Polymorphism in the growth hormone gene, weight in infancy, and adult bone mass

Epidemiological studies point to the importance of gene-environment interactions during early life as determinants of later osteoporosis and fracture. We examined associations between common single nucleotide polymorphisms in the human GH (GH1) gene and weight in infancy, adult bone mass and bone loss rates, and circulating GH profiles. Two hundred and five men and 132 women, aged 61-73 yr, in the Hertfordshire Cohort Study were included; bone mineral density was measured by dual energy x-ray absorptiometry over 4 yr. Twenty-four-hour circulating GH profiles were constructed in a subset of 71 men and women. Genomic DNA was examined for two single nucleotide polymorphisms in the GH gene (one in the promoter region and one in intron 4). Homozygotes at loci GH1 A5157G and T6331A displayed low baseline bone density and accelerated bone loss; there was also a significant (P = 0.04) interaction among weight at 1 yr, GH1 genotype, and bone loss rate. There was a graded association between alleles and circulating GH concentration among men. This study suggests that common diversity in the GH1 region predisposes to osteoporosis via effects on the level of GH expression. The interaction with infant weight suggests that early environment may influence the effect of GH1 genotype on bone loss.     

Detailed analysis of variation at and around mitochondrial position 16189 in a large Finnish cohort reveals no significant associations with early growth or metabolic phenotypes at age 31 years

CONTEXT: Mitochondrial dysfunction is increasingly implicated in pathogenesis of adult metabolic disease. Rare mitochondrial (mt) DNA mutations impair glucose homeostasis, but the contribution of common variants is unclear. In small studies, variation within the OriB origin of replication (at mt16189 in particular) has been associated with both early growth and adult metabolic phenotypes and may contribute to life-course relationships between the two. OBJECTIVE: The aim was to study a large well-characterized cohort to determine whether previously reported small-scale associations between OriB sequence variation and early growth and adult metabolic phenotypes are robust. DESIGN/SETTING/PARTICIPANTS: This was a genetic association study of 5470 individuals from the population-based Northern Finland Birth Cohort of 1966, followed prospectively from pregnancy to age 31 yr. MAIN OUTCOME MEASURES: We measured indices of early growth (including birth weight, placental weight, and ponderal index) and adult metabolic homeostasis (including body mass index, fasting glucose and insulin, indices of insulin action and secretion) and their relationship to variation in the OriB region. RESULTS: Previously reported associations could not be confirmed. There were no significant (P < 0.01, uncorrected) associations between OriB sequence variation and measures of early growth including birth weight (P = 0.52, comparing individuals with mt16189T to those with a homopolymeric C-tract) and placental weight (P = 0.49). There were no significant associations with adult metabolic phenotypes including fasting glucose (P = 0.07), fasting insulin (P = 0.42), and homeostatic model assessment-derived measures of insulin sensitivity or secretion (P = 0.45 and P = 0.56, respectively). CONCLUSION: Despite substantial power to detect previously reported effects, mtDNA variations around OriB are not major contributors to variation in early growth and metabolic phenotypes during early adulthood.     

A longitudinal study of intrauterine growth and the placental growth hormone (GH)-insulin-like growth factor I axis in maternal circulation: association between placental GH and fetal growth

The aim of the study was 1) to evaluate the association of maternal serum levels of placental GH and IGF-I with fetal growth, and 2) to establish reference data for placental GH, IGF-I, and IGF-binding protein-3 (IGFBP-3) in normal pregnancies based on longitudinal measurements. A prospective longitudinal study of 89 normal pregnant women was conducted. The women had, on the average, seven blood samples taken and three ultrasound examinations performed. All had normal umbilical artery pulsatility indexes during pregnancy and gave birth to singletons between 37 and 42 wk gestation with birth weights above -2 SD. Placental GH levels were detectable in all samples from as early as 5 wk gestation and increased significantly throughout pregnancy to approximately 37 wk when peak levels of 22 ng/ml (range, 4.64-69.22 ng/ml) were reached. Subsequently, placental GH levels decreased until birth. The change in placental GH during 24.5-37.5 wk gestation was positively associated with fetal growth rate (P = 0.027) and birth weight (P = 0.027). Gestational age at peak placental GH values (P = 0.007) was associated with pregnancy length. A positive association between the change in placental GH and the change in IGF-I levels throughout gestation was found in a multivariate analysis (r(2) = 0.42; P < 0.001). There was no association between placental GH and IGFBP-3 levels. The change in IGF-I throughout gestation (P = 0.039), but not placental GH, was significantly positively associated with placental weight at birth. We found a significant association between placental GH and fetal growth. In addition, we found a highly significant association between the increase in placental GH and the increase in IGF-I. The gestational age at peak placental GH levels was associated with pregnancy length.     

Serum insulin-like growth factor (IGF)-I and IGF-binding protein-1 in elderly people: relationships with cardiovascular risk factors,body composition,size at birth,and childhood growth

The IGF system is important in regulation of fetal and childhood growth. In later life, IGF-I and IGF-binding protein-1 (IGFBP-1) have been implicated in the pathogenesis of arteriosclerosis. They are, thus, potential candidates in explaining the link between early growth and adult cardiovascular disease. We measured fasting serum IGF-I and IGFBP-1 concentrations in 394 men and women from a cohort of 7086 individuals, born between 1924 and 1933 in Helsinki, Finland, whose weight and height were recorded at birth and from 7 to 15 yr of age. They also underwent clinical examination, including measurement of body fat using bioimpedance, blood pressure, glucose tolerance, and plasma insulin and fibrinogen concentrations. Serum IGF-I was positively correlated with fasting glucose (r = 0.10, P = 0.06) and fibrinogen (r = 0.19, P = 0.0001) concentrations and blood pressure (systolic and diastolic r = 0.10, P 相似文献   

Perinatal growth and plasma GH profiles in adolescent and adult sheep

Poor prenatal growth is associated with limited evidence of GH deficiency in adult humans, which may contribute to their increased risk of cardiovascular and metabolic disease. We therefore examined the effects of placental restriction of fetal growth (PR) on size at birth, neonatal fractional growth rate (FGR) and the circulating GH profile in adolescent and young adult sheep of both sexes. Moderate or severe PR decreased birth size and increased neonatal FGR of weight, crown-rump length and abdominal circumference. In adolescent males, mean and baseline GH concentrations correlated negatively and independently with birth weight and FGR of weight, and mean GH concentrations correlated negatively with current weight. In young adult males, mean GH concentrations correlated negatively and independently with birth shoulder height and FGR of shoulder height whilst, in young adult females, these correlations were positive. This suggests that restricted fetal growth and reduced neonatal growth rate in sheep are followed by elevated circulating GH in adolescent and adult males, but GH deficiency or increased GH clearance in adult females.     

The effects of the ACE gene insertion/deletion polymorphism on glucose tolerance and insulin secretion in elderly people are modified by birth weight

The I allele of an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) appears to be protective against the complications of type 2 diabetes. Low birth weight, a marker of an adverse intrauterine environment, is associated with higher rates of type 2 diabetes. We examined whether the ACE I/D polymorphism could explain or modify the association between low birth weight and adulthood glucose tolerance. We measured plasma glucose and insulin concentrations after an oral glucose challenge in a group of 423 men and women, ages 65-75 yr, with measurements at birth recorded. The presence of the I allele was associated with shorter duration of gestation (P = 0.006) and, relative to gestational age, higher birth weight (P = 0.008) and length (P = 0.02). The I allele was associated with lower glucose at 120 min (P = 0.04) and a greater insulin response (P = 0.03 for insulin at 30 min and P = 0.06 for insulin area under the curve) to a standard oral glucose tolerance test. However, the associations between the ACE genotype and adulthood insulin secretion were only present in people with low birth weight (P for interaction birth weight * ACE genotype on insulin at 30 min = 0.003 and on insulin area under the curve = 0.05). The ACE I allele is associated with shorter duration of gestation and higher birth weight. The association between the presence of the ACE I allele and increased indices of adult insulin secretion is confined to subjects with low birth weight. We suggest that these findings reflect interactions between genotype and intrauterine environment with resulting changes in gene expression.     

Adolescents with partial growth hormone (GH) deficiency develop alterations of body composition after GH discontinuation and require follow-up

It is now a consensus to resume GH treatment in adolescents with severe GH deficiency (GHD) at retesting to prevent the occurrence of adult GHD syndrome. However, we do not have any data on the follow-up of adolescents with nonsevere GHD at completion of treatment. This report presents preliminary data from a 1-yr prospective study that includes the first 91 patients retested. Anthropometric data, IGF-I and IGF binding protein-3 levels, glycemia and insulinemia, lipid profile, and body composition using dual x-ray absorptiometry and abdominal computed tomography scan were recorded at completion of GH treatment and 1 yr later. Body composition was significantly different at both evaluations, with increased total body fat and decreased lean body mass in the partial GHD group vs. the normal group. Moreover, these alterations worsened after 1 yr without GH in the partial GHD group, whereas there were no modifications in the normal group. We did not find any metabolic alterations such as elevated triglyceride, total cholesterol, or insulin levels. Adolescents with reconfirmed partial GHD exhibit alterations in body composition after 1 yr without GH, whereas those retested normal do not. These changes are similar to those described in severe GHD, although less marked, and justify a precise follow-up.     

Early development of visceral fat excess after spontaneous catch-up growth in children with low birth weight

CONTEXT: The sequence of prenatal growth restraint and infantile catch-up of weight is by the age of 4 yr associated with hyperinsulinemic adiposity. We studied whether the adiposity of post-catch-up children born small for gestational age (SGA) is further amplified between age 4 and 6 yr and whether visceral fat excess has already emerged by the age of 6 yr. SETTING: The study took place at a university hospital. STUDY POPULATION AND DESIGN: A longitudinal cohort (age 2-6 yr) of 22 children born appropriate for gestational age (AGA) and 29 born SGA were studied. Auxological, endocrine, metabolic, and body composition (by absorptiometry) assessments were made at 2, 4, and 6 yr, and visceral fat was assessed (by magnetic resonance imaging) at 6 yr. MAIN OUTCOMES: Outcome measures included fasting glucose, insulin, IGF-I, neutrophil to lymphocyte ratio, lean mass, and total, abdominal, and visceral fat mass. RESULTS: Between ages 4-6 yr, the relative adiposity of SGA children was further amplified. Between ages 2-6 yr, SGA children gained more total and abdominal fat and raised their insulin, IGF-I, and neutrophil to lymphocyte ratio more than did AGA children (all P<0.0001). At age 6 yr, the average amount of visceral fat was in SGA children more than 50% higher than in AGA children (P<0.005). The 0- to 2-yr increment in weight Z-score together with the 2- to 6-yr increment in fasting insulin accounted for 62% of visceral fat variability at age 6 yr. CONCLUSION: The amount of visceral fat is in post-catch-up SGA children excessive by the age of 6 yr. In populations at risk for type 2 diabetes or metabolic syndrome after fetal growth restraint, the time window for early intervention may have to be advanced into prepubertal childhood.     

Exogenous GH infusion to late-gestational fetal sheep does not alter fetal growth and metabolism

The role of GH in the regulation of fetal growth and metabolism in late gestation is not well defined. The aim of this study was to determine the effects of exogenous GH infusion on fetal growth and feto-placental metabolism in the normally growing late-gestation fetal sheep. Eleven fetuses received pulsatile GH infusion (3.5 mg/day) for 10 days while 12 control fetuses received vehicle. The GH infusion was given as a continuous infusion (2.5 mg/day) plus an additional pulsatile component (30 pulses equivalent to 1 mg/day) designed to mimic the natural pattern of GH secretion. Fetal GH infusion raised the circulating fetal concentrations of GH threefold, but did not change fetal concentrations of IGF-I, IGF-binding protein-3, insulin or ovine placental lactogen. GH-treated fetuses had blood urea concentrations 15% lower than controls (P<0.05) and glucose uptake 18% lower per kg fetal weig! ht (P=0.06). There were no other differences attributable to fetal GH infusion in feto-placental metabolism, placental function or placental blood flow. GH-treated fetuses were larger than controls at postmortem (weight+13%, P<0.01; girth+5%, P<0.01; crown-rump length+3%, P<0.05). However, there were no differences between groups in measures of fetal growth (increment in chest girth and hindlimb length). GH-treated fetuses had heavier mothers and when maternal weight was included as a covariate in the analysis, there was no significant difference between treatment groups that could be attributed to GH treatment. GH infusion to normal fetal sheep does not appear to have a significant effect on feto-placental metabolism or fetal growth.     

Small for gestational age: short stature and beyond

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.     

Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls

CONTEXT: Low birth weight might increase risk of diabetes mellitus type 2 and metabolic syndrome (MS). GH has insulin-antagonistic properties. Therefore, long-term follow-up of GH-treated children born small for gestational age (SGA) is important. OBJECTIVE AND PATIENTS: The objective of the study was to evaluate insulin sensitivity (Si) and disposition index (DI), all components of the MS and IGF-I and IGF binding protein (IGFBP)-3 levels in 37 previously GH-treated young SGA adults in comparison with 25 untreated short SGA controls. RESULTS: GH-treated subjects were 22.3 (1.7) yr old. Mean duration of GH treatment had been 7.3 (1.3) yr. Mean period after discontinuation was 6.5 (1.4) yr. Si and DI were comparable for GH-treated and untreated SGA subjects. Fasting glucose and insulin levels increased during GH treatment but recovered after discontinuation. Body mass index, waist circumference, high-density lipoprotein cholesterol levels, and triglycerides were equivalent. Systolic and diastolic blood pressure and cholesterol were significantly lower in GH-treated subjects. Thirty-two percent of untreated controls vs. none of the GH-treated subjects had an increased blood pressure. GH-induced rises in IGF-I and IGFBP-3 levels had completely recovered after GH stop. CONCLUSION: At 6.5 yr after discontinuation of long-term GH treatment, Si, DI, fasting levels of glucose and insulin, body mass index, waist circumference, and IGF-I and IGFBP-3 levels were equivalent for GH-treated and untreated young SGA adults. Systolic and diastolic blood pressure and serum cholesterol were even lower in GH-treated subjects. These data are reassuring because they suggest that long-term GH treatment does not increase the risk for diabetes mellitus type 2 and MS in young adults.     

胰岛素-胰岛素样生长因子代谢轴在胎儿生长发育中的作用

目的探讨胰岛素-胰岛素样生长因子（IGF）代谢轴在胎儿宫内生长发育中的作用。方法连续收集266名单胎足月新生儿基本资料,采用放免法检测脐血胰岛素和IGF水平。结果（1）脐血胰岛素水平与出生体重、BMI、身长和胎盘重量均呈正相关（P〈0．01）。（2）脐血IGF水平与出生体重、BMI、身长和胎盘重量均呈正相关（P〈0．01）。（3）脐血胰岛素水平和IGF水平呈显著正相关（P〈0．01）。结论脐血胰岛素、IGF水平可作为评价胎儿宫内生长发育情况的参考指标。     

Reduced foetal growth and growth hormone secretion in adult life

OBJECTIVES: Recent studies suggest that growth restriction or other adverse influences acting in utero or during early infancy lead to permanent alterations in growth hormone (GH) secretion. As GH secretion is known to predict cardiovascular risk, alterations in GH may contribute to the association between reduced foetal growth and cardiovascular disease. We have therefore assessed the relationship between birth size and GH secretion in a prospective study of young adults whose birth size was recorded and who have had their current blood pressure and glucose tolerance measured. DESIGN: Prospective cohort study PATIENTS: 153 healthy men and women, aged 20-21 years. MEASUREMENTS: Subjects carried out a timed overnight urinary collection for analysis of GH excretion. Insulin sensitivity and insulin secretion were measured using the intravenous glucose tolerance test with minimal model analysis. Blood pressure, height, weight, usual level of exercise, smoking habits, alcohol consumption, and socio-economic status were also recorded. RESULTS: GH excretion ranged from 0.01 to 41.8 microU per subject. It did not differ according to gender but was markedly reduced in obese subjects (P < 0.0001) Low birthweight was strongly associated with low GH excretion at age 20 years (P = 0.002). Low placental weight and short body length also predicted low GH (P = 0.02 and P = 0.04, respectively). These relationships were independent of other confounding factors including obesity. GH excretion was not independently related to current levels of blood pressure, insulin sensitivity or insulin secretion. CONCLUSIONS: Body size at birth predicts GH excretion in adult life. Low GH excretion in people who were small at birth may be one mechanism explaining their increased risk of cardiovascular disease.     

Placental GH,IGF-I,IGF-binding protein-1, and leptin during a glucose challenge test in pregnant women: relation with maternal body weight,glucose tolerance,and birth weight

The prediction of birth weight may be improved by the measurement of hormones or growth factors in the mother. We measured body weight (BW) and plasma levels of placental GH (PGH), IGF-I, IGF-binding protein-1 (IGFBP-1), and leptin at the time of the glucose challenge test (GCT) in 289 women, who were pregnant with a single fetus, between 24 and 29 wk gestational age (GA). Delivery occurred 12 +/- 2 (mean +/- SD) wk later. First, we examined which variables regulate these hormonal factors. Multiple regression showed that PGH concentrations were determined by GA at sampling and were negatively related to BW. IGF-I levels were mainly determined by PGH, and also by insulin, BW, and (negatively) age. IGFBP-1 concentrations were negatively determined by BW, insulin, and IGF-I. BW was also a powerful determinant of leptin levels, with insulin as a less robust determinant. Second, we examined the relation to glucose levels. PGH, IGF-I, and IGFBP-1 concentrations were not correlated with post-GCT glucose levels and were comparable in women with a normal or disturbed GCT (glucose >/=7.8 mmol/liter; n = 72). Finally, we examined the relation with birth weight and placental weight. Birth weight, corrected for GA and stratified into percentile groups, and the ponderal index at birth were strongly related to maternal BW, but not to maternal PGH, IGF-I, or IGFBP-1 levels. Neither was maternal leptin related to birth weight, but leptin concentrations were slightly higher in women who delivered obese babies. Placental weight was not related to any of the hormonal factors. This prospective study indicates that the variation in circulating PGH, IGF-I, IGFBP-1, and leptin between 24 and 29 wk of pregnancy is strongly dependent on maternal BW, but is unrelated to glucose tolerance. In addition, the measurement of PGH, IGF-I, IGFBP-1, or leptin at the time of the GCT is not useful clinically to predict birth weight.     

Laparoscopic adjustable gastric banding for the treatment of morbid (grade 3) obesity and its metabolic complications: a three-year study

Weight loss ameliorates arterial hypertension and glucose metabolism in obese patients, but the dietary approach is unsatisfactory because obesity relapses. Durable reduction of body weight, obtained through major nonreversible surgical procedures, such as jejunal and gastric bypass, allows improvement of glucose metabolism and arterial blood pressure in morbid (grade 3) obesity. Laparoscopic adjustable gastric banding (LAGB) is a minimally invasive and reversible surgical procedure that yields a significant reduction of gastric volume and hunger sensation. In this study, 143 patients with grade 3 obesity [27 men and 116 women; age, 42.9 +/- 0.83 yr; body mass index (BMI), 44.9 +/- 0.53 kg/m(2); normal glucose tolerance (NGT; n = 77); impaired glucose tolerance (IGT; n = 47); type 2 diabetes mellitus (T2DM; n = 19)] underwent LAGB and a 3-yr follow-up for clinical (BMI, waist circumference, waist to hip ratio, and arterial blood pressure) and metabolic variables (glycosylated hemoglobin, fasting insulin and glucose, insulin and glucose response to oral glucose tolerance test, homeostasis model assessment index, total and high-density lipoprotein cholesterol, triglycerides, uric acid, and transaminases). At baseline and 1 yr after LAGB, patients underwent computerized tomography and ultrasound evaluation of visceral and sc adipose tissue. One-year metabolic results were compared with 120 obese patients (51 men and 69 women; age, 42.9 +/- 1.11 yr; BMI, 43.6 +/- 0.46 kg/m(2); NGT, n = 66; IGT, n = 8; T2DM, n = 46) receiving standard dietary treatment. LAGB induced a significant and persistent weight loss and decrease of blood pressure. Greater metabolic effects were observed in T2DM patients than in NGT and IGT patients, so that at 3 yr glycosylated hemoglobin was no longer different in NGT and T2DM subjects. Clinical and metabolic improvements were proportional to the amount of weight loss. LAGB induced a greater reduction of visceral fat than sc fat. At 1-yr evaluation, weight loss and metabolic improvements were greater in LAGB-treated than diet-treated patients. We conclude that LAGB is an effective treatment of grade 3 obesity in inducing long-lasting reduction of body weight and arterial blood pressure, modifying body fat distribution, and improving glucose and lipid metabolism, especially in T2DM.     

Sex hormone-binding globulin and insulin-like growth factor-binding protein-1 as indicators of metabolic syndrome, cardiovascular risk, and mortality in elderly men

Two binding proteins, SHBG and IGF-binding protein-1 (IGFBP-1), are both down-regulated by insulin and therefore could serve as potential indicators of the metabolic syndrome and hyperinsulinemia-related cardiovascular risk. We compared serum SHBG and IGFBP-1 as potential markers of abnormal glucose tolerance, the metabolic syndrome, diabetes mellitus, cardiovascular risk factors, and total, cardiovascular, and coronary heart disease mortality in elderly men. Of the original cohort of 1711 men, 524 were alive on January 1, 1989, and 413 participated in the 30-yr examination, of whom 335 men, aged 70-89 yr, formed the study group for the present analysis. Low SHBG and IGFBP-1 were both associated with an increased prevalence of abnormal glucose tolerance and the metabolic syndrome, but only SHBG was associated with diabetes mellitus. SHBG was less influenced by body mass index than IGFBP-1. Low SHBG indicated increased cardiovascular and coronary disease mortality; the association remained after adjustment for abnormal glucose tolerance, but not after adjustment for prevalent cardiovascular disease. IGFBP-1 had no association with mortality. It is concluded that low SHBG is a better indicator of increased cardiovascular mortality than low or high IGFBP-1.     

The exon 3-deleted/full-length growth hormone receptor polymorphism does not influence the effect of puberty or growth hormone therapy on glucose homeostasis in short non-growth hormone-deficient small-for-gestational-age children: results from a two-year controlled prospective study

CONTEXT: The exon 3-deleted/full-length (d3/fl) GH receptor polymorphism (d3/fl-GHR) has been associated with responsiveness to GH therapy in short small-for-gestational-age (SGA) patients, although consensus is lacking. However, its influence on glucose homeostasis, at baseline or under GH therapy, has not been investigated. OBJECTIVE: Our objective was to evaluate whether the d3/fl-GHR genotypes influence insulin sensitivity in short SGA children before or after puberty onset or during GH therapy. DESIGN: We conducted a 2-yr prospective, controlled, randomized trial. SETTING: Thirty Spanish hospitals participated. Auxological, GH secretion, and glucose homeostasis evaluation was hospital based, whereas molecular analyses and data computation were centralized. PATIENTS: Patients included 219 short SGA children [body mass index sd score (SDS) < or = 2.0]; 159 were prepubertal (group 1), and 60 had entered puberty (group 2). INTERVENTION: Seventy-eight patients from group 1 were treated with GH (66 microg/kg.d) for 2 yr (group 3). MAIN OUTCOME MEASURES: Previous and 2-yr follow-up auxological and biochemical data were recorded, d3/fl-GHR genotypes determined, and data analyzed. RESULTS: In groups 1 and 2, fasting glucose, insulin, homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI) were similar in each d3/fl-GHR genotype. Group 2 glucose, insulin, and HOMA were significantly higher and QUICKI lower than in group 1. In group 3 GH-treated patients, height SDS, growth velocity SDS, fasting glucose, insulin, and HOMA significantly increased as did body mass index SDS at the end of the second year, and QUICKI decreased during the first and second years, with no differences among the d3/fl-GHR genotypes. CONCLUSION: In short SGA patients, the d3/fl-GHR genotypes do not seem to influence prepubertal or pubertal insulin sensitivity indexes or their changes over 2 yr of GH therapy (66 mug/kg.d).     

Fetal insulin-like growth factor (IGF)-I, IGF-II, and ghrelin in association with birth weight and postnatal growth in monozygotic twins with discordant growth

OBJECTIVE: To investigate the relative contribution of genetic (fetal) vs. environmental (maternal/placental) factors on growth, we studied monozygotic twins with intertwin birth weight difference. PATIENTS AND METHODS: Twenty-seven twins (15 with discordant growth) who have been treated for severe twin-to-twin transfusion syndrome by laser coagulation were studied. Cord blood samples were analyzed for IGF-I, IGF-II, IGF-binding protein-2, and ghrelin. Intertwin difference (Delta) of birth weight was correlated to Delta of the parameters analyzed. The Delta weight after 1 yr was correlated with Delta birth weight and all hormones. RESULTS: The Delta birth weight was positively correlated with Delta IGF-I (r = 0.66; P < 0.0002) and negatively correlated with Delta IGF-binding protein-2 levels (r = -0.68; P < 0.001) but with neither Delta IGF-II nor Delta ghrelin. There was a strong intertwin correlation for all hormones. By comparing the growth in the first year, we found an overall reduction of the relative weight difference between the twins of 57%. ANOVA was used to calculate factors for prediction of postnatal catch-up growth. Besides the birth weight difference (R2= 0.84; P < 0.0001), only ghrelin was of prognostic value for postnatal catch-up growth (R2= 0.94; P = 0.0035). CONCLUSION: These data confirm the importance of IGF-I in contrast to IGF-II for fetal weight. Additionally, ghrelin seems to be involved in fetal and probably postnatal growth.