Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children

CONTEXT AND OBJECTIVE: Low birth weight followed by rapid postnatal weight gain is associated with long-term risks for central obesity and insulin resistance. However, the timing of these changes is unclear. SETTING, DESIGN, AND PATIENTS: This was a longitudinal cohort study in low birth weight (SGA; birth weight < -2 sd; n = 29) and normal birth weight (AGA; n = 22) children from Barcelona. MAIN OUTCOME MEASURES: Body composition, by dual-energy x-ray absorptiometry scan, and insulin sensitivity, assessed longitudinally at ages 2, 3, and 4 yr, were measured. RESULTS: Mean height, weight, and body mass index at ages 2, 3, and 4 yr were not different between SGA and AGA children. At age 2 yr, SGA children had similar body composition but were more insulin sensitive than AGA children and had lower serum IGF-I levels and lower neutrophil counts. Between ages 2 and 4 yr, despite similar gains in weight and body mass index, SGA children gained more abdominal fat and body adiposity and less lean mass than AGA children; by age 4 yr, SGA children had greater adiposity, insulin resistance, and higher neutrophil counts than AGA children (P = 0.01-0.0004). In SGA children, total and abdominal fat mass at 4 yr was more closely related to rate of weight gain between 0 and 2 yr (P = 0.002-0.0003) than between 2 and 4 yr (P = 0.04-0.1). CONCLUSION: Consequent to catch-up weight gain between birth and 2 yr, SGA children showed a dramatic transition toward central adiposity and insulin resistance between ages 2 and 4 yr. Understanding the mechanisms underlying this predisposition to adverse future health could lead to specific preventive interventions during early childhood.     

Visceral adiposity without overweight in children born small for gestational age

CONTEXT: Children born small for gestational age (SGA) tend to develop catch-up growth in infancy and become overweight by the age of 6 yr. Weight control is advocated as a preventive measure, but it is unknown whether such control suffices to prevent visceral fat excess and hypoadiponectinemia. SETTING: The study was performed at a university hospital. STUDY POPULATION AND DESIGN: A total of 64 children (32 matched pairs) aged 6 yr, of whom 32 were born appropriate for gestational age and 32 were born SGA, and had subsequently developed spontaneous catch-up growth were included in the study; matching was performed for gender, height, weight, and, thus, body mass index. MAIN OUTCOMES: Fasting insulin, IGF-I, high molecular weight adiponectin, leptin, visfatin, and lean and fat mass were calculated by absorptiometry, and abdominally sc and visceral fat by magnetic resonance imaging. RESULTS: After strict matching, SGA children had a total lean mass, total fat mass, leptinemia, and visfatinemia comparable to those in the appropriate for gestational age children, but they still had higher fasting insulin and IGF-I levels (P < 0.01), much lower high molecular weight adiponectin levels (P < 0.0001), and a striking shift from abdominally sc to visceral fat (P < 0.0001). Fasting insulin (r = 0.52; P < 0.00001) was a major determinant of visceral fat in boys and girls, explaining 28% of its variance. CONCLUSIONS: SGA children tend to be viscerally adipose and hypo-adiponectinemic, even if they are not overweight. Therefore, measures beyond weight control seem to be needed to allow most SGA children to normalize their body composition and endocrine-metabolic homeostasis.     

Gender specificity of body adiposity and circulating adiponectin, visfatin, insulin, and insulin growth factor-I at term birth: relation to prenatal growth

CONTEXT: Fetal development is thought to be gender specific for adiposity and circulating insulin and IGF-I but not adipokinemia, as judged by serum visfatin and adiponectin at term birth. We studied the potential relationship between these gender specificities and fetal growth. SETTING: The study was conducted at a university hospital. STUDY POPULATION: Subjects included 96 strictly matched neonates born appropriate for gestational age (AGA; 24 girls, 24 boys) or small for gestational age (SGA; 24 girls, 24 boys). MAIN OUTCOMES: Outcomes included serum insulin, IGF-I, visfatin, total and high-molecular-weight (HMW) adiponectin, osteocalcin at term birth, and neonatal body composition by absorptiometry. RESULTS: Cord insulin and IGF-I levels were higher in girls than boys (P < or = 0.01), in both the AGA and SGA subpopulation. In AGA newborns, fat and lean mass were each gender specific (P < 0.0001), whereas visfatin and total and HMW adiponectin were not. Conversely, in SGA newborns, visfatin and HMW adiponectin were gender specific (higher levels in girls), whereas body adiposity was not. In SGA fetuses, the distribution of adiponectin isoforms was in both genders shifted toward HMW (P < 0.005 vs. AGA). Cord osteocalcin did not differ by either gender or birth weight. CONCLUSION: At term birth, the gender specificity of adiposity and circulating visfatin and HMW adiponectin appeared to depend on prenatal growth, whereas the gender specificity of insulin and IGF-I levels did not. The fetal shift in adiponectin isoforms may contribute to explain why SGA newborns tend to be hypersensitive to insulin.     

Longitudinal changes in insulin-like growth factor-I, insulin sensitivity, and secretion from birth to age three years in small-for-gestational-age children

INTRODUCTION: Insulin resistance (IR) develops as early as age 1 to 3 yr in small for gestational age (SGA) infants who show rapid catch-up postnatal weight gain. In contrast, greater insulin secretion is related to infancy height gains. We hypothesized that IGF-I levels could be differentially related to gains in length and weight and also differentially related to IR and insulin secretion. METHODS: In a prospective study of 50 SGA (birth weight < 5th percentile) and 14 normal birth weight [appropriate for gestational age (AGA)] newborns, we measured serum IGF-I levels at birth, 1 yr, and 3 yr. IR (by homeostasis model assessment) and insulin secretion (by short iv glucose tolerance test) were also measured at 1 yr and 3 yr. RESULTS: SGA infants had similar mean length and weight at 3 yr compared with AGA infants. SGA infants had lower IGF-I levels at birth (P < 0.0001), but conversely they had higher IGF-I levels at 3 yr (P = 0.003) than AGA infants. Within the SGA group, at 1 yr IGF-I was associated with length gain from birth and insulin secretion (P < 0.0001); in contrast at 3 yr IGF-I was positively related to weight, body mass index, and IR. CONCLUSIONS: IGF-I levels increased rapidly from birth in SGA, but not AGA children. During the key first-year growth period, IGF-I levels were related to beta-cell function and longitudinal growth. In contrast, by 3 yr, when catch-up growth was completed, IGF-I levels were related to body mass index and IR, and these higher IGF-I levels in SGA infants might indicate the presence of relative IGF-I resistance.     

Serum levels of adiponectin and IGFBP-1 in short children born small for gestational age

OBJECTIVE: The aim of this study was to quantify serum adiponectin concentrations in short children born small for gestational age (SGA) compared with those in children born appropriate for gestational age (AGA), and to assess the relationship between the serum levels of adiponectin and insulin-like growth factor binding protein-1 (IGFBP-1) known as a predictor of the development of type 2 diabetes mellitus and cardiovascular disease. SUBJECTS AND METHODS: Sixteen prepubertal short children born SGA and 20 short children born AGA, matched for age, body mass index, height, pubertal status, gestational age, bone age and midparental height, were included in the study. The serum levels of adiponectin, IGFBP-1, insulin and insulin-like growth factor-I (IGF-I) were measured in the fasting state. RESULTS: The levels of serum adiponectin were significantly lower in the SGA than in AGA children (10.5 +/- 4.2 vs. 13.9 +/- 5.1 micro g/ml, P < 0.05). The levels of serum IGFBP-1, insulin and IGF-I were all similar in both groups. Overall, there was a significant positive correlation between adiponectin and IGFBP-1 (r = 0.40, P < 0.05). CONCLUSIONS: Our results suggest that hypoadiponectinaemia in short SGA children without catch-up growth may reflect insulin resistance and imply a higher risk of developing type 2 diabetes mellitus. Additionally, adiponectin may be a more sensitive indicator for latent insulin resistance than IGFBP-1 in short SGA children.     

Smallness for gestational age is associated with persistent change in insulin-like growth factor I (IGF-I) and the ratio of IGF-I/IGF-binding protein-3 in adulthood

CONTEXT: Implication of the IGF-IGF-binding protein (IGFBP) axis in the development of metabolic and cardiovascular diseases has been well documented. It has also been shown that an adverse intrauterine environment alters the IGF-IGFBP axis during childhood. OBJECTIVE: The objective of this study was to investigate whether these alterations persist into adulthood. DESIGN AND METHODS: Fasting serum IGF-I, IGFBP-3, and insulin concentrations were measured, and their determinants were analyzed in a cohort of young adult subjects (22 yr of age) born either small (SGA; n = 461) or appropriate (AGA; n = 568) for gestational age. RESULTS: In adulthood, subjects born SGA had significantly lower mean serum IGF-I (320 +/- 137 vs. 348 +/- 143 microg/liter; P = 0.0015), IGFBP-3 (4700 +/- 700 vs. 4800 +/- 800 microg/liter; P = 0.04), and IGF-I/IGFBP-3 ratio (0.067 +/- 0.026 vs. 0.072 +/- 0.025; P = 0.01) than those born AGA. The fasting IGF-I concentration and the IGF-I/IGFBP-3 ratio were significantly inversely associated with age, body mass index, smoking, and oral contraception and were positively related to birth weight and fasting insulin levels. The IGFBP-3 concentration was significantly negatively correlated to age and smoking and was positively related to insulin concentration and oral contraception. After adjustment for age, height, body mass index, gender, smoking, and oral contraception, the mean IGF-I concentration and the mean IGF-I/IGFBP-3 ratio remained significantly lower in the SGA compared with the AGA group (P = 0.003 and P = 0.01, respectively). CONCLUSIONS: Serum IGF-I concentrations and the IGF-I/IGFBP-3 ratio are lower in adult subjects born SGA. Although the origin of this persisting alteration of the IGF-IGFBP axis in adulthood needs to be elucidated, its potential contribution to the long-term metabolic and cardiovascular complications associated with fetal growth restriction is important to consider in the future.     

Glucose tolerance,insulin sensitivity,and insulin secretion in children born small for gestational age

Intrauterine growth retardation is associated with an increased risk of developing adult diseases, such as noninsulin-dependent diabetes mellitus (NIDDM). NIDDM could result from a decreased insulin sensitivity or a reduced insulin secretion or a combination of both. Glucose tolerance, insulin sensitivity, and insulin secretion were studied in prepubertal children born small for gestational age (SGA). Twenty-nine SGA children with a mean age of 9.1 +/- 1.1 yr and 24 children born appropriate for gestational age (AGA), with a mean age of 9.0 +/- 1.1 yr, were studied. All children were born at term and were prepubertal. Children were studied on two separate days after 12 h of overnight fasting. Day 1: Glucose tolerance was studied with an oral glucose tolerance test. AUC(ins0-120 min)/AUC(gluc0-120 min) was used to estimate beta-cell function in the two groups. Day 2: A hyperinsulinemic euglycemic clamp study was performed to determine insulin sensitivity (M-value). Glucose tolerance and beta-cell function were not different between the two groups. M-value in SGA children was significantly lower than M-value in AGA children: 12.9 +/- 4.0 mg/kg.min vs. 15.6 +/- 2.3 mg/kg.min [P = 0.009; after adjustment for appropriate gestational age body mass index (BMI), P = 0.001]. The M-value tended to be higher in SGA children without catch-up growth compared with SGA children with catch-up growth (15.8 +/- 4.3 vs. 12.3 +/- 3.8 mg/kg.min; P = 0.079) and was comparable to AGA controls (15.6 +/- 2.3 mg/kg.min). The M-value in SGA children who had shown catch-up growth was comparable to AGA children (13.4 +/- 3.4 vs. 15.6 +/- 2.3 mg/kg.min; P = 0.06), provided they had a BMI of 17 kg/m(2) or less. However, the SGA children with catch-up growth and a BMI greater than 17 kg/m(2) were those having the lowest M-values (9.3 +/- 3.4 mg/kg.min). In conclusion, during oral glucose tolerance tests, no differences were found in glucose tolerance and beta-cell function between the SGA and AGA groups. However, the hyperinsulinemic clamp showed a reduced insulin sensitivity in SGA children, which may contribute to the enhanced risk of developing NIDDM in adult life, especially in SGA children with catch-up growth and a high BMI. The implications of our findings in relation to height are unclear, but might be of potential importance when considering GH treatment. In addition, interventions to improve fetal growth and to control obesity in childhood seem to be important factors in the prevention of NIDDM.     

小于胎龄儿青春前期线性生长方式与血清胰岛素水平关系的研究

目的 探讨小于胎龄儿(small for gestational age,SGA)出生后生长追赶状态与血清胰岛素水平的关系.方法 青春前期30例有生长追赶SGA(catch-up growth SGA,CUG-SGA组)、37例无生长追赶SGA(NCUG-SGA组)和42例适于胎龄儿(appropriate for gestational age,AGA组),测定空腹血糖、空腹胰岛素(FINS)和血清胰岛素样生长因子I(IGF-I).结果 (1)与NCUG-SGA和AGA组比较,CUG-SGA组FINS和稳态模型评估的胰岛素抵抗指数(HOMA-IR)显著为高(P<0.01或P<0.05),而NCUG-SGA组与AGA组则无显著性差异(P>0.05).CUG-SGA组血清IGF-I水平较NCUG-SGA组显著为高[(212.61±17.81对137.40±14.66)ng/ml,P=0.001],但与AGA组无显著性差异(P=0.095).(2)SGA组HOMA-IR与年龄、身高标准差分值增值(AHtSDS)和体重指数分别正相关;≤6岁SGA组FINS与△HtSDS呈正相关,>6岁组FINS与体重标准差分值增值呈正相关.结论 生后早期胰岛素可能以生长因子角色参与了SGA儿的生长追赶;胰岛素抵抗程度与生长追赶程度相随.

Abstract：

Objective To evaluate the association between two different linear growth patterns with the levels of serum insulin in children bem small for gestational age(SGA).Methods Serum fasting glucose,fasting insulin,and insulin-like growth factor-I(IGF-I)concentrations were determined in 30 catch-up growth(CUG)children bern SGA [CUG-SGA,16 females,14males,(6.62±0.66)year],37 non-catch-up growth(NCUG)children born SGA[NCUG-SGA,15 females,22 males,(5.97±0.56)year],and42 appropriate for gestational age(AGA)children with normal height[AGA,16females,26males,(7.05±0.39)year].Results (1) Basal fasting insulin and homeostasis model assessment for insulin resistance(HOMA-IR)were significantly higher in CUG-SGA group than in NCUG-SGA and AGA group(P<0.01 or P<0.05).But there was no difference in fasting insulin between NCUG-SGA group and AGA group.IGF-I levels in CUG-SGA were significantly higher than in NCUG-SGA group[(212.61±17.81 vs 137.40±14.66)ng/ml,P=0.001],but showed no difference from AGA group(P=0.095).(2)In the SGA group,HOMA-IR showed positive correlation with age,△height SDS,and current body mass index.Fasting insulin showed positive correlation with △height SDS(r=0.500,P=0.002)in≤6 year group as well as with △weight SDS(r=0.496,P=0.030)in>6 year group.Conclusions Insulin as a growth factor may participate in postnatal catch-up growth accompanied with increased insulin resistance in SGA children.     

Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants at age 1 year: results from a prospective cohort

Strong associations between low birth weight and insulin resistance have been described. However, most of these studies have been retrospective. We aimed to determine whether infants born small for gestational age (SGA: birth weight <5th percentile for gestational age) have decreased insulin sensitivity, compared with appropriate for gestational age (AGA: birth weight >10th percentile) at 1 yr of age. We studied blood lipids, fasting insulin levels, other markers of insulin sensitivity, and insulin secretion during an iv glucose tolerance test in a cohort of 85 SGA and 23 AGA 1-yr-old infants. In addition, SGA infants were stratified according to catch-up growth (CUG) in weight (WCUG) or length (LCUG) during the first year of life. 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 (R(2) = 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.     

Reduced ovulation rate in adolescent girls born small for gestational age

FSH and insulin are key hormones involved in spontaneous ovulation. Adolescent girls born small for gestational age (SGA) are at risk for FSH and insulin resistance. We have assessed whether ovulation rate is reduced in SGA girls. Ovulatory function was assessed by weekly filter paper progesterone measurements, obtained by finger-stick auto-sampling for 3 consecutive months in matched populations of asymptomatic, nonobese girls (mean age, 15.5 yr; > or =3 yr postmenarche) who were either born with an appropriate weight for gestational age (AGA; n = 24; mean birthweight, 3.3 kg) or born small for gestational age (SGA; n = 25; mean birthweight, 2.3 kg). The prevalence of anovulation was higher among SGA than AGA girls (40% vs. 4%; P = 0.002). Moreover, in the relatively small fraction of ovulating SGA girls, the ovulation rate was lower than in AGA adolescents (average number of ovulations during the study, 1.4 vs. 1.9; P < 0.01). In conclusion, the endocrine correlates of prenatal growth restraint are herewith extended to include oligo-ovulation and anovulation in adolescence. It remains to be verified whether this SGA-related phenomenon persists into the reproductive age range. If it does, then fetal growth restraint may prove to be one of the enigmatic components underpinning hitherto unexplained female subfertility.     

Both intrauterine growth restriction and postnatal growth influence childhood serum concentrations of adiponectin

OBJECTIVE: Insulin resistance has been linked to intrauterine growth restriction; adiponectin is a strong determinant of insulin sensitivity. We aimed at studying the contributions of birthweight and insulin sensitivity to circulating adiponectin in children born small for gestational age (SGA). DESIGN: Cross-sectional, hospital-based study dealing with insulin sensitivity in SGA children. PATIENTS: Thirty-two prepubertal children born SGA (age 5.4 +/- 2.9 years) and 37 prepubertal children born appropriate for gestational age (AGA, age 5.9 +/- 3.0 years). MEASUREMENTS: Serum levels of fasting glucose, serum lipids, insulin (immunometric assay) and adiponectin concentrations (ELISA) were assessed, and insulin resistance (IR) and insulin secretion (beta-cell) were calculated by the homeostasis model of assessment (HOMA). RESULTS: SGA children had similar HOMA-IR, HOMA-beta-cell and adiponectin concentrations than AGA children. However, in a separate analysis of subjects older than 3 years of age, SGA children showed higher HOMA-IR after adjusting for sex, age and body mass index (BMI) standard deviation score (SDS). Circulating adiponectin was higher in SGA children [adjusted means: 14.5 mg/l (95% CI 12.9-16.1) and 18.7 mg/l (95% CI 17.0-20.3) for AGA and SGA children, respectively; P < 0.0001]. Further analysis revealed that the group of overweight SGA (arbitrarily defined as being in the higher quartile for the BMI SDS distribution in the sample) had decreased serum concentrations of adiponectin, compared to lean SGA children [adjusted means: 12.9 mg/l (95% CI 9.3-16.5) vs. 19.0 (95% CI 16.8-21.3), respectively; P = 0.001]. In a multiple regression model, HOMA-IR and SGA status explained 35% and 15% of adiponectin variance, respectively. CONCLUSIONS: Prenatal growth restriction is associated with insulin resistance but relatively increased adiponectin concentrations, provided overweight does not ensue. The contributions of circulating adiponectin to the increased risks for developing insulin resistance and type-2 diabetes in formerly SGA subjects merit further studies.     

Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial.

The growth-promoting effect of continuous GH treatment was evaluated over 5 yr in 79 children with short stature (height SD score, less than -1.88) born small for gestational age (SGA; birth length SD score, less than -1.88). Patients were randomly and blindly assigned to 1 of 2 GH dosage groups (3 vs. 6 IU/m2 body surface-day). GH deficiency was not an exclusion criterium. After 5 yr of GH treatment almost every child had reached a height well within the normal range for healthy Dutch children and in the range of their target height SD score. Only in children who remained prepubertal during the study period was the 5-yr increase in height SD score (HSDS) for chronological age significantly higher in the study group receiving 6 compared to 3 IU GH/m2 x day. Remarkably, the 5-yr increment in HSDS for chronological age was not related to spontaneous GH secretion, maximum GH levels after provocation, or baseline insulin-like growth factor I levels. GH treatment was associated with an acceleration of bone maturation regardless of the GH dose given. The HSDS for bone age and predicted adult height increased significantly. GH treatment was well tolerated. In conclusion, our 5-yr data show that long term continuous GH treatment at a dose of 3 or 6 IU/m2 x day in short children born SGA results in a normalization of height during childhood followed by growth along the target height percentile.     

Prematurity may be a risk factor for thyroid dysfunction in childhood

CONTEXT: Children born prematurely and/or small for gestational age (SGA) frequently show disturbances in thyroid function. OBJECTIVE: The objective of the study was to determine the role played either by size or gestational age on subsequent thyroid function. DESIGN AND SETTING: This cross-sectional study was conducted at a tertiary referral hospital. PATIENTS: A total of 117 children, 88 of whom were SGA (mean age 7.8 +/- 2.5 yr) and 29 appropriate for gestational age (AGA) (mean age 8.1 +/- 1.9 yr), were selected for the study. MAIN OUTCOME MEASURES: We evaluated TSH, free T(4), free T(3), urinary iodine, and antithyroid antibodies, and all patients underwent a thyroid ultrasound. Insulin sensitivity was assessed with the quantitative insulin sensitivity check index. RESULTS: TSH and free T3 were not significantly different in the two groups, whereas free T4 was higher in the AGA group (P < 0.005). Interestingly, four AGA (13.8%) and 17 SGA (19.3%) patients had TSH levels above the upper limit of normality. Thyroid volume was normal and thyroid autoimmunity was excluded. Urinary iodine was also similar in the two groups (115 +/- 66 vs. 143 +/- 87); however, in both groups there were some children [15 AGA (51%) and 13 SGA (14.7%) (P < 0.001)] with a mild to moderate iodine deficiency. By multiple regression analysis, gestational age was found to be the only determinant of TSH serum levels. Insulin sensitivity was the same in both groups of children and similar to controls. CONCLUSIONS: Some children born prematurely, independently from their birth size, frequently have disturbances of the hypothalamus-pituitary-thyroid axis later in life.     

Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA)

BACKGROUND: Epidemiological studies have shown that the metabolic syndrome, a combination of type 2 diabetes mellitus, hypertension, dyslipidaemia and a high body mass index (BMI), occurs more frequently among adults who were born with a low birth weight. Because insulin is thought to play a key role in the pathogenesis of this syndrome we investigated insulin sensitivity and risk factors for cardiovascular disease in short prepubertal children born small for gestational age (SGA). PATIENTS AND METHODS: Frequently sampled intravenous glucose tolerance tests (FSIGT) were performed in 28 short prepubertal children born SGA. Short stature was defined as a height < -2SD. SGA was defined as a birth length and/or a birth weight for gestational age < -2SD. Twelve short children born appropriate for gestational age (AGA) were used as controls for the FSIGT's results only. AGA was defined as a birth weight and/or birth length for gestational age > -2SD. In short SGA children, blood pressure (BP), fasting levels of serum free fatty acids (FFA), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) were measured and compared to reference values. RESULTS: Mean insulin sensitivity (Si) level in short SGA children was significantly reduced to 38% of the mean Si level measured in short AGA controls (P = 0.004). Mean acute insulin response (AIR) was significantly higher in SGA children compared to short AGA controls (P < 0.001). Differences in Si and AIR between the two groups remained significant after adjusting for age and BMI (P < 0.001 and P = 0.003, respectively). The mean (SD) systolic BP SDS was 1.3 (1,1), being significantly higher than zero. Mean fasting serum levels of FFA, TC, TG, HDL and LDL were all within the normal range. However, 6 of the 28 SGA children had serum FFA levels above the normal range. Cardiovascular risk factors could statistically be represented in two clusters. Both clusters played a significant role in the development of insulin insensitivity (1/Si). CONCLUSION: Although the metabolic syndrome has been described in adulthood, our study showed that risk factors for the development of type 2 diabetes mellitus and cardiovascular disease are already present during childhood in short prepubertal children born SGA, suggesting a pretype 2 diabetes mellitus phenotype.     

Blood glucose concentrations are reduced in children born small for gestational age (SGA), and thyroid-stimulating hormone levels are increased in SGA with blunted postnatal catch-up growth

Fetal growth restriction is associated with an increased risk of developing insulin resistance and type 2 diabetes in adulthood. In addition, 10-20% of children born small for gestational age (SGA) do not achieve a normal final height. The purpose of this study was to investigate insulin sensitivity and endocrine status in SGA children, compared with that in children born appropriate for gestational age (AGA). Furthermore, within the SGA group, we aimed to relate postnatal growth to anthropometric, biochemical, and endocrine parameters. Eighty-two SGA children (with a mean age of 8.6 +/- 3.5 yr) and 53 short-AGA children (with a mean age of 9.3 +/- 3.3 yr) were studied. A case-control study was carried out in 26 SGA and 26 short-AGA subjects. For each SGA subject, we selected a short-AGA child matched for sex, age (within 1 yr), pubertal status, body mass index (within 0.5 kg/m(2)), and height (within 0.25 z-score). Children's statures were corrected for their midparental height, and SGA children were subdivided into 2 groups: catch-up growth (CG) group (children with corrected height with at least 0 z-score); and non-CG (NCG) group (subjects with corrected height with less than 0 z-score). Comparing SGA with short-AGA subjects, no significant differences in fasting insulin, fasting glucose/insulin ratio, homeostasis assessment model for insulin resistance, and homeostasis assessment model-beta-cell values were observed. SGA children showed significantly reduced levels of glucose (4.4 +/- 0.6 vs. 4.9 +/- 0.6 mM, P < 0.0001), total cholesterol (160.1 +/- 28.8 vs. 171.8 +/- 28.5 mg/dl, P = 0.02), and high-density-lipoprotein cholesterol (53.3 +/- 12.1 vs. 58 +/- 11.4 mg/dl, P = 0.02). The analysis of the subjects selected for the case-control study confirmed that SGA children did not have significant differences in the indices of insulin sensitivity but showed significantly lower glucose levels (4.4 +/- 0.7 vs. 4.9 +/- 0.4 mM, P < 0.005). Subdividing the SGA group into CG (n = 25) and NCG (n = 57) children, we found that NCG children showed significantly higher levels of TSH (2.5 +/- 1.3 vs. 1.9 +/- 0.6 mU/liter, P = 0.002). Our data indicate that SGA children do not have altered insulin sensitivity when compared with auxologically identical AGA subjects but show a significant reduction of glucose concentrations. Whether the lower glucose levels are attributable to an early phase of augmented insulin sensitivity, as previously reported in animal models, has to be established. The finding of higher TSH concentrations in SGA children with blunted CG suggests that intrauterine reprogramming might involve thyroid function, which, in turn, might affect postnatal growth and cholesterol metabolism, eventually increasing the risk of cardiovascular disease.     

Insulin, adiponectin, IGFBP-1 levels and body composition in small for gestational age born non-obese children during prepubertal ages

Background Being small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in later life. Adiponectin is a strong determinant of insulin sensitivity. Objective The aim of this study was to evaluate insulin resistance and adiponectin levels in SGA born children with catch‐up growth (CUG) in the absence of obesity in prepubertal ages and relations with body composition and insulin‐like growth factor binding protein (IGFBP)‐1. Methods Twenty‐four (15F, 9M) SGA born children with CUG but without obesity were evaluated at age 6·3 ± 0·5 years with respect to glucose, insulin, IGFBP‐1, leptin and adiponectin levels, and body composition by dual‐energy X‐ray absorptiometry (DEXA). Their data were compared to that of 62 (27F, 35M) appropriate for gestational age (AGA) children. Results SGA and AGA children had similar height standard deviation score (SDS) corrected for parental height and body mass index (BMI) SDS. Homeostasis model for insulin resistance (HOMA‐IR) was significantly high in SGA (0·7 ± 0·6) than in AGA children (0·4 ± 0·2) (P = 0·029). There were no significant differences in leptin, IGFBP‐1, adiponectin, and total and truncal fat between SGA and AGA children. However, being born SGA and having higher BMI in the upper half for the distribution in the sample, although within normal ranges, was associated with lower adiponectin levels (estimated means of log adiponectin levels 3·8 ± 0·3 vs. 4·4 ± 0·1 µg/ml, P = 0·040). Conclusions SGA children with CUG and with no obesity have higher insulin levels compared to AGA children. Both SGA birth and recent size seem to have an effect on serum adiponectin levels in childhood.     

Associations of adiposity from childhood into adulthood with insulin resistance and the insulin-like growth factor system: 65-year follow-up of the Boyd Orr Cohort

CONTEXT: One metabolic pathway through which adiposity influences disease risk may be via alterations in insulin and IGF metabolism. OBJECTIVE: Our objective was to investigate associations of adiposity at different stages of life with insulin and the IGF system. DESIGN, SETTING, AND PARTICIPANTS: The study was a 65-yr follow-up of 728 Boyd Orr cohort participants (mean age, 71 yr) originally surveyed between 1937 and 1939. MAIN OUTCOMES: Outcomes included homeostasis model assessment of insulin resistance, total IGF-I and IGF-II, IGF binding protein (IGFBP)-2, and IGFBP-3 in adulthood. RESULTS: Childhood body mass index (BMI) was weakly inversely related to adult IGF-I (coefficient per BMI sd, -3.4 ng/ml; 95% confidence interval, -7.3 to 0.5; P = 0.09). IGF-II (but not IGF-I) increased with higher current fat mass index (coefficient, 26.1 ng/ml; 95% confidence interval, 4.6 to 47.6; P = 0.02) and waist-hip ratio (30.0 ng/ml; 9.4 to 50.5; P = 0.004). IGFBP-2 decreased by 21.2% (17.2 to 24.9; P < 0.001), and homeostasis model assessment of insulin resistance increased by 38.8% (28.9 to 49.6; P < 0.001) per sd higher adult BMI. Among thin adults (BMI tertiles 1 and 2), IGFBP-2 was positively, and insulin resistance was inversely, associated with childhood BMI. CONCLUSION: There was only weak evidence that associations of childhood BMI with chronic disease risk may be mediated by adult IGF-I levels. Circulating IGFBP-2 in adulthood, a marker for insulin sensitivity, was inversely associated with current adiposity, but overweight children who became relatively lean adults were more insulin sensitive than thinner children. The findings may indicate programming of later insulin sensitivity and consequently IGFBP-2 levels in response to childhood adiposity. The role of IGF-II in obesity-related chronic diseases warrants additional investigation.     

Serum adiponectin levels, insulin resistance, and lipid profile in children born small for gestational age are affected by the severity of growth retardation at birth

OBJECTIVE: Insulin resistance has been linked to intrauterine growth retardation (IUGR); adiponectin is a protein with insulin-sensitizing properties. This study was designed to test whether being born small for gestational age (SGA) has an effect on blood levels of adiponectin and leptin, insulin resistance parameters, and lipid profile in pre-puberty, taking into consideration the severity of IUGR. METHODS: Serum levels of adiponectin, leptin, total cholesterol (t-CHOL), high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides, apolipoproteins A-1 (Apo A-1), Apo B and Apo E, lipoprotein(a) (Lp(a)), fasting glucose, and insulin (Ins), the homeostasis model assessment insulin resistance index (HOMA-IR) and anthropometric indices were evaluated in 70 children aged 6-8 years, born appropriate for gestational age (AGA; n = 35) and SGA (n = 35), matched for age, gender, height, and BMI. SGA children were divided into two subgroups according to the severity of IUGR: SGA<3rd percentile (n = 20), and SGA 3rd-10th percentile (n = 15). They were also subdivided in two subgroups, those with (n = 25) and those without (n = 10) catch-up growth, considering their actual height corrected for mid-parental height. RESULTS: SGA children had higher Ins and HOMA-IR than AGA children (Ins, 42 +/- 23 vs 32 +/- 11 pmol/l; HOMA-IR, 1.30 +/- 0.8 vs 0.92 +/- 0.3; P<0.05). No significant difference in serum leptin was found between the SGA and the AGA groups but adiponectin showed a trend to be higher in SGA children (13.6 +/- 5.7 vs 10.8 +/- 5.9 microg/ml respectively). SGA children without catch-up growth had higher adiponectin (15.6 +/- 8.5 microg/ml, P<0.05) than AGA children. Among the SGA children, the subgroup <3rd percentile had higher Lp(a) than the subgroup 3rd-10th percentile (P<0.05). An independent positive correlation between adiponectin and Lp(a) was observed in SGA children (R = 0.59, P<0.01). CONCLUSION: SGA children, although more insulin resistant, had similar or higher adiponectin levels than matched AGA children in pre-puberty. The severity of IUGR appears to affect their metabolic profile during childhood.     

Insulin resistance and body composition in preterm born children during prepubertal ages

Background Premature born children may show insulin resistance in childhood which may be due to intrauterine or postnatal adverse environmental factors. Objective Aim of this study was to evaluate insulin resistance and body composition in preterm born children born appropriate for gestational age (AGA) or small for gestational age (SGA) and relations with IGF‐I, IGFBP‐3 axis. Methods Ninety‐three preterm born children grouped as premature SGA (n = 30) and premature AGA (n = 63) were evaluated at age 4·6 ± 0·2 years and 4·7 ± 0·1 years with respect to their glucose, insulin, IGF‐I, IGFBP‐3, IGFBP‐1, leptin levels and body composition by dual‐energy X‐ray absorptiometry. Their data were compared to that of body mass index (BMI) matched term SGA (n = 42) and term AGA (n = 44) children of age 4·5 ± 0·2 and 3·8 ± 0·1 years. All children had height appropriate for their target height. Insulin resistance was evaluated by basal insulin and homeostasis model assessment for insulin resistance (HOMA‐IR). Results Basal insulin level was similar in preterm AGA (4·3 ± 1·4 pmol/l) and term AGA (7·9 ± 6·4 pmol/l) children at similar and normal BMI levels. Preterm SGA children had insulin levels (5·0 ± 3·6 pmol/l) similar to preterm AGA children but significantly lower than that in term SGA children (23·7 ± 20·8 pmol/l) (P = 0·001). Similar results were obtained for HOMA‐IR. Term SGA children had also significantly lower IGFBP‐1 levels. Body composition, leptin and IGFBP‐3 did not differ between the respective groups. IGF‐I was lower in preterm AGA (5·0 ± 0·6 nmol/l) than in term AGA (8·3 ± 1·2 nmol/l) (P < 0·001) children. Conclusions Premature born AGA and SGA children do not have insulin resistance when compared to term children if they have made a catch‐up growth appropriate for their target height and have normal BMI. The similar insulin levels in preterm SGA and preterm AGA children together with increased insulin levels in term SGA children points to the fact that it is the intrauterine restriction in the third trimester that has an adverse effect on future adverse metabolic outcome.     

Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA)

OBJECTIVE: Few data are available on the pubertal development of children born small for gestational age (SGA) who fail to show catch-up growth. DESIGN: A longitudinal analysis compared the pubertal course of persistently short children born SGA compared to children with idiopathic short stature who were appropriate for gestational age (AGA). One hundred and twenty-eight short children (height SDS<-1.7), including 76 (31 boys) born SGA and 52 (22 boys) born AGA, were regularly followed from early childhood to completion of puberty. RESULTS: Puberty was attained at normal age (10.5-14 Years in boys, 9.5-13 Years in girls) for most children in both the SGA and AGA groups (boys, 80% and 77%; girls, 76% and 78% respectively). The duration of puberty was similar in the SGA and AGA groups. Menarche occurred at normal age range but was significantly earlier in the SGA girls (P<0.01 by ANOVA). Despite the similar total pubertal growth, the patterns of growth differed significantly: SGA group - accelerated growth and bone maturation rates from onset of puberty with peak height velocity at Tanner stages 2-3, followed by a decelerated growth rate and earlier fusion of the epiphyses; AGA group - steady progression of bone elongation and maturation throughout puberty (pubertal growth, P<0.05 in both sexes; bone maturation, P<0.001 in both sexes). Final height in the SGA group was compromised compared with their target height (P<0.001). CONCLUSION: Children born SGA have a normal pubertal course with a distinct pubertal growth pattern. This pattern may represent an altered regulation of their growth modalities.