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Keywords:

  • fetal growth retardation;
  • IGF-I and IGFBP-1 levels;
  • insulin;
  • preterm birth;
  • serum lipids;
  • women

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

Objective.  Impaired fetal development may contribute to decreased insulin sensitivity. This study was designed to characterize serum markers of insulin resistance in adults born small for date or born prematurely.

Study design.  Fifty subjects, all women, were evaluated at a mean age ± SD of 26 ± 2 years (range: 23–30 years). They were allocated to three groups: (i) born fullterm with birth weight <2600 g (n = 18) (small for gestational age, SGA), (ii) born before gestational week 32 (n = 15) (ex-preterm), and (iii) controls, born fullterm with appropriate birth weight (n = 17). Anthropometric data as well as fasting serum samples of plasma B-glucose, serum lipids, insulin, insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1) levels were determined.

Results.  In the SGA group final height was lower and they weighed less compared with the controls. Fasting insulin and glucose levels did not differ amongst the groups. Triglycerides were lower in the SGA group and in the ex-preterm group compared with the controls (P < 0.05). The SGA group showed lower IGFBP-1 levels compared with the controls median 17 (range 3–121) vs. 26 (7–67) μg L−1; P < 0.05]. The IGF-I levels in the SGA, ex-preterm and control groups were 212 ± 58, 259 ± 37 and 216 ± 32 μg L−1, respectively, corresponding to a mean SD score of −0.8 ± 1.0, 0.1 ± 0.6 and −0.6 ± 0.6.

Conclusion.  As IGFBP-1 is a marker of insulin sensitivity, the low levels observed in adult women with normal BMI, born small for date, suggest relative insulin resistance in spite of normal BMI.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

During the last decade, several studies have shown an association between low birth weight and an increased risk for cardiovascular disease, including higher blood pressure, in adult life[1, 2]. Low birth weight has also been associated with metabolic changes [3] in adult subjects. In an animal model, intrauterine growth retardation gives rise to to the development of type 2 diabetes [4]. Humans born small for gestational age (SGA) seem to have an increased risk of developing insulin resistance [5], fasting hyperinsulinaemia and type 2 diabetes mellitus [3] in adulthood. Hyperinsulinaemia and insulin resistance are thought to be major factors in the pathogenesis of cardiovascular disease [6].

Preterm infants experience a stressed life postpartum which may affect their nutritional balance and postnatal growth in a different way than that provided by a normal intrauterine environment. In adulthood, women born preterm seem to have an impaired blood pressure control and a tendency to hypertension [7]. Studies on adult individuals born with low birth weight have shown that the highest rates of deaths from coronary heart disease occurred in those born preterm [8, 9]. Whether prematurity may predispose to alterations in insulin sensitivity in adulthood is yet unknown.

Insulin-like growth factor-I (IGF-I) stimulates glucose uptake and is of importance for growth. During fetal life, IGF-I production is not growth hormone (GH) dependent but dependent on nutrition, genetic factors and the availability of glucose across the placenta [10]. After delivery the IGF-I production is dependent on GH, insulin and nutrition [11]. Low IGF-I has been associated with relative insulin resistance and an increased risk for type-2 diabetes [12]. The majority of IGF-I circulates in blood bound to a family of proteins (IGFBPs) of which six are known and characterized [13]. Insulin-like growth factor binding protein-1 (IGFBP-1) displays a diurnal variation due to food intake, with the highest levels during night and early morning [14]. IGFBP-1 is insulin regulated [15] and one of its postulated roles is thought to be a direct regulator of bioavailable IGF-I, as well as the small free fraction of IGF-I, both as a transporting protein from the circulation to the target organ and as an inhibitor, binding with high affinity the IGFs and preventing their activation of receptor signalling [15, 16]. Thereby IGFBP-1 can affect IGF-I bioactivity. Fasting serum IGFBP-1 concentrations are inversely correlated with fasting insulin levels and diurnal mean insulin levels [17] and thus a good marker of insulin secretion. IGFBP-1 correlates with insulin sensitivity in non-diabetics [18] and therefore it can be used as a marker for insulin resistance.

The aim of this study was to characterize serum markers of insulin resistance, such as IGF-I, IGFBP-1 and insulin levels in adults born small for date or born prematurely.

Selection of participants

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

Fifty women aged between 23 and 30 years (mean 26 ± 2 years) were included in the present study. They were allocated to three groups: (i) born fullterm (between gestational week 37 and 42) with birth weights <2600 g (n = 18), (SGA), (ii) born before gestational week 32 (n = 15) (ex-preterm) and (iii) controls, born fullterm with appropriate birth weight for gestational age (n = 17). None of the participants suffered from chronic diseases. Twenty-five per cent of the SGAs, 40% of the ex-preterm and 50% of the controls used contraceptives (tablets containing <50 μg ethinyleostradiol per tablet).

Modes of selection

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

During 1966–67, 54 women agreed to take part in a study because they had given birth to a low weight child at Sabbatsbergs Hospital, Stockholm. Thirty-two women in the study had female babies, and the protocols of 19 women were traceable. From the neonatal records, 10 of these now adult infants fulfilled the criteria for the study and were contacted, seven of these individuals agreed to participate. From the National Medical Birth Register a total of 20 female infants, born between 1973 and 1974 in the Stockholm area, were randomly selected and contacted by letters. Eleven agreed to participate in the study. Thus, 18 SGA subjects were included.

Between 1970 and 1973, a majority of the preterm individuals, born in Stockholm, Sweden, were treated at the St Goran Children's Hospital. Nineteen girls were born before 32 gestational weeks, according to neonatal clinical records, were traceable and had survived to adult age. Of these, 12 women accepted to participate in the present study. In addition, during 1973–74, 11 women were born in the Stockholm area, with a gestational age <30 weeks, and had survived to adult age according to the National Medical Birth Register. Nine of them could be traced and contacted and four accepted to participate in the study, although one of them was later excluded due to Down's syndrome. Thus, 15 ex-preterm individuals were included.

Eleven control age-matched women born fullterm with appropriate birth weight in the Stockholm area were randomly selected from the National Medical Birth Register. Of these, three were born on the same day and in the same hospital as subjects in the other two groups. Furthermore four were healthy volunteers and two came from neonatal records taken on the same day and in the same hospital as subjects in the other two groups. Thus, 17 controls were included.

Gestational age and the birth weight data were obtained from medical records. There were no significant differences amongst the three groups in adulthood with regard to smoking (approximately 30% of the subjects in each group were smokers) or alcohol habits. The heredity for type 2 diabetes was approximately the same in the three groups: four of 18 in the SGAs, three of 15 in the preterms and four of 17 in the controls.

Present clinical history was evaluated and investigated by a doctor (AK). The adult height of all the subjects was measured using the same wall-mounted stadiometer. Weight was measured on the same portable scale to the nearest 0.1 kg and weight for height was assessed as body mass index (BMI) [weight(kg)/(height)2(m)] and birthweight for birthlength as ponderal index [birthweight (kg)/(birthlength)3 (m)].

Methods

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

Blood samples were drawn in the morning after an overnight fast. HDL cholesterol was analysed by the N-genous HDL cholesterol method from BIOmed, Sweden. Totel cholesterol and triglycerides were analysed by Vitros (dry chemistry) from Ortho Clinical Diagnostics, Johnson & Johnson, USA. Insulin was determined by a radioimmunoassay (RIA) using guinea-pig antiserum and charcoal addition was used to separate bound and free insulin [19]. IGF-I determinations were made in an assay separating the IGFBPs by acid-ethanol extraction and cryoprecipitation followed by a RIA using des-(1–3) IGF-I as ligand in order to reduce the binding to remaining IGFBPs [20]. As IGF-I decreases with age, IGF-I SD score was calculated according to the equation for the IGF-I SD score [21], deduced from the linear regression line of the serum IGF-I concentration versus age: SD score = 10log (IGF-I level (μg L−1) + 0.00693 × age (years) − 2.581)/0.120. The intra-and inter-assay variation for the IGF-I RIA was 4 and 11%, respectively. IGFBP-1 was determined by RIA developed and described by Póvoa et al. [22]. The inter- and intra-assay variation for the IGFBP-1 RIA was 3 and 10%.

Statistical analysis

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

The results are presented as mean ± SD, median and range. For statistical comparisons, analysis of variance (anova), Student's t-test, the non-parametric Mann–Whitney U-test for unpaired comparisons and regression analysis were used. Student's t-test and the Mann–Whitney U-test were used to compare the result of the SGA group and the ex-preterm group, respectively, with the controls. A P-value <0.05 was considered significant.

Results

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

Clinical characteristics including mean height, weight and BMI as adults are shown in Table 1. The adult SGA group was significantly shorter (P < 0.001) and thinner (P < 0.01) than the adult controls and the ex-preterm group (P < 0.05). No differences in BMI were seen amongst the three groups.

Table 1.  Weight, height and BMI at birth and at follow-up (mean ± SD)
 Small for gestational age (n = 18)Ex-preterm (n = 15)Controls (n = 17)P*
  1. *Analysis of variance; aP < 0.01 vs. controls; bP < 0.05 vs. SGA; cP < 0.001 vs. controls; dP < 0.01 vs. SGA.

Birth weight (g)2175 ± 2781293 ± 2833720 ± 313<0.001
 Height (cm)45.5 ± 1.939.5 ± 2.151.0 ± 1.8<0.001
 Ponderal index (kg m−3)23.0 ± 2.420.8 ± 2.828.1 ± 2.0<0.001
 Gestational age 40 (38–42) 30 (28–32) 41 (39–42)<0.001
Adult weight (kg)57.1 ± 9.2a63.9 ± 9.3b67.9 ± 9.2<0.01
 Height (cm)160.4 ± 5.8c165.3 ± 7.8b168.5 ± 5.6<0.01
 BMI (kg m−2)22.2 ± 4.023.4 ± 2.923.9 ± 3.10.32
 Age 25 (24–29) 24 (23–26)d 25 (24–30) 

Metabolic analysis

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

Mean values of serum lipids are shown in Table 2 and those of glucose, median insulin, IGFBP-1, IGF-I and IGF-I SD score are shown in Table 3. The total cholesterol, HDL and LDL fractions were not significantly different amongst the three groups but triglycerides were lower in the SGAs as well as in the ex-preterm group compared with controls (P < 0.05) (Table 2). Fasting glucose and insulin levels were not different amongst the three groups. IGFBP-1 was lower in the SGA group compared with those born appropriate for gestational age (P < 0.05) (Table 3, Fig. 1). The ex-preterm group showed significantly higher IGF-I levels compared with the control group (P < 0.01) as well as a significantly higher IGF-I SD score compared with the controls (P < 0.05) (Table 3). Neither the IGF-I level nor the IGF-I SD score were significantly different in the SGA compared with the controls (Table 3). Two individuals in the SGA group had an IGF-I SD score lower than −2 SD. In the preterms and in the controls, all subjects had an IGF-I SD score within the normal range (±2 SD). In the control group ponderal index was significantly correlated with IGFBP-1 (r = 0.51, P = 0.04). There was an inverse correlation between final height and IGFBP-1 (r = −0.59, P = 0.01) in the controls but not in the SGA or the ex-preterm groups. In the SGA group no correlations were found amongst ponderal index, adult height, insulin or IGFBP-1.

Table 2.  Concentration of serum lipids at follow-up (mean ± SD)
 Controls (n = 17)Small for gestational age (n = 18)P*Ex-preterm (n = 15)P*
  1. *Student's t-test.

Cholesterol (mmol L−1)4.7 ± 0.94.5 ± 0.70.634.5 ± 0.70.61
 HDL (mmol L−1)1.4 ± 0.31.3 ± 0.30.651.4 ± 0.20.85
 LDL (mmol L−1)2.7 ± 0.72.8 ± 0.60.682.7 ± 0.80.94
 LDL/HDL2.0 ± 0.72.2 ± 0.90.312.0 ± 0.80.98
Triglycerides (mmol L−1)1.3 ± 0.50.9 ± 0.30.0221.0 ± 0.30.047
Table 3.  Concentrations of serum glucose, insulin, IGF-I, IGFBP-1 and leptin [mean ± SD or median (range)]
 Controls (n = 17)Small for gestational age (n = 18)P*Ex-preterm (n = 15)P*
  1. *Mann–Whitney U-test; **Student's t-test.

Glucose (mmol L−1)4.3 ± 0.14.3 ± 0.10.99**4.3 ± 0.10.66**
Insulin (mU L−1)  16 (9–27)  12 (6–30)0.25  14 (8–28)0.54
IGFBP-1 (μg L−1)  26 (7–67)  17 (3–121)0.047  22 (7–52)0.26
IGF-I (μg L−1) 215 (150–303) 212 (120–364)0.78 259 (209–329)0.002
IGF-I SD score−0.61 (−1.93 to 1.81)−0.76 (−2.57 to 1.51)0.550.018 (−0.79 to 0.85)0.019
image

Figure 1. IGFBP-1 concentrations in individuals born small for gestational age (n = 18), ex-preterms (n = 15) and controls (n = 17).

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

In the present study we found a lower IGFBP-1 level in the adult women born SGA compared with controls born fullterm, which may implicate that they are high insulin responders to hyperglycaemia [17]. IGFBP-1 is mainly regulated by insulin at the transcriptional level and can be used as a marker of insulin secretion and a measure of insulin resistance [17]. Fasting IGFBP-1 levels are inversely correlated with insulin secretion and the insulin response to oral glucose tolerance or hyperinsulinaemia [13]. Counter regulatory stress hormones, glucagons, cortisol, adrenaline and GH increase the IGFBP-1 production [23, 24]. However, the IGFBP-1 response is inversely related to the insulin response, i.e. the higher insulin response, the lower increase in IGFBP-1 during stress [25]. The findings in the present study suggest that low levels of IGFBP-1 are related to higher diurnal insulin secretion. As the subjects have normal glucose levels, it also suggests relative insulin resistance. Babies born small for date have lower levels of IGF-I and higher levels of IGFBP-1 than normal infants at birth [26]. One might speculate that a compensatory increase in insulin is mediated through an increased GH secretion, stimulated by the low bioavailability of IGF-I. Hyperinsulinaemia should lead to an increase in body weight, although not in conditions with insulin resistance in adipose tissue, which further suggests insulin resistance in our SGA subjects.

In the control group we found a correlation between ponderal index and fasting IGFBP-1 and a negative correlation between IGFBP-1 and final height. These results suggest that a low ponderal index in ‘normal’ healthy newborns also results in low IGFBP-1 in adulthood. Thus, an adequate nutrition in fetal life and an uncomplicated pregnancy may result in a higher IGFBP-1 in adulthood. The inverse correlation between final height and IGFBP-1 (shorter individuals have a higher IGFBP-1) has been shown earlier [27].

In the SGA group no correlations were found between ponderal index, adult height or IGFBP-1, which might suggest an abnormal regulation of the IGF/IGFBP-1 system in these subjects. A subgroup of adult men with borderline hypertension (30%) exhibited insulin resistance with low levels of IGF-I and IGFBP-1, similar to our SGAs [28]. Low IGFBP-1 levels were significantly associated with impaired glucose tolerance in a study of adult subjects of European and Pakistani origin [29]. In middle-aged subjects, low IGF-I levels increase the risk of developing an impaired glucose tolerance or type-2 diabetes [12]. Subjects with low IGFBP-1 levels and low IGF-I levels were those at highest risk [12]. As the SGA in our study exhibited low levels of IGFBP-1 and possible reduced IGF-I secretion they may also have an increased risk to develop an impaired glucose tolerance.

Despite the lack of correlation between IGFBP-1 and insulin the lower IGFBP-1 levels found in the SGAs may suggest a decreased insulin sensitivity. In a study of obese prepubertal children, it was concluded that the serum level of IGFBP-1 may be an early predictor of insulin resistance in these children [30]. They exhibited lower IGFBP-1 levels compared with controls, and no correlation was found between insulin and IGFBP-1 levels. These findings are in accordance with the present study, although the SGAs are adult and not obese. Fasting insulin does not necessarily represent the diurnal daytime insulin secretion. In obese type-2 diabetics we have previously not found this correlation [31]. An increase in insulin suppresses IGFBP-1 expression in the liver [14], which in turn lowers the serum concentration of IGFBP-1 and increases IGF-I bioactivity. The low IGFBP-1 could thus be a compensatory mechanism to increase available IGF-I. It has been speculated that lower IGFBP-1 levels play a pathogenetic role in the development of obesity by increasing the levels of free IGF-I, which in turn could suppress GH secretion and contribute to a reduced lipolysis in adipose tissue [32].

The contraceptive pills used were containing <50 μg ethinyleostradiol per tablet, which affects glucose homeostasis and it therefore seems unlikely that they could explain the differences in IGFBP-1 levels between SGAs and controls.

Women born small for date (SGA) had normal BMI but lower weight and a reduced final height compared with controls. Cholesterol levels did not differ, but triglyceride levels were lower compared with controls (P = 0.02). Higher insulin and/or lower GH-secretion may explain these findings.

A reduced mean final height in subjects born fullterm but SGA have been observed in several other studies [33, 34]. Reduced final height could be attributed to several causes, i.e. malnutrition and early placental dysfunction, which may lead to low IGF-I bioactivity [35]. However, short children born small for date seem to exhibit increased levels of IGF-I [36], and it has therefore been proposed that they may have or develop a decreased sensitivity to IGF-I. Indeed experimental studies in sheep have documented an altered IGF-I sensitivity in growth-retarded foetuses [37]. These factors may contribute to the reduced final height. This could explain the normal IGF-I level in spite of reduced final height in our SGA subjects.

The ex-preterm subjects had lower triglyceride levels and higher IGF-I levels and IGF-I SD scores compared with the controls, otherwise they did not differ from the controls. At birth, babies born prematurely have lower levels of IGF-I and higher levels of IGFBP-1 than infants born at term [38]. But during the first year of life the IGF-I level increased in infants born prematurely compared with full-term born subjects [39]. The IGF-I level can therefore be increased to stimulate faster growth and catch-up in these subjects. We have earlier shown that the present ex-preterms also exhibited a higher blood pressure compared with the control group [7]. Thus, a higher total IGF-I level may be associated with an increased risk of developing high blood pressure [28].

In summary, in the controls born fullterm ponderal index may predict adult IGFBP-1. The SGAs were shorter, with a lower weight compared with controls. They exhibited a lower IGFBP-1 level with an impaired correlation to insulin. These findings suggest that adult SGA subjects are high-insulin responders to carbohydrates with early signs of insulin resistance.

Acknowledgements

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References

This work was supported by the Martin Rind Foundation, the Samariten Foundation, the Swedish Medical Research Council 02442 and the Swedish Medical Society.

We sincerely want to thank Ella Wallerman for skilful laboratory work and Agneta Hilding for valuable discussions regarding statistical analyses.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Material and methods
  5. Selection of participants
  6. Modes of selection
  7. Methods
  8. Statistical analysis
  9. Results
  10. Metabolic analysis
  11. Discussion
  12. Conflict of interest statement
  13. Acknowledgements
  14. References
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