding to IGFBPs and appearance in three Mr forms. Total and free IGF-I and IGF-II could therefore be expected to change similarly in response to increased IGFBP-3 proteolysis. In conclusion, the present results on free and total IGF-I and IGF-II support the concept of an important role for IGFBP-3 proteolysis in the maintenance of free IGF-I levels postoperatively.


   Acknowledgments
 
Joan Hansen, Karen Mathiasen, Kirsten Nyborg, Nina Rosenqvist, and Susanne Sørensen are thanked for their skilled technical assistance. GH was generously provided by Novo Nordisk (Gentofte, Denmark).


   Footnotes
 
1 This work was supported by the Danish Medical Research Council, Grant 9600822 (Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration) and Grant 9700592 (to A.F.), the Aarhus University Research Foundation, the Danish Diabetes Association, the Novo Foundation, the Nordic Insulin Foundation, the Aage Louis Petersen Foundation, and the Institute of Experimental Clinical Research, University of Aarhus (Aarhus, Denmark). Back

Received January 13, 1998.

Revised March 24, 1998.

Accepted April 8, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4551 - 4555.
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