Ruben H. Willemsen

Health Profile of Young Adults Born Preterm: Negative Effects of Rapid Weight Gain in Early Life

INTRODUCTION Early postnatal weight gain is associated with determinants of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM2) in adults born term. We aimed to investigate the association of weight gain during different periods, and weight trajectories in early life after preterm birth, with determinants of CVD and DM2 in early adulthood. METHODS Associations of first-year growth and tempo of weight gain with determinants of CVD and DM2 in 162 young adults (18-24 yr) born preterm (gestational age <36 wk) were determined and compared with data of young adults born term (n = 217). RESULTS Gain in weight for length in the period from preterm birth up to term age, and in the first 3 months after term age, was positively associated with body fat percentage and waist circumference at 21 yr. Gain in weight for length in the first 3 months after term age was also positively associated with total cholesterol and low-density lipoprotein cholesterol levels in early adulthood. Subjects with the highest gain in weight from birth to term age (highest quartile) had significantly higher body fat percentage, waist circumference, acute insulin response, and disposition index in early adulthood than the subgroups with moderate and low gain in weight. Rapid catch-up in weight during the first 3 months after term age resulted in a higher fat percentage, waist circumference, and serum triglycerides level than slower catch-up in weight. CONCLUSION Accelerated neonatal gain in weight relative to length after preterm birth (immediately after birth and during the first 3 months after term age) is associated with determinants of CVD in early adulthood and should therefore be avoided.

Long‐term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small‐for‐gestational‐age: six‐year follow‐up of a randomized controlled GH trial

Context  Alterations in the GH‐IGF‐I axis in short small‐for‐gestational‐age (SGA) children might be associated with abnormalities in bone mineral density (BMD) and body composition. In addition, birth weight has been inversely associated with diabetes and cardiovascular disease in adult life. Data on detailed body composition in short SGA children and long‐term effects of GH treatment are very scarce.

Prematurity is not associated with reduced insulin sensitivity in adulthood.

BACKGROUND In 2005, 12.7% of all babies were born preterm, and the incidence is rising. Nowadays, due to improved survival, an increasing number of children born preterm reach young adulthood. A recent report suggested lower insulin sensitivity in children born preterm, which may put them at risk for the development of type 2 diabetes. It is, however, still unknown whether this reduced insulin sensitivity persists into adulthood. METHODS We determined insulin sensitivity and beta-cell function with frequently sampled iv glucose tolerance tests in 305 young adults (aged 18-24 yr; 169 preterm and 136 term). Adult body composition was measured by dual energy x-ray absorptiometry. We investigated the effect of gestational age, size at birth, and adult body composition on insulin sensitivity. RESULTS In contrast to previous reports, we found no evidence that preterm birth has a deleterious effect on insulin sensitivity in young adulthood. Adult trunk fat and the use of oral contraceptives in women were the most important determinants of insulin insensitivity, independently of size at birth and duration of pregnancy. CONCLUSION Contrary to our hypothesis, preterm birth was not associated with reduced insulin sensitivity in young adulthood.

Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): Correlation with serum IGFBP-3 levels and growth in short children born small for gestational age

CONTEXT IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. OBJECTIVE To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. PATIENTS 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. INTERVENTION Short prepubertal SGA children received GH 1mg/m(2)/day. OUTCOME MEASURES Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. RESULTS At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P<0.001). Children with C(-202)/C(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. CONCLUSION Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.

Bloom syndrome in short children born small for gestational age: A challenging diagnosis

BACKGROUND GH treatment has become a frequently applied growth-promoting therapy in short children born small for gestational age (SGA). In some disorders GH treatment is contraindicated, eg, chromosomal breakage syndromes. Bloom syndrome is a rare chromosomal breakage syndrome characterized by severe pre- and postnatal growth deficiency, a photosensitive facial erythema, immunodeficiency, mental retardation or learning disabilities, endocrinopathies, and a predisposition to develop a wide variety of cancers. OBJECTIVE We report 2 patients with Bloom syndrome illustrating the variety in clinical manifestations. They were initially diagnosed with short stature after SGA birth and Silver Russell syndrome and treated with GH. CASES Both patients presented with pre- and postnatal growth failure but no clear other characteristic features associated with Bloom syndrome. Photosensitive skin lesions developed only at a pubertal age and were minimal. Also, both children showed normal immunoglobulin levels, normal development, and no signs of endocrinopathies at start of GH. Dysmorphic features resembling Silver Russell syndrome were observed in both patients. Remarkably, during GH treatment IGF-1 levels increased to values greater than 3.5 SD score, with normal IGF binding protein-3 levels. CONCLUSION Short children born SGA comprise a heterogeneous group. Bloom syndrome should be tested for in children with consanguineous parents, dysmorphic features (particularly resembling Silver Russell syndrome), skin abnormalities, and/or IGF-1 levels greater than 2.5 SD score during standard GH treatment with normal IGF binding protein-3 levels.

Longitudinal Changes in Insulin Sensitivity and Body Composition of Small-For-Gestational-Age Adolescents after Cessation of Growth Hormone Treatment

CONTEXT GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, beta-cell function, and body composition change over time after stopping GH treatment. OBJECTIVE Our objective was to investigate longitudinal changes in Si, beta-cell function, and body composition after cessation of long-term GH treatment. DESIGN AND PATIENTS We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points. OUTCOME MEASURE We took paired measurements of Si and beta-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry. RESULTS After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and beta-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher. CONCLUSIONS The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.

Insulin-Like Growth Factor-Binding Protein-1: Serum Levels, Promoter Polymorphism, and Associations with Components of the Metabolic Syndrome in Short Subjects Born Small for Gestational Age

CONTEXT IGF binding protein (IGFBP)-1 is the only acute regulator of IGF-I bioavailability. Its production is suppressed by insulin, and low levels are associated with hyperinsulinemia and cardiovascular disease risk in adults. Data on IGFBP-1 levels in short, small for gestational age (SGA) subjects are scarce, and associations with IGFBP1 promoter single nucleotide polymorphisms have not been established. OBJECTIVE The aim of the study was to determine IGFBP-1 levels in short SGA subjects compared with those in controls, to assess genotype frequency of the -575 G/A single nucleotide polymorphism, and to determine its impact on IGFBP-1 levels. SUBJECTS A total of 272 short subjects born SGA and 330 subjects with normal stature (245 children, 85 young adults) participated in the study. OUTCOME MEASURES We measured fasting levels of IGFBP-1, IGF-I, insulin and lipid parameters, and body composition. RESULTS IGFBP-1 sd score (SDS) was comparable to controls in lean, short, SGA children but significantly lower in short SGA adults with normal fat mass (P < 0.001). IGFBP-1 SDS correlated significantly with insulin levels, systolic blood pressure SDS, and various lipid parameters. Baseline IGFBP-1 SDS was lowest in SGA children with -575 GG genotype and significantly higher in SGA children with one or two copies of the A allele. In response to a given insulin level, children with the AA genotype had a significantly higher IGFBP-1 SDS compared to children with the GG genotype. CONCLUSION Normal IGFBP-1 levels in lean, short, SGA children may reflect a normal metabolic state, despite reported hyperinsulinemia. IGFBP-1 is modulated by polymorphic variability and seems to be an additional player in the complex interaction between the IGF-IGFBP axis, glucose homeostasis, and lipid metabolism.

The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children

Context  We previously reported that short, small for gestational age (SGA) children who were born preterm have a lower body fat percentage and a higher blood pressure, insulin secretion and disposition index than short SGA children born at term. Whether preterm birth also influences these parameters during GH treatment is unknown.

Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children?

Objective  To investigate whether prematurity has an independent influence on the response to GH treatment in short, small for gestational age (SGA) children.

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment

Context  Disturbances in thyroid function have been described in small‐for‐gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children.