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* Institute for Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile
Neonatology Unit, Sótero del Río Hospital, Santiago, Chile
Neonatology Unit, San Borja-Arriarán Hospital, Santiago, Chile
|| Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods. We studied 136 small for gestational age (SGA) and 34 appropriate for gestational age (AGA) term neonates who were born in Santiago, Chile. Prefeeding venous blood was obtained 48 hours after birth for determination of glucose, free fatty acids, ß-hydroxy butyrate, insulin, C-peptide, leptin, sex hormone-binding globulin, insulin-like growth factor-binding protein-1 (IGFBP-1), and cortisol.
Results. SGA newborns had lower glucose (SGA versus AGA, median [interquartile range]: 3.6 mmol/L [2.9–4.1 mmol/L] vs 3.9 mmol/L [3.6–4.6 mmol/L]) and insulin levels (31.3 pmol/L [20.8–47.9 pmol/L] vs 62.5 pmol/L [53.5–154.9]) than AGA infants, and they had higher glucose/insulin ratios (13.9 mg/dL/uIU/mL [8.6–19.1 mg/dL/uIU/mL] vs 8.2 mg/dL/uIU/mL [4.6–14.1 mg/dL/uIU/mL]). SGA infants also had higher levels of IGFBP-1 (5.1 nmol/L [4.4–6.7 nmol/L] vs 2.9 nmol/l [1.4–4.2 nmol/L]), free fatty acids (0.72 mEq/L [0.43–1.00 mEq/L] vs 0.33 mEq/L [0.26–0.54 mEq/L]) and ß-hydroxy butyrate (0.41 mEq/L [0.15–0.91 mEq/L] vs 0.09 mEq/L [0.05–0.13 mEq/L]). Sex-hormone binding globulin levels were not significantly different between the 2 groups.
Conclusions. In early postnatal life, SGA infants display an increased insulin sensitivity with respect to glucose disposal but not with respect to suppression of lipolysis, ketogenesis, and hepatic production of IGFBP-1. It will be important to determine how these differential sensitivities to insulin vary with increasing age.
Key Words: Barker hypothesis • low birth weight • insulin sensitivity
Abbreviations: LBW, low birth weight • SGA, small for gestational age • AGA, appropriate for gestational age • SHBG, sex hormone-binding globulin • IGFBP-1, insulin-like growth factor-binding protein-1 • FFA, free fatty acid • RIA, radioimmunoassay • CV, coefficient of variation • bOH-B, ß-hydroxy-butyrate • G/I, glucose/insulin • HOMA, homeostasis model assessment • GH, growth hormone
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The pathophysiological determinants for these strong epidemiologic associations have proved hard to identify.4 It remains questionable whether a specific genetic background explains both LBW and adult disease.5 Alternatively, an "in utero programming" model has been proposed by Barker et al.1 According to these authors, an adverse intrauterine environment during a critical period of development induces a metabolic response for survival that persists into adulthood. The nature of this programming is not yet clear, but long-term, tissue-specific modifications of insulin sensitivity may be critical.1,6 Mechanisms involved in this process have also been elusive, but a role for elevated in utero plasma levels of glucocorticoids in growth-restricted fetuses has been proposed.7
A central prediction of Barker’s model is that the results of metabolic and endocrine programming should be present during early postnatal life and infancy. More precise, it can be expected that small for gestational age (SGA) newborns, when compared with their appropriate for gestational age (AGA) counterparts, should display differences in their sensitivity to insulin. However, assessment of insulin sensitivity in newborns is complicated by risks imposed by classical methodologies, which need multiple blood samples and the infusion of exogenous glucose and/or insulin.8 In addition, most of these methods have not been validated in children. Therefore, we are reliant on measures of fasting blood glucose, insulin, and C-peptide levels, complemented by other indirect measures of insulin sensitivity, such as plasma sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein-1 (IGFBP-1) levels.9–11 In addition, lipid metabolism, as evidenced by plasma levels of triglycerides, cholesterol, free fatty acids (FFAs), and ketone bodies, has been found to reflect insulin action in different conditions, including the newborn.12
Previous reports show significant differences regarding hormonal levels in SGA versus AGA newborns. Low cord blood levels of insulin, IGF-I, and leptin, as well as high IGFBP-1 values, have been consistently found in SGA neonates.11,13,14 However, a simultaneous and integral profile of the effects of LBW on insulin sensitivity and ß-cell function shortly after birth, in otherwise healthy infants, is still lacking.
To determine the metabolic and endocrine consequences of LBW during early postnatal life, we are prospectively studying a cohort of full-term SGA and AGA newborns from Santiago, Chile. In this report, we describe preliminary results from this cohort in the early neonatal period regarding whole-body intermediate metabolism.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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A total of 136 SGA newborns (46 boys and 90 girls) were recruited. The inclusion criteria for infants were born at term (gestational age >37 weeks), a birth weight below the fifth percentile for the Chilean population adjusted for gender and gestational age,15 and an uneventful delivery. Infants who showed malformations or evidence for genetic disorders were excluded. Thirty-four healthy, full-term AGA newborns (birth weight between percentiles 10 and 90; 19 boys and 15 girls) were also recruited as controls. All infants in both groups were breastfed, with similar frequencies ranging from 3 to 4 hours.
At recruitment, anthropometric data from parents, as well as pregnancy and delivery events were retrieved from clinical records. Data from newborns (gender, gestational age, birth weight, crown-heel length, and head circumference) were also recorded, and z scores for anthropometric parameters were calculated using local normative data.15
Forty-eight hours after birth (range: 40–48 hours), a 3-mL blood sample was obtained from newborns. Samples were withdrawn immediately before feeding, ie, in fasting conditions (range: 3- to 4-hour fasting). Blood was immediately centrifuged, and the serum was stored at -20°C until processing. Concomitantly, blood glucose concentration was determined using a commercial glucometer (Accutrend Sensor Comfort, Roche Diagnostics Inc, Basel, Switzerland), which yields values 8 ± 5% higher than standard enzymatic methods for glycemias between 2.2 and 5 mmol/l.
Laboratory Procedures
Serum insulin was measured using a commercial radioimmunoassay (RIA) from Immunotech (Marseille, France). Serum cortisol and C-peptide were also determined by RIA, using kits supplied by DPC (Los Angeles, CA). Serum leptin, IGFBP-1, and SHBG were measured by immunoradiometric assays from DSL (Webster, TX). Intra-assay coefficients of variation (CVs) were 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 were 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. Cross-reactivities for our insulin RIA were declared by the manufacturer as follows: 68% against des-64-65-proinsulin, 55% against proinsulin, and 50% against des-31-32-proinsulin.
FFAs were determined using a kit from Wako Chemicals (Neus, Germany). This assay is based on the esterification of FFA into acyl-co-enzyme A, followed by its enzymatic oxidation. This latter reaction yields hydrogen peroxide, which is then colorimetrically quantified. ß-Hydroxy-butyrate (bOH-B) was measured using a kit from Sigma (St Louis, MO). This measurement relies on the enzymatic oxidation of ß-HBA into acetoacetate in presence of nicotinamide-adenine dinucleotide. The resulting product is then spectrophotometrically detected at 340 nm wavelength. Intra-assay CVs were 1.7% for FFA and 3.7% for bOH-B. Interassay CVs were 7.2% for FFA and 10.3% for bOH-B.
Assessment of Insulin Sensitivity
None of the parameters used to assess insulin sensitivity in adults has been validated in neonates. Despite this, it seems reasonable that plasma glucose and insulin levels start regulating each other in a closed loop shortly after birth (see Results). Therefore, we calculated the plasma glucose/insulin (G/I) ratio, as well as the homeostasis model assessment (HOMA) of insulin sensitivity and ß-cell function16 using the HOMA-CIGMA Calculator program v2.00 (Diabetes Research Laboratory, Oxford, United Kingdom). This model, originally developed in prediabetic adults, relies on the inverse relationship between plasma levels of glucose and insulin in fasting conditions. In addition, SHBG and IGFBP-1 were used as indicators of hepatic sensitivity to insulin.
Statistical Analysis
Results are expressed as median [interquartile range]. Differences between groups were assessed by nonparametric tests (Mann-Whitney U), as a result of different sample sizes and nonnormal distribution of some variables. Correlation between variables was evaluated using parametric statistics (Pearson), except for variables displaying nonnormal distributions even after log transformation (Spearman 
test). Analyses were performed with SPSS v 10.0 (SPSS, Inc, Chicago, IL), in a x86-based computer. Differences and correlations were considered significant at P < .05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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= 0.238; P < .01). As shown in Fig 1, the G/I ratio was significantly higher in SGA newborns when compared with AGA infants (13.9 mg/dL/uIU/mL [8.6–19.1 mg/dL/uIU/mL] vs 8.2 mg/dL/uIU/mL [4.6–14.1 mg/dL/uIU/mL]; P < .01), and the homeostasis model assessment of insulin sensitivity suggested that SGA infants were more insulin sensitive than AGA infants (206% [140–314%] vs 103% [67–122%]; P < .001). Conversely, HOMA ß-cell function was lower in SGA than in AGA infants (84% [52–158%] vs 136% [90–238%]; P < .05; Fig 1).
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Plasma IGFBP-1 levels were significantly higher in SGA infants compared with AGA newborns (5.1 nmol/L [4.4–6.7 nmol/L] vs 2.9 nmol/L [1.4–4.2 nmol/L]; P < .001). The IGFBP-1/insulin ratio was also higher in SGA infants (0.16 [0.09–0.29] vs 0.04 [0.01–0.07]; P < .001). No difference in plasma cortisol was found (SGA: 231.8 nmol/L [162.8–378.1 nmol/L]; AGA: 191.8 nmol/L [129.7–436.1 nmol/L]).
Plasma concentrations of SHBG and leptin were analyzed separately by gender because of previously reported differences in these parameters (Table 2). For SHBG, there were no differences between SGA and AGA in both boys (40.8 nmol/L [30.5–54.8 nmol/L] vs 42.1 nmol/L [24.6–64.3 nmol/L]) and girls (37.7 nmol/L [29.8–50.7 nmol/L] vs 42.8 nmol/L [34.7–60.1 nmol/L]). In addition, no correlation was observed between plasma insulin and SHBG levels. Plasma leptin concentrations were much lower in SGA than in AGA infants (13.1 pmol/L [3.1–26.6 pmol/L] vs 153.4 pmol/L [60.0–287.5 pmol/L]; P < .001). Leptin levels were higher in girls both in SGA (18.8 pmol/L [6.3–31.3 pmol/L] vs 6.3 pmol/L [3.1–18.8 pmol/L]; P < .001) and in AGA newborns (200.0 pmol/L [119.4–423.1 pmol/L] vs 106.9 pmol/L [31.3–231.3 pmol/L]; P < .001). None of the remaining metabolic measures showed any difference between genders.
When used as a continuous variable, ponderal index was positively correlated with C-peptide (Spearman = 0.191, P = .014) and leptin levels (Spearman = 0.381, P < .001). A negative correlation between ponderal index and IGFBP-1 (Spearman = -0.230, P < .01) and FFA levels (Spearman = -0.212, P < .01) was also observed.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Our observations are in accordance with a number of animal studies indicating that glucose metabolism and insulin action are profoundly modified in situations in which a low birth weight is present. Assessment of glucose metabolism in the growth-retarded lamb shows a long-term tendency to hypoglycemia and hypoinsulinemia, with an increased G/I ratio.18 The same has been observed in the growth-restricted rat, which in addition displays a significant ß-cell hypoplasia.19,20 Nevertheless, analysis of glucose metabolism in the newborn should be taken cautiously: first-phase insulin release appears only 12 hours after birth in the neonatal lamb, and full closed-loop glucose homeostasis is thought to be achieved in this model after 5 days of postnatal life.18
Studies in humans have resulted in similar conclusions. Economides et al21 measured plasma glucose and insulin in third-trimester SGA and AGA fetuses by chordocentesis. They found lower glucose and insulin, as well as a higher G/I ratio in growth-retarded fetuses. Hawdon et al12,22–24 also examined some aspects of neonatal glucose metabolism in the SGA infant. They found lower plasma glucose levels in SGA newborns only at birth (as measured in cord blood) but not during the following days. They also found higher plasma lactate, pyruvate, glycerol, and FFA levels in SGA newborns within the first 6 hours of life. However, starting from the second day after birth, these gluconeogenic substrates were lower in SGA than in AGA infants, which was attributed to a higher caloric intake as a result of hospital care practices.22,23 Importantly, these authors did not find a significant correlation between blood glucose and plasma insulin/C-peptide levels. This precluded any conclusion regarding insulin sensitivity and/or secretion in the neonatal period.22–24
In contrast to Hawdon et al, we did find such a correlation, which may be attributable to our larger sample size, as well as stricter inclusion criteria and tighter time frame. This correlation may be interpreted as a result of full closed-loop control of insulin secretion and suggests that G/I ratio and HOMA might be useful parameters for evaluating insulin sensitivity in neonates. We found that SGA infants, as compared with AGA newborns, during the third day of life seem to be more insulin sensitive.
Unfortunately, we could not establish whether this pattern is maintained during the first week of postnatal life, because of local hospital practices encouraging early discharge after delivery. Nonetheless, results from Hawdon et al12,22–24 indicate that after 48 hours of life, the acute metabolic modifications induced by parturition (possibly mediated by cortisol and catecholamines) have already subsided. Therefore, it is possible that our findings reflect metabolic modifications that may persist after a normal glucose supply is restored.
Besides controlling glucose concentrations, insulin has other metabolic actions that were also modified in SGA newborns. Plasma FFA and bOH-B levels, which are negatively regulated by insulin, were higher in SGA infants than in AGA newborns. This finding is somewhat difficult to interpret considering insulin secretion only: both FFA/insulin and bOH-B/insulin ratios were also higher in SGA infants. Therefore, lipolysis and ketogenesis in SGA newborns seem to be less inhibited by insulin than in AGA infants. This might result from the action of insulin-antagonizing hormones, particularly in the presence of lower glucose and insulin levels. In fact, it has been shown that SGA newborns have higher plasma growth hormone (GH) and lower IGF-I levels than AGA infants during the first week of life.11,14 GH is a potent lipolytic and ketogenic hormone, and it has been proposed to protect the fetal and neonatal brain from hypoglycemia.25
IGFBP-1 is a sensitive marker of insulin action on the hepatocyte, and its expression is both potently and rapidly downregulated by insulin.10 Our results show that SGA infants have higher IGFBP-1 levels than AGA newborns, which could not be explained by lower plasma insulin because the IGFBP-1/insulin ratio was also higher in SGA neonates. Higher plasma GH levels in this group may be again contributing to increased hepatic expression of IGFBP-1.11,14
Regarding SHBG, another hepatic protein regulated by insulin, Simmons26 reported in newborns a negative correlation between cord blood insulin and serum SHBG levels, in both boys and girls. In our group, we did not find any difference in plasma SHBG between SGA and AGA infants (either boys or girls). It is possible that in presence of lower insulin levels, as those observed in SGA newborns, other factors (eg, sex steroids) might be more potent regulators of SHBG than insulin. Taken together, our observations on IGFBP-1 and SHBG levels suggest that hepatic insulin sensitivity, in contrast to peripheral, may not be increased in SGA infants shortly after birth.
Plasma leptin has been repeatedly found to correlate with adipose mass,13 and that is confirmed by our results. It is interesting that the previously reported sex differences in leptin concentrations are clearly present 48 hours after birth.
Our findings highlight the complexity of the metabolic adaptation in SGA neonates, as evident shortly after birth. Regarding glucose metabolism, the combination of increased peripheral insulin sensitivity and reduced insulin secretion in SGA newborns seems to be adequate in conditions of limited nutrient availability and reduced energy stores. This may be particularly relevant during the first hours of extrauterine life, characterized by an intense catabolism. However, because these modifications are still present after 48 hours of free access to nutrients, it might be possible that some of them persist in the long term.
Our data indicate that insulin actions on lipolysis, ketogenesis, and IGFBP-1 secretion were not increased. As mentioned, lower IGF-I and higher GH levels, consistently reported in SGA infants, may explain these latter findings. However, they might also be expected to result in reduced sensitivity to insulin with respect to glucose uptake, which we did not observe.
To our knowledge, this is the first large study specifically designed to assess changes in intermediate metabolism in SGA newborns. In particular, we studied breastfed infants during a very short time frame (48 hours after delivery), whereas previous reports include infants within the first 211 or 712,22–24 days of life. Nonetheless, it should be noted that all newborns in our cohort were delivered at full term. Therefore, our observations may not reflect metabolic adaptation in infants exposed to more adverse conditions in utero, who are usually delivered earlier.
Moreover, it has been proposed that the results of prenatal growth retardation, as evident in SGA newborns, are modified by events during early postnatal life, as a result of an accelerated growth in these children (the "catch-up growth" hypothesis).27 This idea has received support from a number of studies showing that the metabolic consequences of LBW are more evident in individuals who become obese during childhood.3 In addition, it has been shown that SGA children are at a higher risk of obesity.28 In the long term, this "adiposity rebound" could overcome the effects of LBW observed at birth and lead to the development of insulin resistance. At present, there is only 1 prospective study (the ALSPAC cohort in the United Kingdom)14,28 analyzing the combined effects of LBW and weight gain on sensitivity to insulin. Critically, in this cohort, children were not metabolically studied during early infancy, thus limiting the chance to detect such interaction.
With the aim of detecting potential risk factors arising during early postnatal life, infants recruited for the present study will also participate in a yearly follow-up, assessing both changes in glucose metabolism and anthropometric variables.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Reprint requests to (M.V.M.) Institute for Maternal and Child Research, School of Medicine, University of Chile, Casilla 226-3, Santiago, Chile. E-mail: vmericq{at}machi.med.uchile.cl
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REFERENCES |
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