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Original Studies |
Pediatric Endocrinology Unit, Department of Woman and Child Health (P.B., C.C.-S.), and Department of Surgery (J.N., A.T., O.L.), Karolinska Institute and Hospital, 171 76 Stockholm, Sweden
Address all correspondence and requests for reprints to: Peter Bang, M.D., Ph.D., Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: peter.bang{at}kbh.ki.se
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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IGFBP proteolytic activity was first demonstrated in pregnancy serum (9, 10) to predominantly affect IGFBP-3, which carries the majority (90–95%) of circulating IGFs in a ternary complex consisting of IGF, IGFBP-3, and an acid-labile subunit (11). Although proteolytic cleavage of IGFBP-3 occurs within the ternary complex (12) and does not lead to dissociation of the complex in vivo (10, 13), it destabilizes the complex and increases the release of IGF from proteolyzed IGFBP-3 10-fold (7). Intravascular proteolysis of IGFBP-3 could be expected to increase IGF bioavailability locally at a site of increased protease activity. We have suggested that plasmin may act in such a way by inducing proteolysis of IGFBP-3 after vascular damage and repair (14). Alternatively, the expression of IGFBP-3 proteolytic activity may be generalized to include the entire intravascular compartment and thus release large quantities of IGFs from the pool of ternary complexed IGF. As systemic changes in IGFBP-3 proteolytic activity have previously been observed over the course of days or months, the resulting changes in IGF bioavailability have been thought to primarily affect long term growth, whereas IGFBP-1 has been implicated in short term regulation of IGF bioavailability with an impact on glucose metabolism (15).
Increased IGFBP-3 proteolytic activity (IGFBP-3-PA) in serum has been demonstrated in severe illness and after surgery (16, 17, 18, 19, 20), and we have reported increased IGFBP-3-PA in noninsulin-dependent diabetes mellitus (NIDDM) patients (21). Based on these findings we have hypothesized that the induction of IGFBP-3 proteolytic activity in serum may be associated with insulin resistance, a common feature of these states. In the present report we have compared the development of postoperative insulin resistance in two groups, fasted (FAST) or given an oral glucose load (OGL) before surgery, and demonstrated a relation to the induction of IGFBP-3 protease activity and cleavage of endogenous IGFBP-3. In the postoperative state, infusion of insulin and glucose during a hyperinsulinemic, normoglycemic clamp employed to measure insulin sensitivity further increased IGFBP-3 protease activity and IGFBP-3 cleavage. These events may regulate IGF bioavailability and could have a major impact on glucose homeostasis in the insulin-resistant state.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen patients scheduled for elective colo-rectal surgery were studied. The data for 14 of these patients were presented in detail previously (22). Patients had no history or signs of metabolic diseases. Fasting blood glucose levels, C reactive protein, and liver tests were within the normal range in all subjects. The surgical and anesthetic procedures as well as the perioperative care of all patients were standardized as previously described (23). The patients were allocated to 1 of 2 groups (OGL or FAST groups). The patients in the OGL group [n = 8; age, 45 ± 5 yr; body mass index (BMI), 24 ± 1 kg/m2] received 800 mL of an isoosmolar carbohydrate-rich OGL (12.5% carbohydrates; Nutrica, Zoetermeer, Holland) the evening before surgery and an additional 400 mL no later than 2 h before the induction of anesthesia (24). The patients in the FAST group (n = 10; age, 45 ± 4 yr; BMI, 24 ± 1 kg/m2) underwent surgery after an overnight fast. Of the 18 patients, 4 patients diverged from the original protocol (23) by not receiving peri- and postsurgery epidural pain relief (1 in the OGL group and 3 in the FAST group). However, they did not diverge in any response parameter studied from patients in their respective group. The study protocol was approved by the institutional ethical committee at the Karolinska Hospital, and informed consent was given by each subject before entering the study.
Study design
All patients underwent the same study protocol twice. At 0800 h on the day before surgery (pre-op) as well as at the same time on the first postoperative day (post-op), a normoglycemic, hyperinsulinemic, two-step clamp (Actrapid, Novo, Bagsvaerd, Denmark; 0–120 min, 0.3 mU/kg·min; 120–240 min, 0.8 mU/kg·min) was performed after an overnight fast (23). Arterialized blood from a heated hand vein was sampled immediately before and every 30 min during the clamps (±0, 60, 90, 120, 180, 210, and 240 min), substrates were assayed immediately, and serum/plasma was stored at -20 C for analysis of hormones and growth factors as described below.
Materials
Aprotinin, 
2-antiplasmin, and tissue inhibitor of
metallo proteinase-1 (TIMP-1) were purchased from Calbiochem (La Jolla,
CA). IGFBP-3 was provided by Dr. Paul Fielder, Genentech (South San
Francisco, CA). IGFBP-2 was provided by Sandoz (Basel, Switzerland).
125I-Labeled IGFBP-1 was a gift from Dr. Kerstin Hall,
Karolinska Hospital (Stockholm, Sweden). IGFBP-5 was a gift from Dr.
Gunnar Nordstedt, Pharmacia & Upjohn (Uppsala, Sweden). Recombinant
human IGF-I was a gift from Pharmacia & Upjohn.
Substrate and hormone assays
Glucose was measured at least every 10 min during the study immediately upon collection using the glucose oxidase method (Yellow Springs Instruments Co., Yellow Springs, OH). Serum insulin was analyzed by RIA as previously described (25), and C peptide was analyzed by RIA using a commercially available kit (Novo).
Insulin resistance
The glucose infusion rate (GIR) during the hyperinsulinemic, normoglycemic clamp at the high insulin infusion rate (0.8 mU/kg·min) was used as a measure of whole body insulin sensitivity. Due to large individual variation in pre-op insulin sensitivity, we used the relative change in GIR from the pre-op to the post-op state (%GIR) to express changes in insulin sensitivity.
IGFBP-3 protease assay
Proteolytic activity was measured as the ability of a sample to degrade labeled [125I]IGFBP-3 (26). Human recombinant glycosylated IGFBP-3 was 125I labeled using the chloramine-T method and purified on a PD-10 column (Pharmacia, Sweden). Serum (4 µL) with or without the indicated concentrations of protease inhibitors was incubated with 30,000 cpm [125I]IGFBP-3 for 5 h at 37 C in a total volume of 50 µL 25 mmol/L HEPES (pH 7.4), 2.5 mmol/L Ca2+, and 0.1% BSA. The reaction was terminated by the addition of SDS sample buffer, and the reaction mixture was separated by SDS-PAGE (12% gels) at 45 V overnight as previously described (21). Gels were dried and analyzed by Phos-phorImager (Fujifilm BAS-1000 System, Fuji, Tokyo, Japan) displaying linear detection of 125I-labeled IGFBP-3 in the range of 103-105 cpm (our unpublished data) and in some cases were exposed to x-ray films for 1–4 days at -70 C. IGFBP-3-PA was determined as the sum of the intensity of the 30-, 18-, and 15-kDa bands, respectively, relative to the total intensity of all bands.
Other IGFBP protease assays
IGFBP-1-PA, IGFBP-2-PA, and IGFBP-5-PA were determined similarly to IGFBP-3-PA. IGFBP-1 was 125I labeled using the lactoperoxidase method, and IGFBP-2 and IGFBP-5 were 125I labeled using the chloramine-T method and purified by PD-10 desalting chromatography. The protease assays were performed as described for IGFBP-3.
Characterization of circulating IGFBP-3 forms by Western immunoblotting (WIB)
The effect of increased IGFBP-3-PA on the circulating forms of
IGFBP-3 was determined by WIB using the enhanced chemiluminescence
detection technique as previously described (21). Briefly, serum (5
µL) was diluted with nonreducing SDS sample buffer and processed by
SDS-PAGE (12% gels) at 45 V overnight. Prestained mol wt standards
were processed in parallel. Separated proteins were electroblotted onto
nitrocellulose filters (0.45-µm pore size) in a Hoefer Semiphore
semi-dry transfer unit (San Francisco, CA) at 200 mA. Filters were
washed twice for 30 min each time in 0.1% Tween-20 in Tris-buffered
saline (TBS) at 20 C, blocked for 4 h in TBS with 1% BSA at 20 C,
and thereafter incubated with anti-IGFBP-3 antibody (IGFBP-3-g1
(21); 1:1000 dilution in TBS) overnight at 4 C. Filters were washed in
0.1% Tween-20 and incubated with donkey antirabbit IgG conjugated with
horseradish peroxidase (Amersham, Arlington Heights, IL) for 1 h
at 20 C, and subsequently washed with 0.1% Tween-20. Filters were then
exposed to enhanced chemiluminescence reagents (Amersham) for 1 min at
20 C and exposed to x-ray film for 45–60 min at 20 C.
Western ligand blotting (WLB)
Serum IGFBPs were determined by WLB analysis, performed as originally described by Hossenlopp et al. (27) with minor modifications. Briefly, serum (5 µL) was processed by SDS-PAGE (12% gels) and electroblotted to nitrocellulose filters. Filters were sequentially treated with 3% Nonidet P-40 and 1% BSA in 0.1 mol/L TBS and probed with a mixture of equal quantities of 125I-labeled IGF-I and IGF-II in TBS containing 1% BSA (2 x 106 cpm of each tracer/25 mL) overnight at 4 C. Filters were washed with 0.1% Tween-20 in TBS, dried, and autoradiographed. Relative changes in band intensities were determined after scanning the filters in a PhosphorImager (Fuji).
Statistics
All data are given as the mean ± SEM for sampling performed basally and at steady state during the clamp. Comparisons within and between groups were performed using one- or two-way ANOVA for repeated measurements. Regression analysis was performed using simple or multiple regression. Statistical significance was accepted at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Substrates and hormones
Fasting blood glucose levels increased 11 ± 3% after surgery (P < 0.005), with no difference between groups. During clamps, normoglycemia was maintained in both groups, with mean intraindividual coefficients of variation in blood glucose during pre- and post-op clamps of 3.2 ± 0.3% and 4.5 ± 0.5% in the OGL and FAST groups, respectively (P > 0.05). Basal serum insulin increased 26 ± 9% after surgery (P < 0.05), with no difference between groups. The approximately 15% increase in C peptide levels after surgery was not statistically significant in any group, as previously reported (22).
Development of insulin resistance and changes in IGFBP-3 proteolysis
Response to surgery. After surgery, insulin sensitivity was reduced in both patient groups, with a mean relative reduction in the GIR of 58 ± 4% (P < 0.0001 = 18). Multiple regression analysis with the relative change in whole body insulin sensitivity (percent GIR) as a dependent variable and treatment (whether an oral glucose load was given before surgery or not) and duration of surgery as two independent variables could predict 56% of the variability in the GIR (adjusted r2 = 0.56; P = 0.0014). A significant predictive value was found for treatment (B = -18.0; 95% confidence interval, -29.7 to -6.2; P < 0.01), demonstrating that when the confounding effect of the duration of surgery was taken into account, the FAST group was 18% less insulin sensitive than the OGL group. Duration of surgery was also predictive of the change in GIR (B = -0.09; 95% confidence interval, -0.14 to -0.04; P < 0.005), demonstrating that insulin sensitivity decreases with increasing duration of surgery.
In the OGL group, IGFBP-3-PA was 24.4 ± 0.8% pre-op and
32.4 ± 2.6% post-op, whereas the values in the FAST group were
28.4 ± 1.2% vs. 30.5 ± 1.8%, respectively. The
relative increases in IGFBP-3-PA were 32.9 ± 7.1% and 8.6
± 6.7%, respectively (Fig. 1
). Two-way
ANOVA demonstrated a significant increase in IGFBP-3-PA after surgery
(P < 0.005; n = 18) and a significantly greater
increase in the OGL group compared with the FAST group
(P < 0.05). Multiple regression analysis confirmed
that treatment was of predictive value for the relative change in
IGFBP-3-PA from the pre- to the post-op state (B = -20.9; 95%
confidence interval, -38.3 to -3.5; P < 0.05).
Interestingly, using the relative change in C peptide concentration as
a second independent variable, an inverse correlation to the change in
IGFBP-3-PA could be demonstrated (B = -0.24; 95% confidence
interval, -0.41 to -0.07; P < 0.05). The combined
explanatory value of these two independent variables was 48% (adjusted
r2 = 0.48; P = 0.0029). Although the
percent GIR as a single independent variable correlated with the
relative change in IGFBP-3-PA, multiple regression analysis
demonstrated, as expected, that this effect was overridden by the mode
of treatment. Other parameters, such as duration of surgery, blood
loss, BMI, age, sex, or relative changes in serum cortisol or glucagon
concentrations, were of no significant predictive value.
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, administration of exogenous
insulin during the post-op hyperinsulinemic clamp induced a significant
increase in IGFBP-3-PA, as demonstrated by two-way ANOVA
(P < 0.005), with no statistical difference in
response between the OGL and FAST groups (13.6 ± 6.4% and
11.0 ± 3.2% relative increases, respectively; P
= 0.85). Multiple regression analysis demonstrated that 59% of the
variability in the relative increase in IGFBP-3-PA during the post-op
clamp could be explained using age, BMI, and duration of surgery as
independent variables (adjusted r2 = 0.587;
P = 0.0078). However, only duration of surgery was a
statistically significant independent predictor of the relative
increase in IGFBP-3-PA (B = 0.093; 95% confidence interval,
0.043–0.143; P < 0.005). No significant increase in
IGFBP-3-PA was observed during the pre-op clamp. Rather, there was a
tendency toward attenuation of the IGFBP-3-PA during the pre-op clamp
(P = 0.07) in both groups (Fig. 2).
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The circulating forms of IGFBP-3 were studied by WIB using an
IGFBP-3 antibody that recognizes intact IGFBP-3 as well as several of
the fragmented forms, as reported previously (21). Before surgery,
serum contains intact 39/41-kDa IGFBP-3 as the major form, with 30-kDa
fragmented IGFBP-3 constituting approximately 30% of the total
immunoreactivity. The induction of IGFBP-3-PA after surgery was
followed by a simultaneous conversion of intact 39/41-kDa IGFBP-3 to
predominantly 30-kDa IGFBP-3 and a minor contribution of an 18-kDa
IGFBP-3 form (Fig. 4, lanes pre-op 0'
vs. post-op 0'). Interestingly, 4 h of hyperinsulinemia
during the post-op clamp induced an almost complete conversion of the
large circulating pool of intact IGFBP-3 to fragmented forms in several
of the subjects (Fig. 4; lanes post-op 0' vs. 210'). This
conversion is much faster than has previously been reported in other
states. As shown in Fig. 4, there was a high concordance between
increases in IGFBP-3-PA and conversion of intact IGFBP-3 to its
fragmented forms. We also examined changes in IGFBP-3 mol wt forms in
ethylenediamine tetraacetate (EDTA) plasma to exclude that fragments of
IGFBP-3 resulted from in vitro proteolysis during blood
sampling. Although the addition of EDTA was demonstrated to completely
block the increase in post-op IGFBP-3-PA in serum in
vitro (see below), fragmented IGFBP-3 was present in equivalent
quantities in plasma and serum (data not shown).
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WLB confirmed the changes in intact IGFBP-3 determined by
WIB, as shown in Fig. 4
; however, as fragments of IGFBP-3 after
separation on SDS-PAGE lose the ability to bind
125I-labeled IGFs (28), the fragments of IGFBP-3 cannot be
visualized. WLB demonstrated that the disappearance of IGFBP-3 due
to proteolysis was accompanied by an induction of an IGFBP with the
apparent size of IGFBP-2. In parallel with the changes in intact
IGFBP-3, concomitant changes were seen in the 30-kDa band, which most
likely represents IGFBP-5/-6. However IGFBP-1, which in our hands
usually migrates slightly faster and with low intensity, may partly
contribute to the 30-kDa band. Finally, IGFBP-4 migrating at 24 kDa did
not demonstrate any consistent changes.
Characterization of the insulin-induced IGFBP-3 proteolytic activity
Incubation of post-op sera with 125I-labeled IGFBP-1,
-2, and -3 demonstrated that only IGFBP-3 was significantly degraded
using prolonged incubation up to 8 h at 37 C (data not shown). The
preparation of 125I-labeled IGFBP-5 was unstable at 37 C in
the presence or absence of serum, but was stable at 4 C (data not
shown). Both basal as well as surgery-induced IGFBP-3-PA were
significantly inhibited by 5 mmol/L EDTA and 500 µg/mL aprotinin, but
were not inhibited by inhibitors of plasmin such as 40 µg/mL of
2-antiplasmin (Table 1).
These characteristics are similar to those of a
Ca2+-dependent serine protease (excluding fibrinolytic
enzymes). Zinc at 0.05 mmol/L did not significantly change IGFBP-3-PA,
whereas 0.5 mmol/L zinc inhibited the surgery-induced IGFBP-3-PA. A
specific inhibitor of matrix metalloproteinases (MMPs), TIMP-1 dose
dependently inhibited the surgery-induced rise in IGFBP-3-PA (Fig. 5). This was in contrast to the lack of
TIMP-1 inhibition of the pregnancy-associated IGFBP-3-PA (Fig. 5).
Increased IGFBP-3-PA after the post-op clamp responded in a similar way
to the addition of protease inhibitors and thus did not disclose any
difference from the surgery-induced activity (Table 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We have demonstrated that insulin infusions at identical rates during hyperinsulinemic, normoglycemic clamps resulted in increased IGFBP-3-PA in the insulin-insensitive state post-op, but failed to induce a similar activity in the insulin-sensitive state pre-op. The present study does not exclude that a rise in IGFBP-3-PA during this post-op period may occur even in the absence of insulin/glucose infusion. However, Cwyfan Hughes et al. (18) demonstrated elevated unchanged IGFBP-3-PA during this post-op period in a study of heart surgery patients, where clamps were not performed. We have recently confirmed their finding in 20 patients after bypass surgery (Wallin, M., and P. Bang, unpublished observations). Thus, taken together these data argue that surgery, which is associated with increased peripheral insulin resistance (22), may by some as yet unknown mechanism develop competence to express IGFBP-3-PA in response to hyperinsulinemia. That the duration of surgery strongly predicts the decrease in insulin sensitivity after surgery as well as the relative increase in IGFBP-3-PA during the post-op clamp further support this view. It is also in concordance with our previous finding of increased IGFBP-3-PA in obese NIDDM patients, who also display peripheral insulin resistance and hyperinsulinemia (21).
The present study demonstrates for the first time that very fast and dramatic changes in the circulating forms of IGFBP-3 occur as a result of increased IGFBP-3-PA. Previously reported changes in the molecular forms of circulating IGFBP-3 have been in the order of days (17) to months (9, 10). IGFBP-3 carries 90–95% of the circulating pool of IGFs in a ternary complex, and proteolysis of IGFBP-3 within this complex may lead to as much as a 10-fold decrease in the affinity for IGF (7). Therefore, such a fast proteolytic cleavage of intact IGFBP-3 may have a dramatic impact on IGF bioavailability, although further studies are needed to finally prove this. IGF-I and -II increase glucose transport in human muscle via the type 1 IGF receptor and elicit a maximal response comparable to that of insulin, although with 10- to 20-fold lower potency (29, 30). However, an increase in the bioavailable fraction of circulating IGF of a few percent exceeds the half-maximal dose for glucose uptake via the IGF-I receptor. We are currently determining total and free dissociable IGF-I concentrations to elucidate further the effects of increased IGFBP-3-PA on IGF-I bioavailability. In contrast to IGFBP-3, IGFBP-1 and IGFBP-2 were not degraded, whereas no conclusive results were obtained regarding IGFBP-4, -5, and -6. The present study adds further to previous evidence that the large pool of IGFs in the circulating ternary complex may become accessible and demonstrates that this may occur much faster than previously thought.
The identity of the IGFBP-3 proteases in human pregnancy (14) and in
insulin-resistant states such as NIDDM, severe illness, and after
surgery is not yet known. In agreement with previous reports (16, 17, 18, 19, 20),
we demonstrated that the IGFBP-3-PA induced by surgery is inhibited by
inhibitors of serine proteases such as aprotinin and by EDTA.
2-Antiplasmin is not inhibitory, demonstrating that the
plasmin system is not activated. TIMP-1, a specific inhibitor of MMPs,
inhibited the increased IGFBP-3-PA after surgery. Although MMPs are
zinc-dependent proteases, we did not observe any significant effects of
zinc on increased IGFBP-3-PA after surgery. Thus, in addition to the
induction of cation-dependent serine-like IGFBP-3 protease activity by
surgery and accentuation of this activity during the post-op clamp,
MMPs may be involved. As elevated tumor necrosis factor- (TNF)
levels after surgery (31, 32) may be involved in the postreceptor
uncoupling of the insulin receptor (33, 34), and TNF induces
cellular release of MMPs from endothelial cells (35, 36), it is
possible that TNF is the link between insulin resistance and
increased IGFBP-3-PA. Although other growth factors, such as nerve
growth factor, have IGFBP-3 proteolytic activity (37), TNF does not
have any intrinsic IGFBP-3-PA nor does it activate IGFBP-3-PA in serum
(our unpublished obser-vations).
In summary, we have demonstrated that induction of IGFBP-3-PA occurs in patients after surgery and is dependent on their initial metabolic status and that attenuation of developed insulin resistance is associated with increased IGFBP-3-PA. After surgery, patients are peripherally insulin resistant, and in this state, insulin induces a further increase in IGFBP-3-PA, resulting in extensive conversion of endogenous 39/42-kDa IGFBP-3 to its 30-kDa form within 4 h. These observations raise the possibility that in states of insulin resistance, IGF bioavailability is increased by the induction of an IGFBP-3-PA and proteolytic conversion of circulating IGFBP-3 to low affinity fragments.
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Footnotes |
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Received September 30, 1997.
Revised January 26, 1998.
Accepted March 30, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and interleukin-6 in
infected patients. Crit Care Med. 24:423–428.[CrossRef][Medline]
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