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Institute of Maternal and Child Research (IDIMI) (N.S., R.A.B., V.P., T.S., A.A., G.I., M.V.M.), Faculty of Medicine, University of Chile, Casilla 226-3, Santiago, Chile; and Department of Paediatrics (K.K.O., D.B.D.), University of Cambridge, United Kingdom
Address all correspondence and requests for reprints to: M. Verónica Mericq, M.D., IDIMI, University of Chile, Casilla 226-3, Santiago, Chile, E-mail: vmericq{at}machi.med.uchile.cl.
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Abstract |
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At 1 yr, SGA infants had a clear tendency to higher triglycerides. Fasting insulin was significantly higher in SGA infants with WCUG, compared with those who did not catch up and AGA infants (mean ± SEM, 32.6 ± 4.6 vs. 14.9 ± 2.3 vs. 21.4 ± 3.3 pM, respectively; P < 0.05). Length increment (in SD score) was the principal determinant of postload insulin secretion (R2 = 0.1, P < 0.01).
We conclude that insulin secretion and sensitivity are closely linked to patterns of rapid WCUG and LCUG during early postnatal life. Fasting insulin sensitivity is more related to WCUG and current body mass index, whereas insulin secretion seems to be directly related to LCUG.
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Introduction |
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One common feature of these disease associations is the presence of high insulin levels, which are thought to play a pathogenic role. Barker postulated that the postnatal decrease in insulin sensitivity may result from the fetal adaptation to an adverse intrauterine environment during a critical period, leading to a long-lasting programming of fetal gene expression (3). A cornerstone of the Barker hypothesis is the idea of a critical window, as launched by McCance and Widdowson (14) in the early sixties. They showed that early undernutrition had a permanent effect on the subsequent growth of rats, whereas later undernutrition had only a transient effect (14). It is common that critical windows coincide with periods of rapid growth. This principle seems to be also applicable to humans, whose most dynamic growth occurs in utero and during early infancy; both periods might be key to long-term metabolic modifications (15). During the first 2 yr of life, SGA infants are usually able to catch up their normal counterparts by means of a faster rate of weight and/or length gain, thus crossing growth chart centiles (16). The extent of this catch-up growth (CUG) not only contributes to adult size and body proportions but has also been linked to changes in insulin sensitivity (12, 17). Nonetheless, the relative contribution of low birth weight and accelerated postnatal growth, to the development of insulin resistance, is not known.
To study early changes in insulin sensitivity and secretion associated with birth weight and postnatal growth, we assessed infants born SGA, at 48 h of life and at age 1 yr, comparing insulin sensitivity and insulin secretion to those observed in control infants born appropriate for gestational age (AGA).
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Subjects and Methods |
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All infants had a gestational age between 37 and 41 wk and underwent, during their second day of life, a clinical evaluation to exclude those with significant medical, neurological, or genetic conditions. Infants were also excluded if they were on unusual diets or were taking any medication that could interfere with growth or appetite. A complete record with parental, pregnancy, and perinatal information was filled at entry.
All infants were exclusively breast fed for a mean of 3.7 months (range, 0–8 months). This was not different in relation to birthweight or CUG categories. Thereafter, they received standard formula and solid meals as recommended by the American Academy of Pediatrics (19).
The study protocol was approved by the San Borja Arriarán Hospital Institutional Review Board. Parents or guardians gave written informed consent at recruitment.
Measurements
All children were measured at birth and at 1 yr of age. Height and weight were measured by one nurse (A. Avila). Supine length was measured with a wooden box consisting of a fixed board for the infant’s head and a movable board allowing feet to be placed perpendicular to the longitudinal axis of the infant. Weight was measured using a manual scale with a 10-g graduation (Seca, QuickMedical, Snoqualme, WA).
At 48 h after birth, a prefeeding 3-ml venous blood sample was obtained for determination of glucose and insulin, as previously reported for a larger group of newborns (20).
At 1 yr of age, a short iv glucose tolerance test (sIVGTT) was performed after an overnight fast (mean duration of fast, 9 h). Two venous accesses were established in contralateral antecubital veins. Glucose (25% dextrose solution) was administered at a 0.5-g/kg (maximum, 35 g) dose by continuous infusion over 3 min. Blood samples were obtained at -5, 0, 1, 3, 5, and 10 min for determination of glucose and insulin levels. Glucose was measured immediately, whereas samples for insulin were kept on ice, centrifuged within 30 min, and sera frozen at -20 C. In the -5-min sample, C-peptide, leptin, sex hormone-binding globulin (SHBG), free fatty acids (FFA), ß-hydroxybutyrate (ßOH-B), IGF-binding protein-1 (IGFBP-1), and cortisol levels were also determined.
Assays
Blood glucose concentration was determined using a commercial glucometer (Accutrend Sensor Comfort, Roche Diagnostic, Inc., Basel, Switzerland), which yields values 8 ± 5% (mean ± SD) higher than standard enzymatic methods, with a correlation coefficient of 0.987 for glycemias between 2.2 and 8 mM.
Serum insulin was measured using a commercial RIA from Diagnostic Systems Laboratories, Inc. (Webster, TX). This assay has a cross-reactivity of 27.5% with proinsulin and 25% with insulin 32,33. The sensitivity of this assay is 5.6 pM.
Serum cortisol and C-peptide were also determined by RIA, using kits supplied by Diagnostic Product Corp. (Los Angeles, CA). Serum leptin, IGFBP-1, and SHBG were measured by immunoradiometric assays from Diagnostic Systems Laboratories, Inc. Intraassay coefficients of variation (CVs) are: 3.8% for insulin, 4.1% for C-peptide, 4.5% for cortisol, 4.6% for leptin, 3.5% for IGFBP-1, and 3.1% for SHBG. Interassay CVs are: 4.7% for insulin, 5.6% for C-peptide, 5.9% for cortisol, 6.2% for leptin, 4.2% for IGFBP-1, and 5.4% for SHBG.
FFA were determined using a kit from Wako Chemicals GmbH (Neus, Germany). This assay is based on the sterification of FFA into acyl-coenzyme A, followed by its enzymatic oxidation. This latter reaction yields hydrogen peroxide, which is then colorimetrically quantified. ßOH-B was measured using a kit from Sigma (St. Louis, MO). This measurement relies on the enzymatic oxidation of ßOH-B into acetoacetate in the presence of nicotinamide adenine dinucleotide. The resulting reduced nicotinamide adenine dinucleotide is then espectrophotometrically detected at 340-nm wavelength. Intraassay CVs are: 1.7% for FFA and 3.7% for ßOH-B. Interassay CVs are: 7.2% for FFA and 10.3% for ßOH-B.
Calculations and analysis
Weights and lengths, at birth and at 1-yr, were converted into SD scores to adjust for age and sex, using the National Center for Health Statistics growth curves, which have been found to be applicable to the Chilean population (21). Midparental height was calculated and similarly converted to a SD score.
We stratified SGA infants according to CUG, using criteria indicating clinically significant centile crossing as previously described (22). Weight CUG (WCUG) was defined as a weight gain, between zero and 1 yr, greater than 0.67 SDS, which represents the width of each percentile band in standard growth charts. CUG in height was defined as an increment greater than 0.67 SDS in height [length CUG (LCUG)] during the same period.
Adiposity at 1 yr of age was estimated using body mass index (BMI). Using weight in kilograms and length in meters, Benn index (weight/[length]P) (23) was also calculated for each infant, using the AGA group as a reference for calculating the P value. For simplicity, and because results were indistinguishable when using either BMI or Benn index, BMI values are shown.
Insulin sensitivity was estimated using basal insulin levels, which have been shown to be useful in nondiabetic children (24). Because fasting glucose levels were very similar in all groups, computing homeostasis model assessment of insulin sensitivity yielded no additional information. Insulin secretion during the sIVGTT is expressed either as area under the curve (AUC, calculated using the trapezoidal rule) or first-phase insulin release (FPIR, sum of insulin levels at 1 and 3 min, minus basal insulin) (25).
Statistical analysis
Results are expressed as mean ± SEM. Differences between groups were assessed by nonparametric tests (Mann-Whitney U or Kruskall Wallis) for variables displaying nonnormal distribution (fasting insulin, FPIR, AUC insulin, C-peptide, triglycerides). When variables showed normal distribution, ANOVA was used. In addition, analysis of covariance models were developed to estimate the contribution of different anthropometric parameters on insulin sensitivity and secretion. Special care was taken to avoid including colinear variables in the same model. All statistics were run on SPSS 10.0 for Windows (SPSS, Inc., Chicago, IL).
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Results |
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SGA infants, compared with AGA infants, were significantly lighter and shorter at birth. Head circumferences were also significantly smaller in SGA vs. AGA newborns (Table 1
). Parental heights were not different between SGA vs. AGA infants (maternal height, -1.4 ± 0.1 SDS vs. -1.1 ± 0.3 SDS, P = 0.227; paternal height, -1.3 ± 0.2 SDS vs. -1.3 ± 0.2 SDS, P = 0.820) (Table 1).
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One year of life
At 1 yr, differences in weight and length SD score (SDS) between SGA and AGA infants persisted but were less pronounced (Table 1
). Weight for length SDS were still lower in SGA infants, compared with AGA infants (-0.2 ± 0.1 SDS vs. 0.9 ± 0.3 SDS, P < 0.01); and the BMI showed the same trend (Table 1).
There were no differences between SGA and AGA regarding fasting glucose, fasting insulin levels, C-peptide, AUC insulin, and FPIR. (Table 1, Fig. 1). SGA infants displayed a tendency to higher triglyceride levels (111.9 ± 6.8 mg/dl vs. 88.7 ± 10.2 mg/dl, P = 0.053) despite their lower weight, BMI, and leptin (0.29 ± 0.19 nM vs. 0.40 ± 0.07 nM, P < 0.05), compared with AGA infants (Table 1). No differences in SHBG, IGFBP-1, cortisol, cholesterol, ßOH-B, and FFA levels were found in SGA vs. AGA infants (data not shown).
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According to our arbitrary criteria of CUG, 62 (73%) SGA infants showed WCUG, and 44 (52%) displayed LCUG. Twenty-four (28%) SGA infants showed WCUG but no LCUG, whereas 5 (6%) presented with LCUG but no WCUG.
Data stratified by WCUG
At birth, infants showing WCUG were thinner than those who did not (Table 2). At 1 yr, weight SDS and BMI were higher in this group, compared with SGA with no WCUG, but still lower than AGA infants (Table 2).
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), even after adjusting for BMI and sex. There were no differences in insulin AUC, FPIR (Table 2, Fig. 1), IGFBP-1, SHBG, cortisol, cholesterol, and triglycerides (not shown) among the three groups. Data stratified by LCUG
At birth, SGA infants showing LCUG were slightly lighter and shorter than SGA infants, who did not catch up in length. At 1 yr, weight SDS and BMI were similar in the two SGA subgroups but were still lower than in AGA infants (Table 3). By definition, SGA infants with LCUG were significantly taller than those without LCUG but were shorter than AGA infants (Table 3).
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, Fig. 1). There were no differences in basal C-peptide, IGFBP-1, SHBG, cortisol, cholesterol, and triglycerides (not shown) among the three groups. Effect of CUG on insulin sensitivity/secretion
Analysis of covariance was used to explore the effects of sex, birthweight (SDS), postnatal growth (either weight or length), and current body proportions (as assessed by BMI) on insulin secretion and sensitivity at age 1 yr. Length increment during the first year (in SDS) was the only independent determinant of postload insulin secretion (evaluated as either insulin AUC or FPIR) (R2 for model = 0.1, P < 0.01). The effect of weight increment during the first year (in SDS) was harder to ascertain, because it exhibits strong colinearity with birthweight. When controlling for sex and BMI, weight increment did not reach significance as an independent determinant of insulin secretion or sensitivity. The same was observed when SGA infants who did not catch-up in either weight or length were analyzed separately.
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Discussion |
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A possible limitation of our study is the method for assessment of insulin sensitivity. Few of the available methods have been validated in infants, because most of them are highly invasive. Fasting insulin levels are probably a useful approximation (24), because they only assume the existence of a closed-loop regulation of glucose and insulin levels, and this has been shown as early as the second day of extrauterine life (20). Forty-eight hours after birth, our SGA newborns had significantly lower serum insulin and C-peptide levels than AGA newborns (20). These findings, which we have previously reported in a larger cohort, indicate that SGA newborns may have increased insulin sensitivity, at least with respect to glucose, resembling conditions of prolonged fasting (20, 26). Interestingly, these modifications seem to be reversed at 1 yr of age. No differences in fasting insulin were evident at this time, but SGA infants had a tendency toward higher triglyceride levels than those of AGA infants, despite being still lighter, shorter, and thinner. Serum triglyceride levels are accepted as a good indicator of insulin resistance (27, 28); and therefore, this preliminary finding in our cohort may help identify those infants at risk of future metabolic derangements.
Recent data indicate that the development of insulin resistance may relate to an interaction between birth weight and postnatal growth rates (15, 22, 29). In our cohort, CUG was present in a significant number of SGA infants, as previously reported (16). According to our criteria (22), 74% of SGA infants displayed WCUG, and these infants had the highest fasting insulin levels at 1 yr, although they were not overweight. Recently, Veening et al. (17) demonstrated, in a group of 9-yr-old children, that WCUG is associated with a decrease in glucose consumption during an euglycemic hyperinsulinemic clamp. Taken together, available data suggest that insulin resistance may precede the development of obesity, because, in our cohort, SGA infants displaying CUG are less insulin sensitive than AGA infants, in spite of their lower weight and BMI. In our cohort, BMI values were highly correlated with leptin levels (not shown), which are also a good indicator of fat mass across all ages (30). However, BMI may not be sensitive enough to detect subtle or regional differences in fat mass.
Interestingly, insulin secretion, as assessed by AUC or FPIR, was more closely related to LCUG. This is in accordance with a previous work by Colle et al. (31), showing a direct correlation between longitudinal growth velocity and FPIR in 6-month-old infants. Insulin is an important growth factor during infancy, and improved secretion may lead to greater gains in length and higher IGF-I levels, as recently reported at 5 yr (34). On the other hand, height gain could reflect higher IGF-I generation, which may influence ß-cell mass, as recently demonstrated in adults (32).
In this study, we did not find any relationships between birth size, catch-up, and other potential markers of disease risk, such as cholesterol (12, 33) and cortisol. If present, such differences might appear at a later stage.
In summary, we have prospectively studied 85 SGA and 23 AGA newborns at 48 h and 12 months of age. SGA infants display a trend to higher triglycerides but similar IGFBP-1, SHBG, cortisol, leptin, cholesterol, FFA, and ßOH-B with respect to their AGA counterparts at age 1 yr. At the same age, SGA infants exhibiting WCUG had higher fasting insulin levels, and those displaying LCUG had a clear tendency to higher basal and stimulated insulin levels.
These data suggest that the pathophysiological mechanisms linking prenatal growth and postnatal sensitivity to insulin are present as early as age 1 yr. Fasting insulin sensitivity seems to be more related to WCUG and current BMI, whereas insulin secretion seems to be directly related to LCUG. We are currently following this cohort to determine whether these tendencies are maintained, reverted, or accentuated later in life.
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Footnotes |
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Abbreviations: AGA, Appropriate for gestational age; AUC, area under the curve; BMI, body mass index; CUG, catch-up growth; CV, coefficients of variation; FFA, free fatty acids; FPIR, first-phase insulin release; IGFBP, IGF-binding protein; LCUG, length CUG; ßOH-B, ß-hydroxybutyrate; SDS, SD score; SGA, small for gestational age; SHBG, sex hormone-binding globulin; sIVGTT, short iv glucose tolerance test; WCUG, weight CUG.
Received January 7, 2002.
Accepted April 10, 2003.
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