Elsevier

The Lancet

Volume 361, Issue 9363, 29 March 2003, Pages 1089-1097
The Lancet

Mechanisms of Disease
Low nutrient intake and early growth for later insulin resistance in adolescents born preterm

https://doi.org/10.1016/S0140-6736(03)12895-4Get rights and content

Summary

Background

In animals, acceleration of neonatal growth is thought to increase the later propensity to insulin resistance and non-insulin-dependent diabetes, whereas slow growth as a consequence of undernutrition is thought to have a beneficial effect. To test this hypothesis in people, we measured fasting concentrations of 32–33 split proinsulin, a marker of insulin resistance, in adolescents born preterm who had participated in randomised intervention trials of neonatal nutrition, and in adolescents born at term.

Methods

We determined fasting 32–33 split proinsulin concentration in participants aged 13–16 years born preterm and randomised to receive a nutrient-enriched or lower-nutrient diet (n=216) or in a reference group born at term (n=61).

Findings

Fasting 32–33 split proinsulin concentration was greater in children given a nutrient-enriched diet (geometric mean 7·2 pmol/L, 95% CI 6·4–8·1) than in those given the lower-nutrient diet (5·9 pmol/L [5·2–6·4]; mean difference 20·6% [5·0–36·3]; p=0·01). Healthy babies born at term had similar fasting 32–33 split proinsulin concentrations (6·9 pmol/L; 6·0–8·2) to the nutrient-enriched group. In non-randomised analyses, fasting 32–33 split proinsulin concentration was associated with greater weight gain in the first 2 weeks of life (13·2% [5·4–20·9] change per 100 g weight increase; p=0·001) independent of birthweight, gestation, neonatal morbidity, and demographic, anthropometric, and socioeconomic factors.

Interpretation

Our results suggest that relative undernutrition early in life in children born preterm may have beneficial effects on insulin resistance.

Introduction

Developing organisms have a compensatory increase in growth after a period of nutritional deficit.1 Although such growth is beneficial in the short term, it could have a profound adverse effect on the subsequent long-term life history of an organism.1 For instance, accelerated growth during crucial times early in development reduces the rate of growth and fat deposition in Atlantic salmon, reduces resistance to starvation in the speckled wood butterfly, and impairs glucose tolerance and life span in the rat.1 The possible long-term cost of accelerated growth in human beings, however, although an issue of potentially major biological and public health importance, has not been fully explored.

Since nutrition affects growth, restriction of growth during key periods in development as a consequence of relative undernutrition might have a beneficial effect in the long term. This hypothesis is lent support by the improvement in longevity as a consequence of nutritional restriction first described in rats more than 60 years ago2 and recently confirmed for cardiovascular risk factors in primates.3 Conversely, overfeeding during the brief suckling period in rats (which accelerates growth) permanently increases later plasma insulin and cholesterol concentrations,4 obesity,5 and tendency to diabetes5, 6 and syndrome X.6 In infants the greatest acceleration in growth takes place in the first weeks after birth.7, 8 Therefore, if data from animals applied to human beings, current public-health advice and practice, which strongly supports promotion of infant growth, would be contradicted.9 However, present recommendations are based on short-term data, and the long-term effects of early nutrition in human beings have not been investigated experimentally.

We aimed to investigate the effect of early nutrition on cardiovascular risk factors in infants born preterm, which is one human population without a specific disease that can have substantial early undernutrition. Our participants were born in the 1980s. At that time the diets commonly in use included unsupplemented donor breast milk and standard infant term formula. These diets did not meet the nutritional requirements of infants born preterm, resulting in lower rates of growth, poor bone mineralisation, and specific nutrient deficiencies. Since at the time, the clinical effects of such diets had been poorly defined we could randomly assign these infants to lower-nutrient diets or to high-nutrient preterm formula specifically designed to meet their increased nutrient needs. We had the unique opportunity, therefore, to compare relatively undernourished preterm infants with those better nourished and with infants born at term and fed normally. We tested the hypothesis that a lower-nutrient intake in early life results in lower insulin resistance, as measured by fasting 32–33 split proinsulin concentration later in life, since this major cardiovascular risk factor has been shown to be programmed by early factors in human beings10 and in animals.

Section snippets

Participants

Participants were part of a cohort of 926 children who were born preterm and participated in studies that investigated the effects of early diet on later cognitive function and cardiovascular disease.11, 12, 13 Between 1982 and 1985, babies free from major congenital anomalies and below 1850 g in birthweight were recruited from centres in Norwich, Cambridge, Sheffield, Ipswich, and King's Lynn (all UK).11 A reference group of children of the same age, but born at term and with a birthweight

Results

Birthweight, gestation, z scores for birth and discharge weight, and clinical variables did not differ between children who were reviewed at age 13–16 years and those who were not in either trial (table 2). As expected, the proportion of adolescents from a non-manual social background was greater at follow-up than at birth for both trials (table 2). However, neonatal characteristics did not differ between groups and neither did anthropometry, Tanner stage (median 4, IQR 4–5 for both groups), or

Discussion

We found that adolescents born preterm who were randomised to a lower-nutrient diet, now recognised to be suboptimal in terms of growth, had lower fasting 32–33 split proinsulin concentrations–markers of insulin resistance–than those given a nutrient-enriched diet. These dietary effects, seen up to 16 years after dietary randomisation, were probably the result of diet affecting the neonatal growth rate. We suggest therefore that reduced early growth rate as a consequence of relative

GLOSSARY

fasting 32–33 split proinsulin
A partly processed form of proinsulin, higher concentrations of which may indicate greater insulin resistance
lower-nutrient diets
The commonly used diets in infants born preterm in the 1980s (unsupplemented banked donated breast milk and standard formula suitable for infants born at term) now shown to be nutritionally suboptimal
preterm formula
A nutrient-enriched formula specially designed to meet the nutritional requirements of infants born preterm
programming
The

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