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ORIGINAL RESEARCH |
From the Department of Gynecology, Skejby Hospital and Medical Research Laboratory M (Diabetes and Endocrinology), Aarhus Municipal Hospital, Aarhus, Denmark.
Address reprint requests to: Finn F. Lauszus, PhD Department of Gynaecology Holstebro Central Hospital Laegaardsvej 12 DK-7500 Holstebro Denmark E-mail: affl{at}ringamt.dk
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Abstract |
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Methods: This was a prospective, observational study of 45 pregnant women with insulin-dependent diabetes mellitus without overt nephropathy, examined in an outpatient, antenatal diabetic clinic. Maternal venous serum samples were collected from week 14 every fourth week until week 30, and every other week until delivery. Levels of IGF-I and -II were measured in maternal serum by immunoassays. The repeated measurements were tested with two-way analysis of variance. The outcome measures were birth weight and serum IGF-I, IGF-II, IGF binding protein (BP)-3, and IG-FBP-3 proteases. Before the study, minimum sampling size was calculated as 14 subjects in each group if a difference in IGF-I of 50 µg/L was to be detected with an estimated standard deviation of 40, a two-sided P value (
) of .05, and a power of 90 (ß = .1).
Results: Increasing levels of IGF-I and -II were significantly associated with the birth-weight groups: The higher the birth-weight ratio, the higher the levels of IGF-I and -II (P < .01).
Conclusion: Macrosomia in diabetic pregnancy is associated with high levels of maternal IGF-I and -II.
Insulin-like growth factors (IGFs) constitute a system of peptides that promote mitosis and growth of various organs. Insulin-like growth factors are bound to and modulated by at least six specific IGF-binding proteins (IGFBPs), which themselves are modulated by proteolysis and phosphorylation.1,2
These IGFBPs are believed to prolong the half-life of the IGFs in the circulation and, at the cellular level, to modulate local actions of the IGFs.1,3 Specific IGFBP proteases have been studied under several physiologic and pathophysiologic conditions.
Maternal serum IGF-I and IGF-II levels have been associated with birth weight and are thought to promote growth of the fetus.4–6 In pregnancy, this effect could be achieved as IGFBP-3 proteolysis is apparently increased with the presence of proteolysed IGFBP-3 fragments in the circulation. The IGF-binding affinity of IGFBP-3 has been reported to be decreased or unaltered.7–10 Further, enhanced IGFBP-3 protease activity may explain the findings of a correlation of birth weight with the IGF system, as found in restricted and excessive fetal growth and multiple pregnancies.11–13
Insulinopenia and hyperglycemia in insulin-dependent diabetes mellitus are followed by increased IGFBP-3 proteolysis and increasing levels of IGF-I.14 The enhanced IGFBP-3 proteolysis is reversed by appropriate insulin therapy. However, diabetic pregnancy is characterized by increased growth of the fetus despite good glycemic regulation. This may be caused by fetal hyperinsulinemia.15,16 In contrast, fetal growth restriction (FGR) is often seen with prominent maternal vascular endothelial complications, such as overt nephropathy, proliferative retinopathy, preeclampsia, and hypertension.17,18
The aim of the present study was to measure the changes in serum IGF-I, IGF-II, IGFBP-3, and IGFBP-3 proteolysis in the serum of women with insulin-dependent diabetes mellitus and to evaluate their possible correlations with birth weight.
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Materials and Methods |
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). The study was approved by the local ethics committee, and all women gave informed consent.
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Serum samples for measurement of IGF-I, IGF-II, and IGFBP-3 were drawn at weeks 14, 18, 22, 26, 30, 32, 34, 36, and 38, and in those women who attended a follow-up visit 3–6 months postpartum. In this way, 351 of 360 possible blood samples were obtained from weeks 14 to 36; 32 of 45 were taken at week 38 (13 women had delivered before week 38); and 19 of 45 possible samples were taken postpartum.
Analyses of IGFBP-3 with Western ligand blotting and Western immunoblotting were performed in randomly chosen samples in each group: White class B (n = 5), White class C (n = 5), White class D with no retinopathy (n = 5), White class D with simple retinopathy (n = 5), and White class R (n = 4). From weeks 14 to 36, 164 of 168 possible analyses were performed; at week 38, 17 of 24; and postpartum, 14 of 24.
Serum IGF-I and IGF-II levels were measured by a noncompetitive time-resolved immunofluorometric assay.19 Cross-reactivity for IGF-I and IGF-II in the heterologous assay was below 0.0002%. The detection limits were 0.0025 µg/L and 0.010 µg/L for the IGF-I and IGF-II assays, respectively. The operating ranges were 0.0025 to 2.5 µg/L and 0.02 to 10 µg/L for the IGF-I and IGF-II assays, respectively. The intra- and interassay variations were 5% and 10%, respectively.
Serum IGFBP-3 was measured by an IGFBP-3 immunoassay (Diagnostic Systems Laboratories, Webster, TX). The intra- and interassay coefficients of variation were less than 5% and 10%, respectively.
Sodium dodecyl sulfate–polyacrylamide gel electrophoresis ligand blotting analysis was performed as described.20,21 Two microliters of serum was subjected to this procedure (10% polyacrylamide) under nonreducing conditions and transferred overnight onto nitro-cellulose. Nitrocellulose sheets were incubated with 125I-labeled IGF-I, washed, and autoradiographed. Specificity of the IGFBPs was ensured by competitive coincubation with unlabeled IGF-I (Bachem, Bubendorf, Switzerland). All samples from each subject were analyzed in the same gel.
After electrophoresis of the serum sample and transfer as described above, nitrocellulose sheets were blocked with 5% nonfat dry milk and incubated overnight with anti–IGFBP-3 antibody (Upstate Biotechnology Inc., Lake Placid, NY) at a 1:1000 dilution. Subsequently, the nitrocellulose sheets were washed vigorously, incubated with 35S-protein A (specific activity 500 Ci/mmol; Amersham International, Bucks, United Kingdom), and autoradiographed.
Autoradiograms of Western ligand blottings, Western immunoblottings, and IGFBP-3 protease assays were quantified by densitometry using a Shimadzu CS-9001 PC dual-wavelength flying spot scanner (Shimadzu Europe GmbH, Duisburg, Germany). The relative density of the bands was measured as arbitrary absorbance units per square millimeter (AU/mm2).
The IGFBP-3 protease assay was performed as described previously using 125I–rhIGFBP-3 (Diagnostic Systems Laboratories). 125I–IGFBP-3 (approximately 30,000 counts per minute) was incubated for 18 hours at 37 C with 2 µL of serum samples from the pregnant diabetic women and subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis as described above. On each gel, internal control sera from normal controls and term pregnant subjects were present. After electrophoresis, the gels were fixed in a solution of 7% acetic acid, dried, and autoradiographed. The amount of proteolysis was calculated as a ratio of the absorbance of fragmented 125I–IGFBP-3 divided by the sum of all 125I–IGFBP-3 (38–42, 30, and 16–18 kd) related optical densities in that lane and expressed as a percentage (in vitro proteolysis). In the same way, IGFBP-3 proteolysis (in vivo proteolysis) was calculated from Western immunoblottings as a ratio of fragmented IGFBP-3 (30 and 16–18 kd) to all the IGFBP-3 (38–42, 30, and 16–18 kd) in each lane.
Results are presented as mean ± standard error of the mean (SEM) unless otherwise indicated. In the case of duration of diabetes and insulin dose, median values and 95% confidence intervals are given. Differences between means were tested with Student t test if a gaussian distribution was assured with the Kolmogorov-Smirnov test; otherwise, Mann-Whitney test was applied. Consecutive measurements were analyzed by two-way analysis of variance. The associations between the continuous variables were tested with a regression model. Correlations between IGF-I and -II and IGFBP-3 were adjusted for body mass index (BMI) and birth-weight ratio. Before the study, the minimum sampling size was calculated as 14 subjects in each group if a difference in IGF-I of 50 µg/L was to be detected, with an estimated standard deviation of 40, a two-sided P value () of .05, and a power of 90 (ß = .1).19 A statistical software package (SOLO; distributed by BMPD Statistical Software, Los Angeles, CA) was used for analysis.
Birth-weight ratio was calculated by dividing the actual birth weight by the expected birth weight for the same gestational age and sex. The expected birth weights were calculated from a cohort of 4742 normal singleton births occurring during the same period at the same clinic. A post hoc grouping was performed to sort the 45 births into three equal-sized groups of increasing birth-weight ratio: Group 1, birth-weight ratio up to 1.18; group 2, birth-weight ratio between 1.18 and 1.4; and group 3, birth-weight ratio above 1.4. This allowed calculation of the time-dependent association of the birth weight group by two-way analysis of variance.
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). At week 26, class B had lower glycosylated hemoglobin than classes D and R and a shorter duration of diabetes than classes C, D, and R. The group with a birth-weight ratio between 1.18 and 1.4 had lower glycosylated hemoglobin at week 14 (Table 2). No other differences were found in any other measurements among the White classes and birth-weight groups.
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). From weeks 14 to 38, IGF-I was significantly associated with the birth-weight groups (P < .02; Figure 1B): The higher the birth-weight ratio, the higher the IGF-I. In gestational week 30, the level of IGF-I was 75% higher in women from the group with a birth-weight ratio greater than 1.4 than in the group with a birth-weight ratio less than 1.18 (Figure 1B).
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). From weeks 14 to 36, IGF-II levels were significantly associated with the birth-weight groups (P < .004; Figure 2B): The higher the birth-weight ratio, the higher the IGF-II. In gestational week 36, the level of IGF-II was 29% higher in women from the group with a birth-weight ratio greater than 1.4 than in the group with a birth-weight ratio less than 1.18.
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). In week 38, IGFBP-3 tended to decline (P < .2). Insulin-like growth factor binding protein-3 was correlated with IGF-I and IGF-II during pregnancy: for IGF-I, r = .51, r = .71, and r = .77 at weeks 14, 26, and 34, respectively (all P < .01); for IGF-II, r = .60, r = .56, and r = .77 at weeks 14, 26, and 34, respectively (all P < .01). Postpartum, IGFBP-3 correlated with IGF-I (r = .80; P < .01).
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). In the first half of pregnancy, IGFBP-3 was higher than in the second half (weeks 14 and 18 compared with weeks 30, 32, and 36, respectively; P < .05). Insulin-like growth factor binding protein-3 showed a significant decrease during pregnancy of about 37% from weeks 14 to 38 (P < .05). The level of IGFBP-3 during pregnancy was 20% of the level postpartum (Figure 3C).
The in vitro IGFBP-3 protease activity increased about 55% during pregnancy, reaching a plateau of about 70% in weeks 32–38, as calculated from the 125I–IGFBP-3 degradation assay (P < .01; Figure 4A). In vivo proteolysis calculated from IGFBP-3 Western immunoblottings was significantly higher during pregnancy than postpartum (P < .01; Figure 4B). Proteolysis tended to increase throughout pregnancy; however, this was not statistically significant (P < .11).
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Discussion |
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The difference in serum IGF-I and -II with respect to birth weight was present throughout the diabetic pregnancy. The different levels of macrosomia had corresponding IGF-I levels as early as the first trimester. This finding has not been confirmed in normal, nondiabetic pregnancies.4,18 However, serum IGF-I has been reported to correlate with fetal size as measured by ultrasound during pregnancy.22 Apparently, in women with insulin-dependent diabetes mellitus with increasing macrosomia, higher levels of serum IGF-I seem to imply excessive fetal growth from the start of pregnancy. Other conditions associated with early vigorous fetal growth (eg, multiple pregnancies) do not present with higher levels of IGF-I early in pregnancy.11 Moreover, maternal levels of serum IGF-I were similar in normal, small for gestational age (SGA), and multiple pregnancies.11,13
Total IGF-I and -II are largely dependent on the levels of IGFBP-3, which in turn are regulated by variations in IGFBP-3 proteolysis during pregnancy. Thus, the effect on the fetus may be directly mediated by IGF-I, IGF-II, or IGFBP-3. Hill et al4 showed that macrosomia was not associated with increased levels of IGF-I in umbilical cord blood. Another study indicated that maternal serum IGF-I may stimulate a specific placental growth hormone to act directly on fetal growth.12
Whether the binding affinity of IGF-I and -II to IGFBP-3 is altered by the pregnancy-induced IGFBP-3 proteolysis is controversial.6–8,10,23,24 In the present study, we found a correlation between IGF-I and -II and total IGFBP-3 measured by immunoblotting. However, we found no association between birth weight and IGFBP-3 levels when measured by immunoblotting, Western immunoblotting, or Western ligand blotting techniques. Similarly, no association was found with IGFBP-3 proteolysis in vivo or in vitro. This corroborates the findings of others that an increasing level of IGF-I corresponds to a similar increase of IGFBP-3 and accordingly indicates that the affinity of IGFBP-3 for IGF-I and -II may be unaltered in diabetic pregnancy even though proteolysis is prominent.8
The low levels of IGFBP-3 proteolysis seen early in pregnancy may enable the binding proteins to inhibit the action of IGF-I and -II in susceptible subjects. This would account for a possible reduction in growth potential for the early fetus. The finding of an association between birth weight and IGF-I and -II from data obtained early in pregnancy could support this theory. Because of the low incidence of FGR, this could not be examined in this study. Similarly, we found a two- to threefold increase in the in vitro IGFBP-3 proteolysis in women with insulin-dependent diabetes mellitus during pregnancy, as compared with values after delivery. This is in contrast to the limited proteolysis found by others.20,25 Similar techniques were applied; however, the mixture of sampling times and low numbers of subjects may have influenced these findings.
Conflicting reports have been published on the changes in IGFBP-3 during pregnancy. We found decreasing levels of IGFBP-3 measured by Western immunoblotting, as did others.20,25,26 Differences have been found between diabetic and healthy subjects in IGFBP-3 measured by Western ligand blotting, but not in IG-FBP-3 measured by radioimmunoassay.27 However, molecular sizes of IGFBP-3 proteolytic fragments and the inhibition profile of IGFBP-3 proteases were similar in insulin-dependent diabetes mellitus and in pregnancy sera.14 Early in multiple pregnancy, levels of IGFBP-3 and IGFBP-3 protease activity in maternal serum were increased.11 Later in pregnancy, maternal levels of IGFBP-3 were similar to those found in pregnancies with normal, SGA, and multiple fetuses. However, no differences were seen in IGFBP-3 proteolysis in the sera of the fetuses themselves, even in those with FGR. This is in contrast to the maternal situation.11
No differences in glycemic regulation and insulin regimen were found throughout pregnancy. Women in White class R initially had elevated glycosylated hemoglobin levels, which, in nonpregnant diabetic subjects, are associated with increased IGFBP-3 proteolysis and decreased intact IGFBP-3.14,28 However, we failed to confirm such an association. As for the role of IGF in glycoregulation, only one severe incidence of hypoglycemia was observed during pregnancy, in a woman delivering a neonate with a birth-weight ratio of 1.8. Further, it seems unlikely that IGFBP-3 proteolysis was due to differences in age or BMI because the groups were similar in these aspects.
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Footnotes |
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Received August 23, 2000. Received in revised form November 28, 2000. Accepted December 15, 2000.
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2. Gibson JM, Westwood M, Lauszus FF, Klebe JG, Flyvbjerg A, White A. Phosphorylated insulin-like growth factor-binding protein 1 is increased in pregnant diabetic subjects. Diabetes 1999;48: 321–6.[Abstract]
3. Baxter RC. IGFBPs: The role of serum IGFBPs in regulating IGF availability. Acta Pediatr Scand 1991;372:107–14.
4. Hill WC, Pelle-Day G, Kitzmiller JL, Spencer EM. IGFs in fetal macrosomia with and without maternal diabetes. Horm Res 1989; 32:178–82.[Medline]
5. Iwashita M, Kobayashi M, Matsuo A, Nakayama S, Mimuro T, Takeda Y, et al. Feto-maternal interaction of IGF-I and its binding proteins in fetal growth. Early Hum Dev 1992;29:187–91.[Medline]
6. Wang HS, Chard T. The role of IGF-I and IGFBP-1 in the control of human fetal growth. J Endocrinol 1992;132:11–9.[Medline]
7. Lassarre C, Binoux M. IGFBP-3 is functionally altered in pregnancy plasma. Endocrinology 1994;134:1254–62.[Abstract]
8. Suikkari A, Baxter RC. Insulin-like growth factor binding protein-3 is functionally normal in pregnancy serum. J Clin Endocrinol Metab 1992;74:177–83.[Abstract]
9. Lassarre M, Lalou C, Perin L, Binoux M. Protease-induced alteration of IGFBP-3 as detected by radioimmunoassay. Agreement with ligand blotting data. Growth Regul 1994;4:48–55.[Medline]
10. Blat C, Villaudy J, Binoux M. In vivo proteolysis of serum IGFBP-3 results in increased availability of IGF to target cells. J Clin Invest 1994;93:2286–90.
11. Langford KS, Nicolaides KH, Jones J, Abbas A, McGregor AM, Miell JP. Serum IGFBP-3 levels and IGFBP-3 protease activity in normal, abnormal, and multiple pregnancy. J Clin Endocrinol Metab 1995;80:21–7.[Abstract]
12. Caufriez A, Frankenne F, Hennen G, Copinschi G. Regulation of maternal IGF-I by placental growth hormone in pregnancy. Possible action of maternal IGF-I on fetal growth. Horm Res 1994;42: 62–5.[Medline]
13. Holmes RP, Holly JM, Soothill PW. A prospective study of maternal serum insulin-like growth factor I in pregnancies with appropriately grown or growth restricted fetuses. Br J Obstet Gynaecol 1998;105:1273–8.[Medline]
14. Bereket A, Lang CH, Blethen SL, Fan J, Frost RA, Wilson TA. Effect of insulin on IGF system in children with new onset IDDM. J Clin Endocrinol Metab 1990;80:1312–7.
15. Simmons D. Interrelation between umbilical cord serum sex hormones, sex hormone-binding globulin, IGF-I, and insulin in neonates from normal pregnancies and pregnancies complicated by diabetes. J Clin Endocrinol Metab 1995;80:2217–21.[Abstract]
16. Pedersen J. The pregnant diabetic and her newborn. 2nd ed. Copenhagen: Munksgaard, 1977:211–21.
17. Delmis J, Drazancic A, Ivanisevic M, Suchanek E. Glucose, insulin, hGH, and IGF-I levels in maternal serum, amniotic fluid and umbilical serum: A comparison between late normal pregnancy and pregnancies complicated with diabetes and fetal growth retardation. J Perinat Med 1992;20:47–56.[Medline]
18. Reece EA, Wiznitzer A, Le E, Homko CJ, Behrmann H, Spencer EM. The relation between human fetal growth and fetal blood levels of IGF-I and -II, their binding proteins, and receptors. Obstet Gynecol 1994;84:88–95.
19. Frystyk J, Dinesen B, Ørskov H. Non-competitive time-resolved immunofluorometric assays for determination of human IGF-I and -II. Growth Regul 1995;5:169–76.[Medline]
20. Hossenlopp P, Segovia B, Lassarre C, Roghani M, Bredon M, Binoux M. Evidence of enzymatic degradation of insulin-like growth factor-binding proteins in the 150K complex during pregnancy. J Clin Endocrinol Metab 1990;71:797–805.[Abstract]
21. Flyvbjerg A, Kessler U, Dorka B, Funk B, Ørskov H, Kiess W. Transient increase in renal insulin-like growth factor binding proteins during initial kidney hypertrophy in experimental diabetes in rats. Diabetologia 1992;25:589–93.
22. Kubota T, Kamada S, Taguchi M, Aso T. Determination of IGF-II in feto-maternal circulation during human pregnancy. Acta Endocrinol (Copenh) 1992;127:359–65.[Medline]
23. Binoux M, Lalou C, Lassarre C, Segovia B. Regulation of IGF bioavailability by IGFBP proteases. In: Baxter ED, Gluckmann PD, Rosenfeld RD, eds. The IGFs and their regulatory proteins. Amsterdam: Elsevier Science BV, 1994:217–26.
24. Hughes SCC, Wass JAH, Holly JMP. Two site-specific radioimmunoassays which demonstrate the presence of proteolytically modified IGFBP-3 in the circulation. J Endocrinol 1993;137:321–8.[Abstract]
25. Guidice LC, Farrell EM, Pham H, Lamson G, Rosenfeld RG. Insulin-like growth factor binding proteins in maternal serum throughout gestation and in the puerperium: Effects of a pregnancy-associated serum protease activity. J Clin Endocrinol Metab 1990;71:806–16.[Abstract]
26. Wang HS, Chard T. Chromatographic characterization of insulin-like growth factor binding proteins in human pregnancy serum. J Endocrinol 1992;133:149–59.[Abstract]
27. Bang P, Brismar K, Rosenfeld RG. Increased proteolysis of insulin-like growth factor binding protein 3 (IGFBP-3) in noninsulin-dependent diabetes mellitus serum, with elevation of a 29 kilodalton (kDa) glycosylated IGFBP-3 fragment contained in the approximately 130- to 150-kDa ternary complex. J Clin Endocrinol Metab 1994;78:1119–27.[Abstract]
28. Bereket A, Lang CH, Blethen SL, Fan J, Frost RA, Wilson TA. IGFBP-3 proteolysis in children with IDDM: A possible role for insulin in the regulation of IGFBP-3 proteases activity. J Clin Endocrinol Metab 1995;80:2282–8.[Abstract]
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