Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency.

BACKGROUND: Growth hormone insufficiency (GHI) is diagnosed conventionally by short stature and slow growth, and is confirmed by diminished peak GH response to a provocation test. Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) have previously been considered individually OBJECTIVE: To test the hypothesis that the combined analysis of IGF-I and IGFBP-3 could act as a surrogate marker for the diagnosis of GHI. DESIGN: Reference ranges for IGF-I and IGFBP-3 were calculated using 521 normal individuals. A retrospective analysis was performed on 318 children referred for investigation of short stature. RESULTS: No significant difference was found between either the IGF-I or IGFBP-3 standard deviation scores (SDSs) in children with and without GHI. If the requirement were for both tests to be positive (< -2 SDS) for a diagnosis of GHI, then 99% of children without GHI would be correctly identified; however, the sensitivity of the test was only 15%. CONCLUSIONS: Neither IGF-I nor IGFBP-3 alone is a marker for GHI. In addition, they cannot be used as an effective screening test in combination.     

早期不同饮食营养干预对宫内生长迟缓幼鼠生长追赶的影响

目的　探讨生后早期给予不同饮食构成的营养干预对宫内生长迟缓 (IUGR)幼鼠生长追赶的影响。方法　采用孕母饥饿法建立IUGR大鼠模型 ,32只IUGR新生雌鼠和 8只正常新生雌鼠随机分为五组 (每组 8只 ) :①正常对照组 (C组 ) ,②IUGR模型组 (S组 ) ,③IUGR低蛋白组 (SL组 ) ,④IUGR高蛋白组 (SH组 ) ,⑤IUGR高热卡组 (SA组 )。于生后第 4周测定各组幼鼠的血清胰岛素样生长因子 1(IGF1)及其结合蛋白 3(IGFBP3)浓度和体重、身高、小肠重量、长度及小肠绒毛高度 (VH)、隐窝深度 (CD)、吸收表面积 (VSA)、粘膜厚度 (MT)。结果　IUGR高蛋白组血清IGF1、IGFBP3和小肠VH、VSA、MT及体重均高于C组和S组 (P <0 0 5或P <0 0 1) ;小肠重量、长度和身高与C组比较差异无显著意义 (P >0 0 5 )。血清IGF1与IGFBP3、小肠重量、长度和VH、VSA及体重、身高均呈正相关 (均P <0 0 5 )。结论　血清IGF1是反映生长追赶和营养状态的灵敏指标 ,与小肠和体格的生长追赶呈正相关。生后早期予高蛋白饮食组干预效果较佳 ,可通过促进小肠绒毛的发育和增加营养物质吸收表面积而达到满意的生长追赶。     

Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency

BACKGROUND—Growth hormone insufficiency (GHI) is diagnosed conventionally by short stature and slow growth, and is confirmed by diminished peak GH response to a provocation test. Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) have previously been considered individuallyOBJECTIVE—To test the hypothesis that the combined analysis of IGF-I and IGFBP-3 could act as a surrogate marker for the diagnosis of GHI.DESIGN—Reference ranges for IGF-I and IGFBP-3 were calculated using 521 normal individuals. A retrospective analysis was performed on 318 children referred for investigation of short stature.RESULTS—No significant difference was found between either the IGF-I or IGFBP-3 standard deviation scores (SDSs) in children with and without GHI. If the requirement were for both tests to be positive (< ?2 SDS) for a diagnosis of GHI, then 99% of children without GHI would be correctly identified; however, the sensitivity of the test was only 15%.CONCLUSIONS—Neither IGF-I nor IGFBP-3 alone is a marker for GHI. In addition, they cannot be used as an effective screening test in combination.     

Insulin-like growth factor-I (IGF-I) ameliorates and IGF binding protein-1 (IGFBP-1) exacerbates the effects of undernutrition on brain growth during early postnatal life: studies in IGF-I and IGFBP-1 transgenic mice

Insulin-like growth factor-I (IGF-I) plays an important role in the stimulation of postnatal brain growth. In transgenic (Tg) mice, IGF-I overexpression stimulates postnatal brain growth, whereas decreased IGF-I availability caused by ectopic brain expression of IGF binding protein-1 [(IGFBP-1), an inhibitor of IGF-I action] retards postnatal brain growth. Because undernutrition during early postnatal development profoundly retards growth and maturation of the brain in rodents, we sought to determine the influence of IGF-I on undernutrition-induced brain growth retardation. Caloric restriction was imposed on IGF-I Tg mice, IGFBP-1 Tg mice, and their non-Tg littermates by separating half of each litter from their dams during the suckling period, postnatal d 1 to 21. Undernutrition reduced the brain growth of each group of mice, but the growth of undernourished IGF-I Tg mice was comparable to that of well-fed control mice (increased 4.13- and 4.22-fold, respectively) and greater than that of undernourished control mice (increased 3.45-fold), whereas undernourished IGFBP-1 Tg mice exhibited less growth (increased 3.15-fold) than undernourished control mice. When the effects of undernutrition were examined in specific brain regions of each group, the same pattern was observed, and IGF-I was found to be more effective in preserving the growth of the regions with the highest transgene expression (cerebral cortex, hippocampus, and diencephalon). Despite undernutrition, IGF-I transgene expression stimulated overgrowth of these regions as well as that of the posterior medial barrel subfield, a somatosensory area of the cerebral cortex in which IGF-I may be especially important in development. These data indicate that IGF-I can ameliorate the brain growth retardation caused by undernutrition imposed during development, although it is unclear whether IGF-I directly opposes the impact of undernutrition or acts independently of nutritional status. Nonetheless, these findings raise the possibility that the relatively high IGF-I expression during early postnatal life may be responsible for sparing the brain from the full impact of undernutrition during this time in development.     

Aortic intima-media thickness, serum IGF-I, IGFBP-3, and leptin levels in intrauterine growth-restricted newborns of healthy mothers

Neonates with intrauterine growth restriction (IUGR) are associated with reduced concentrations of IGF-I that might contribute to arterial wall thickening. Direct atherogenic effects of leptin have been described. We aimed to investigate the relationship among abdominal aortic intima-media thickness (aIMT), serum IGF-I, IGF binding protein-3, and leptin levels in neonates with IUGR. Abdominal aIMT was measured in 40 term neonates with IUGR and in 40 controls. Mean aIMT was significantly greater in neonates with IUGR (0.45 +/- 0.03 mm) than in controls (0.39 +/- 0.04 mm, p < 0.0001). Serum IGF-I and leptin levels were lower in neonates with IUGR than in controls. There was a significant positive correlation between aIMT and gestational age, whereas a significant negative correlation was determined between aIMT and IGF-I in the IUGR neonates. For aIMT, significant associations included serum IGF-I level (beta = -0.406, p = 0.006) and gestational age (beta = 0.331, p = 0.022) in a multiple stepwise linear regression analysis. In control neonates, serum IGF-I levels were negatively related to aIMT (beta = -0.750, p < 0.001). Neonates with IUGR have significant aIMT with decreased IGF-I. IGF-I levels determine aIMT not only in neonates with IUGR but also in healthy controls.     

Ghrelin, IGF-I and IGFBP-3 levels in children with type 1 diabetes mellitus

There is a strong relationship between ghrelin, insulin, glucose and IGF-I/IGFBP-3 metabolism. This aim of this study was to investigate ghrelin level, and its relationship with IGF-I and IGFBP-3 levels in children with type 1 diabetes mellitus (DM1). Twenty-seven children with DM1 and 25 healthy controls were investigated. Ghrelin levels were similar, and IGF-I and IGFBP-3 levels were lower, in prepubertal and pubertal patients compared to controls. In the patient group, ghrelin levels were negatively correlated with chronological age, height, weight, pubertal status and IGF-I, but had no correlation with fasting glucose, HbA1c, insulin dose, duration of insulin therapy, and IGFBP-3 levels. Similar ghrelin levels in patients compared to controls may suggest that ghrelin levels remain unchanged in children with DM1, or that altered ghrelin levels at diagnosis recover as a consequence of insulin therapy. The lack of correlation of serum ghrelin levels with fasting plasma glucose, HbA1c and insulin dose suggests that ghrelin level is not affected by these parameters. Decreased IGF-I level and its negative correlation with ghrelin are compatible with previous findings.     

早期营养干预对宫内生长迟缓大鼠胰岛素样生长因子和小肠发育及生长追赶的影响

目的　探讨早期营养干预对宫内生长迟缓 (IUGR)幼鼠血清胰岛素样生长因子 (IGF)和小肠发育及生长追赶的影响。方法　将 2 4只IUGR新生雌鼠和 8只正常新生雌鼠随机分为 4组 :IUGR模型组 ,IUGR低蛋白组 ,IUGR高蛋白组 ,正常对照组。于生后 4周时检测各组大鼠血清IGF1、胰岛素样生长因子结合蛋白 3(IGFBP3)浓度、体重、身长和小肠重量、长度及肠黏膜组织结构变化。结果　 4周时IUGR高蛋白组血IGF1、IGFBP3和小肠黏膜绒毛高度、吸收表面积均显著高于对照组和IUGR模型组 (P <0 .0 5或P <0 .0 1) ;小肠重量、长度和体重、身长与对照组比较无显著性差异 (P均 >0 .0 5 )。结论　生后头 4周予高蛋白饮食早期营养干预IUGR幼鼠 ,可通过促进小肠发育达到满意的体格生长追赶。血清IGF1是反映生长追赶的灵敏指标     

Alterations in serum growth hormone (GH)/GH dependent ternary complex components (IGF-I, IGFBP-3, ALS, IGF-I/IGFBP-3 molar ratio) and the influence of these alterations on growth pattern in female rhythmic gymnasts

BACKGROUND AND AIM: Normal growth in children is regulated to a great extent through the actions of the GH/IGF-I axis, a system consisting of GH and its mediators (ternary complex) that modulate growth in many tissues. The ternary complex (IGF-I/IGFBP-3/ALS) provides an acute regulatory mechanism in which IGF-I may be mobilized from the circulating reservoir of 150 kDa complexes to the tissues. Acute exercise is known to be a stimulus for GH secretion. The beneficial effects of scheduled exercise on body composition are also well established. However, the impact of strenuous exercise on the pubertal development of child athletes is still not well understood. The first goal of this study was to assess the acute effects of high intensity exercise training on GH-dependent ternary complex components in female rhythmic gymnasts compared to age-matched healthy female controls with normal physical activity. The second goal was to explore the influence of these exercise-induced changes on skeletal and pubertal growth in the same group prospectively over a period of 4 years. SUBJECTS AND METHODS: Seventeen female rhythmic gymnasts, aged 11.4 +/- 0.9 years, who had 10 h per week intense exercise for at least 4 months volunteered to participate in this study. Anthropometric measurement of height (Height SDS for chronological age [HtSDS(CA)], parentally adjusted height, predicted adult height), bone age and weight (BMI) were made using standard techniques in gymnasts and controls (aged 12.5 +/- 3.0 years, n = 12). Gymnasts were followed up to 4 years to observe growth velocity and pubertal progression. In order to determine the acute impact of exercise on levels of GH and GH-dependent ternary complex component (IGF-I, IGFBP-3, ALS, IGF-I/IGFBP-3 molar ratio), blood samples were obtained from gymnasts after a routine 2-h high-intensity training program and then after a 2-day rest period. These results were compared with age-matched controls with no scheduled sports activity. RESULTS: Despite the significant increment in serum GH and GH-dependent components immediately following the exercise, serum GH/IGF-I levels showed a significant decrement (p < 0.01) after a 2-day rest in gymnasts, to a nadir as low as those of the control subjects' baseline levels (p < 0.01). There was no difference in anthropometric characteristics of gymnasts and controls except BMI; gymnasts were leaner than controls. During a 4-year follow up, there were no differences between the gymnasts and controls in regard to skeletal growth and reaching their predicted height. However, in gymnasts there was a delay in pubertal tempo but not in growth. CONCLUSION: Intense exercise induces an acute rise in GH levels, but this acute elevation rapidly normalizes after a 2-day rest in female rhythmic gymnasts. These fluctuations in serum GH and GH-dependent ternary complex components had no reflection on the skeletal growth patterns in gymnasts over the 4-year follow up but there was a delay in their pubertal progression.     

生长追赶及宫内生长迟缓对大鼠脂肪细胞增殖分化及功能的影响

目的探讨宫内生长迟缓(IUGR)生长追赶对大鼠脂肪细胞增殖分化及功能的影响。方法母鼠孕期饥饿法建立IUGR模型,仔鼠出生后减少每窝仔鼠数以实现生长追赶;大鼠4周时取肾周白色脂肪组织进行前脂肪细胞和成熟脂肪细胞培养并诱导分化。测定前脂肪细胞增殖能力,成熟脂肪细胞脂联素分泌水平、葡萄糖摄取率,以及各前脂肪细胞及成熟脂肪细胞的二酰基甘油酰基转移酶(DGAT)、脂蛋白脂肪酶(LPL)、胰岛素受体底物1和2(IRS1、IRS2)、磷脂酰肌醇3-激酶(PI3K)mRNA表达水平。结果 IUGR大鼠前脂肪细胞的后期增殖能力高于对照组(P<0.05);IUGR大鼠成熟脂肪细胞的脂联素分泌水平低于对照组(P<0.01),葡萄糖摄取率无变化(P>0.05)。IUGR大鼠前脂肪细胞,成熟细胞的DGAT、LPL mRNA表达水平高于对照组(P<0.01),IRS1、IRS2 mRNA表达水平均低于对照组(P<0.05),PI3K mRNA表达水平无变化(P>0.05)。结论 IUGR可能在大鼠胎儿期即引起脂肪组织多基因改变,影响前脂肪细胞的增殖分化,改变成熟脂肪细胞的糖脂代谢功能,进而造成生后生长追赶者胰岛素抵抗的易感性。     

Effects of catch-up growth and intrauterine growth retardation on proliferation,differentiation and function of adipocytes in rats

目的 探讨宫内生长迟缓(IUGR)生长追赶对大鼠脂肪细胞增殖分化及功能的影响.方法 母鼠孕期饥饿法建立IUGR模型,仔鼠出生后减少每窝仔鼠数以实现生长追赶;大鼠4周时取肾周白色脂肪组织进行前脂肪细胞和成熟脂肪细胞培养并诱导分化.测定前脂肪细胞增殖能力,成熟脂肪细胞脂联素分泌水平、葡萄糖摄取率,以及各前脂肪细胞及成熟脂肪细胞的二酰基甘油酰基转移酶(DGAT)、脂蛋白脂肪酶(LPL)、胰岛素受体底物1和2(IRS1、IRS2)、磷脂酰肌醇3-激酶(P13K)mRNA表达水平.结果 IUGR大鼠前脂肪细胞的后期增殖能力高于对照组(P<0.05);IUGR大鼠成熟脂肪细胞的脂联索分泌水平低于对照组(P<0.01),葡萄糖摄取率无变化(P>0.05).IUGR大鼠前脂肪细胞,成熟细胞的DGAT、LPLmRNA表达水平高于对照组(P0.05).结论 IUGR可能在大鼠胎儿期即引起脂肪组织多基因改变,影响前脂肪细胞的增殖分化,改变成熟脂肪细胞的糖脂代谢功能,进而造成生后生长追赶者胰岛素抵抗的易感性.     

宫内发育迟缓与胰岛素样生长因子及其结合蛋白关系研究

为了解脐血中胰岛素样生长因子_I(IGF -I)、胰岛素样生长因子结合蛋白_3(IGFBP_3)的水平变化与胎儿期生长的关系 ,将86例新生儿脐血标本分为宫内发育迟缓 (IUGR ,即小于胎龄儿 )组 (22例 )及适于胎龄儿 (AGA)组 (64例 )两组 ,采用竞争性放射免疫分析法 (RIA)测定IGF_1水平、非竞争性免疫放射分析法 (IRMA)测定IGF BP_3水平。结果显示 ,与AGA组相比 ,IUGR组脐血中IGF_1和IGFBP_3水平显著降低 (P均<0.01) ;IGF_1、IGFBP_3水平均随胎龄及出生体重增加而增加 (P均<0.01) ;IGFBP_3与IGF_1呈正相关 (P<0.01)。提示IUGR与IGF_1及其结合蛋白降低密切相关 ;脐血中IGF_1、IGFBP_3水平与胎龄及出生体重呈正相关     

Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3

OBJECTIVE: To examine the effect of carbamezapine and valproate on bone mineral density (BMD), IGF-I and IGFBP-3 levels in children. METHODS: The effects of at least 2 years valproic acid and carbamazepine therapy on BMD were evaluated in a cross-sectional and retrospective study. All children were ambulatory, prepubertal, and had normal activity and nutritionally adequate diets. Ambulatory epileptic patients were divided into two groups. Thirty-three patients (group 1; 17 boys, 16 girls; mean age: 8.8 +/- 2.0 years) were treated with valproic acid and 33 patients were treated with carbamazepine (group 2; 20 boys, 13 girls; mean age: 9.7 +/- 1.6 years). The control group consisted of 22 healthy children (13 boys, 9 girls; mean age: 8.9 +/- 2.3 years), who were age- and sex-matched with the patient groups. Children with metabolic bone disease, growth and neurological impairment, signs of malnutrition, or any chronic disease were excluded from the study. RESULTS: BMD values at lumbar spine in both the carbamazepine (-1.69 +/- 0.85 mean L1-4 BMD z-scores, mean 35.5 +/- 12.8 months treatment, and 19,478.6 +/- 6,301.3 mg/kg cumulative dose) and valproic acid (-1.28 +/- 0.80 mean L1-4 BMD z-scores, mean 33.7 +/- 15.0 months treatment, and 22,852.4 +/- 12,477.4 mg/kg cumulative dose) groups were significantly lower than that of the control group (-0.23 +/- 0.87 mean L1-4 BMD z-score). Serum ALP and PTH levels were significantly higher in the carbamazepine-treated group (65.4 +/- 21.1 pg/ml, 767 +/- 267 U/l, respectively) than those of the valproic acid-treated (39.1 +/- 12.8 pg/ml, 561 +/- 166 U/l, respectively) and control groups (36.3 +/- 4.9 pg/ml, 487 +/- 82 U/l, respectively). Serum 25-hydroxyvitamin D of the carbamazepine-treated group (9.8 +/- 3.2 microg/l) was significantly lower than the other groups (15.1 +/- 3.5, 16.6 +/- 4.7 microg/l, respectively). There were eight and 13 patients with plasma intact PTH above reference values in groups 1 and 2, respectively. Valproic acid and carbamazepine therapy results in a hyperparathyroid state and altered vitamin D metabolism, respectively. CONCLUSION: BMD values at lumbar spine were significantly reduced in both carbamezapine and valproic acid treated groups. Valproic acid and carbamazepine therapy do not change IGF-I and IGFBP-3 levels. Altering the hepatic conversion of vitamin D may be the mechanism of carbamazepine-associated reduction in BMD, but the mechanism of decreased BMD in valproate therapy remains unclear.     

The relationship between ovarian structure and serum insulin, insulin-like growth factor-I (IGF-I) and its binding protein (IGFBP-1 and IGFBP-3) levels in premature pubarche

The aim of this study was to determine serum insulin, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-1 and IGFBP-3) levels and their relationship with androgen levels and ovarian structure in 23 girls with premature pubarche (PP). Fasting levels of testosterone, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), androstenedione (delta4A), sex hormone binding globulin (SHBG), glucose (G), insulin (I), IGF-I, IGFBP-1, IGFBP-3 were measured. Androgens or steroid hormone levels > 3 SD of normal postpubertal levels were considered as an exaggerated response to the ACTH test. The fasting I to G ratio (FIGR) was calculated and FIGR > 22 was suggestive of insulin resistance (IR). A pelvic ultrasound (US) was carried out and the ovarian structure was divided into five classes (c): c1--homogeneous, c2--microcystic, c3--multicystic, c4--polycystic and c5--follicular. The girls with PP were divided into two groups according to the main ovarian classes observed: PPc1 (n = 6) and PPc2 (n = 15). The FIGR showed IR in 44% of patients. The androgens, SHBG, G, I, FIGR, IGF-I and IGFBP-1 levels were similar among the groups (PPc1 vs PPc2). An exaggerated response to ACTH was more common and IGFBP-3 levels were higher in the PPc2 than in the PPc1 group (p = 0.04). Regression analysis revealed that I was correlated with DHEAS (r = -0.43, p = 0.04) and IGFBP-1 (r = -0.51, p = 0.01); IGF-I was correlated with DHEA (r = -0.42, p = 0.05), delta4A (r = -0.47, p = 0.02), SHBG (r = -0.43, p = 0.04), IGFBP-1 (r = -0.61, p = 0.002) and IGFBP-3 (r = 0.56, p = 0.005); IGFBP-1 was correlated with SHBG (r = 0.56, p = 0.005). These findings suggest that there might be interactions between the insulin-IGF-I-IGFBPs system and hyperandrogenism. However, the possible causal role of adrenal androgen hypersecretion on the insulin-IGF-I-IGFBPs axis and ovarian structure in girls with PP remains to be established. Since studies reveal that IGFBP-3 levels could be a negative predictor for insulin sensitivity throughout puberty, we hypothesize that girls with PP and microcystic ovaries are at risk of developing IR in the course of normal puberty.     

Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome

It is well established that insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and insulin are low in growth hormone deficiency, but due to their dependence on nutrition, they are elevated in healthy obese children. As the presence of growth hormone deficiency in Prader-Labhart-Willi syndrome (PWS) is still controversial, we studied insulin, IGF-I and IGFBP-3 levels in 19 children with PWS (age range 0.5–14.6 years). Serum concentrations of insulin (SDS: −0.7±0.9, P=0.01) and IGF-I (SDS: −0.7±0.8,P=0.002) were low, but IGFBP-3 (SDS: −0.3±1.2, P=0.2) was normal compared to normal weight age-matched children. Since children with PWS are typically obese, insulin, IGF-I and IGFBP-3 levels should be compared to normal obese children who present increased levels of these hormones. In comparison to data of healthy obese children reported in the literature, not only IGF-I, but also IGFBP-3 levels are low and fasting insulin levels even very low, suggesting a growth hormone deficiency. Received: 19 November 1997 / Accepted in revised form: 2 March 1998     

Influence of maternal smoking on neonatal aortic intima-media thickness,serum IGF-I and IGFBP-3 levels

Epidemiological studies have reported associations between a range of cardiovascular risk factors such as smoking and intima-media thickness (IMT). Some reports indicate that the maternal tobacco smoking causes disturbances of the endocrine status of the foetus. There are several potential mechanisms by which insulin-like growth factor I (IGF-I) could modify atherosclerotic processes either locally or in a systemic manner. The aim of this study was to investigate the influence of maternal smoking on neonatal aortic IMT (aIMT), serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels. Aortic intima-media thickness was measured in 28 neonates whose mothers smoked during the pregnancy and 28 control neonates. Mean and weight-adjusted aIMT were significantly greater in the neonates whose mothers smoked (0.455 ± 0.009 mm and 0.151 ± 0.005 mm/kg, respectively) than in controls (0.403 ± 0.029 mm and 0.118 ± 0.014 mm/kg, respectively). Birth-weight of newborns whose mothers smoked was less than that of the controls. The decreases in serum IGF-I and IGFBP-3 observed in the infants whose mothers smoked were non-significant. Mean aIMT was negatively associated with birth-weight and IGF-I level. In conclusion, neonates whose mothers smoked have significantly increased aIMT. It might play a role in the pathogenesis of atherosclerosis in adult life.     

生长追赶宫内发育迟缓大鼠早期糖脂代谢及脂肪细胞功能的改变

目的：探讨生长追赶宫内发育迟缓(IUGR)大鼠早期糖脂代谢及脂肪细胞功能的改变。方法：母孕期饥饿法建立IUGR大鼠模型。禁食组仔鼠作为生长追赶IUGR模型组（IUGR组）,正常喂养仔鼠作为对照组（AGA组）。12周龄时检测血浆甘油三酯（TG）、胆固醇（TC）、低密度脂蛋白-C（LDL-C）、高密度脂蛋白-C（HDL-C）以及脂联素、促酰化刺激蛋白（ASP）的水平。隔日行糖耐量试验（OGTT）,检测血浆葡萄糖和胰岛素水平,计算胰岛素抵抗指数（IRI）。随后仔鼠断头处死,共聚焦显微镜下观察免疫荧光染色的成熟脂肪细胞中葡萄糖转运体-4（GLUT-4)的表达。结果：12周末时IUGR组大鼠体重、BMI显著高于AGA组（均P<0.01）,血TG、TC、LDL-C水平显著高于AGA组,HDL-C水平明显低于AGA组（P<0.05）。OGTT中IUGR组注射葡萄糖后各时间点血糖水平均高于AGA组（P<0.05）,IRI值亦显著增高（P<0.05）。与AGA组比较,IUGR组ASP水平明显升高(P<0.05）,而脂联素水平显著降低（P<0.05）。IUGR大鼠成熟脂肪组织中GLUT-4在基础状态和不同浓度胰岛素刺激下的表达水平与AGA组相比均明显降低（P<0.05）。结论：IUGR大鼠生后发生明显的生长追赶,12周时即存在高血脂、高血糖及胰岛素抵抗。脂肪细胞分泌功能的异常和脂肪组织GLUT-4表达水平的降低可能参与了生长追赶IUGR大鼠胰岛素抵抗的形成。     

Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3 and insulin in obese children.

In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.     

Effect of zinc supplementation on growth hormone secretion, IGF-I, IGFBP-3, somatomedin generation, alkaline phosphatase, osteocalcin and growth in prepubertal children with idiopathic short stature

Controversy exists about the effect of zinc on growth and the GH-IGF system. Zinc supplementation has been shown to stimulate linear growth in zinc-deficient children. However the mechanism of this effect has not been well characterized. Furthermore, the effect of zinc supplementation on non-zinc-deficient short children is unknown. We investigated the effect of zinc supplementation on endogenous GH secretion, serum IGF-I and IGFBP-3 concentrations, IGF-I and IGFBP-3 generation in response to exogenous GH, bone formation markers, and linear growth of non-zinc-deficient children with idiopathic short stature. We analyzed prospectively serum zinc, IGF-I, IGFBP-3, alkaline phosphatase, osteocalcin, and GH response to clonidine test, and performed a somatomedin generation test before and 6 weeks after zinc supplementation in 22 (16 M, 6 F) prepubertal children with idiopathic short stature. Serum IGF-I increased from 67.4+/-70.6 to 98.2+/-77.3 ng/ml (p <0.001), IGFBP-3 from 2326+/-770 to 2758+/-826 ng/ml (p <0.001), alkaline phosphatase from 525+/-136 to 666+/-197 U/l (p <0.0001), and osteocalcin from 16.8+/-10.6 to 25.8+/-12.8 ng/ml (p <0.05) after zinc supplementation despite there being no difference in GH response to clonidine after zinc supplementation (peak GH 11.6+/-6.9 vs 13.4+/-7.8 ng/ml, GH area under the curve during clonidine test 689+/-395 vs 761+/-468, NS). Percent change in IGF-I and IGFBP-3 during the somatomedin generation test was not significantly affected by zinc supplementation (118% vs 136% and 57% vs 44%, respectively). There was no significant correlation between percentage increase in zinc levels and percentage increase in parameters tested. Height SDS or weight SDS did not improve significantly in 17 patients who continued on zinc supplementation for at least 6 months (6-12 months) (-2.59 vs -2.53 SDS and -1.80 vs -1.67 SDS, respectively). Zinc supplementation increased basal IGF-I, IGFBP-3, alkaline phosphatase and osteocalcin without changing GH response to clonidine. Zinc supplementation did not affect sensitivity to exogenous GH as tested by IGF-I and IGFBP-3 generation test. These results suggest a direct stimulatory effect of zinc on serum IGF-IGFBP-3, alkaline phosphatase and osteocalcin. Despite improvements in the above parameters, zinc supplementation to children with idiopathic short stature with normal serum zinc levels did not significantly change height or weight SDS during 6-12 months follow-up.     

The contributions of plasma IGF-I, IGFBP-3 and leptin to growth in extremely premature infants during the first two years

We determined the contributions of IGF-I, IGFBP-3 and leptin to growth in extremely premature infants over the first two years. Weight (Wt), crown-to heel length (CHL), plasma IGF-I, IGFBP-3 and leptin were measured in infants (gestation 24-33 wk) at birth (n = 54), expected date of delivery (EDD) and 6, 12 and 24 mo post-EDD (n = 29). Area under the curve (AUC) for hormone levels was calculated over 4 periods: birth-EDD, EDD-200 d, EDD-350 d and EDD-700 d. IGFBP-3, but not IGF-I or leptin, on day 1 correlated with birth Wt SD scores (SDS) (r = 0.46, p = 0.002) and CHL SDS (r = 0.41, p = 0.01). Wt SDS at EDD correlated with AUC IGF-I, IGFBP-3 and leptin (birth-EDD), but leptin was the best predictor in multiple regression (r = 0.65, p < 0.0001). Wt at EDD + 700 d correlated with AUC leptin (EDD-700 d) (r = 0.62, p = 0.002). CHL SDS at EDD correlated with AUC IGFBP-3 and leptin (birth-EDD), but IGFBP-3 was the best predictor (r = 0.55, p < 0.0001). CHL at EDD + 700 d correlated with AUC IGF-I and IGFBP-3 (EDD-700 d), but IGFBP-3 was the best predictor (r = 0.47, p = 0.01). Wt and CHL at birth were associated with IGFBP-3 levels in these infants. Wt at EDD and EDD + 700 d was predicted by concurrent leptin output while linear growth at EDD and EDD + 700 d was predicted by IGFBP-3 output.     

Effect of dexamethasone treatment on serum GH,IGF-I,and the binding proteins IGFBP-1 and -3 in ventilated very preterm infants

Very preterm infants developing bronchopulmonary dysplasia frequently show a compromised growth in the neonatal period especially when steroids are given to facilitate weaning from the ventilator. The aim of this study was to evaluate the short-term effect of dexamethasone (DEXA) on the GH-IGF axis in ventilated very preterm infants developing bronchopulmonary dysplasia. We studied 10 very preterm artificially ventilated infants with bronchopulmonary dysplasia [median (range) gestational age 27.5 wk (25.9-32.0 wk), median (range) birth weight 970 g (610-2150 g)] immediately before and 2 d after the start of DEXA treatment. On both days of study, serum GH profiles were obtained, and serum IGF-I and IGF binding protein (IGFBP) -1 and -3 levels were measured. The ventilation score and the nutritional intake were calculated. Before the start of DEXA treatment, the median serum mean GH level was 12.0 microg/L (6-28.4 microg/L), whereas 2 d after the start of DEXA treatment the median serum mean GH level declined significantly to a value of 4.4 microg/L (1.7-11.9 microg/L). During DEXA treatment, mean, baseline, and maximal GH levels (Pulsar analysis) were significantly lower compared with pretreatment levels (p < 0.01, p < 0.01, and p < 0.05, respectively). Serum IGF-I and IGFBP-3 levels did not decline during DEXA. Serum IGFBP-1 levels were significantly lower compared with pretreatment levels (p < 0.01). Serum GH levels during DEXA treatment were correlated with neither the time interval between the administration of DEXA and the second GH profile nor the cumulative DEXA dose administered. Ventilation score and nutritional intake did not significantly correlate with serum GH, IGF-I, or IGFBP-1 or -3 levels, either before or after the start of DEXA. Two days of DEXA treatment in very preterm ventilated infants has a suppressive effect on serum GH levels, without an acute decline in serum IGF-I levels. A concomitant decrease in serum IGFBP-1 levels was found.