IGF-1和IGFBP-3在生长激素治疗中的安全性和有效性的研究

基因重组人生长激素(recombinant human growth hormone,rhGH)已广泛应用于儿科临床治疗生长激素缺乏症,并已取得较满意的疗效.生长激素(growth hormone,GH)通过刺激肝脏细胞产生胰岛素样生长因子(insulin-like growth actor,IGF-1)来介导GH的促生长作用.血浆中大部分IGF-1与胰岛素样生长因子结合蛋白3结合,IGF-1具有促进细胞有丝分裂抑制细胞凋亡的作用,近年来发现IGF-1与肿瘤的发生发展有一定相关性,因而引发了对rhGH治疗的安全性和有效性的关注.     

营养肾病和糖皮质激素对大鼠肝肾组织IGF-I/IGFBPs mRNA表达的影响

目的：探讨营养不良、肾病本身和糖皮质激素作为各自独立因素对大鼠肝肾组织胰岛素样生长因子I/胰岛素样生长因子结合蛋白(IGF-I/IGFBPs) mRNA表达和血清浓度的影响。方法：24只周龄相同体重相近的雄性SD大鼠被随机分成正常对照、食物对照、阿霉素肾病和地塞米松治疗肾病4组。血清IGF-I/IGFBPs和肝肾组织IGF-I/IGFBPs mRNA表达分别采用RIA,Western ligand blot和RT-PCR法检测。结果：①营养不良大鼠血清IGF-I减低,肝肾组织IGF-I mRNA表达增高;肾病本身对血清IGF-I,肝脏IGF-IA mRNA表达无影响,肾脏表达减低;激素治疗使血清IGF-I,肝肾组织IGF-IA mRNA表达均下降。②营养不良大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达减低,肾脏表达正常;肾病本身使大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达增高,肾脏表达减低;激素治疗使肝肾组织IGFBP-2 mRNA表达均下降,但对血清浓度无影响。③营养不良大鼠血清IGFBP-3减低,肝脏IGFBP-3 mRNA表达正常;肾病本身使血清IGFBP-3,肝脏IGFBP-3 mRNA表达均下降;激素治疗使血清IGFBP-3增高,但肝脏IGFBP-3 mRNA表达下降。肾脏IGFBP-3 mRNA表达仅在激素治疗组大鼠能检测到。结论：营养、肾病和糖皮质激素对大鼠肝肾组织IGF-I/IGFBPs mRNA表达的调节具有器官特异性;除血清IGF-I减低部分源于肾脏合成下降外,血清IGFBPs紊乱主要与肝脏合成有关;肾病时IGFBPs可能在不同的水平对IGF-I生物效应发挥调节作用。     

Growth hormone insensitivity syndromes: a preliminary report on changes in insulin-like growth factors and their binding proteins during treatment with recombinant insulin-like growth factor I

Serum levels of insulin-like growth factor (IGF) binding proteins (IGFBPs) 1, 2 and 3 were studied by radioimmunoassay in 29 patients with growth hormone (GH) insensitivity syndromes (GHIS) before and during treatment with IGF-I. As in normal subjects, there was a highly significant correlation between IGFs and IGFBP-3 but not between IGFs and the other binding proteins, though IGFBP-3 represented only about one-third of the total IGFBP concentration. In 6 patients with GH deficiency and in 5 patients with GHIS, the pharmacokinetic profile of IGF-I after a single injection was strongly dependent on the IGFBP-3 concentration. A slight but significant increase in IGFBP-3 was observed coincident with the IGF-I peak, whereas IGFBP-2 increased after a delay of about 10 hours. In the patients with GHIS, chronic IGF-I treatment, with twice-daily injections for 6 months, caused a significant steady decline of IGF-II and an increase in IGFBP-2, but had no effect on IGFBP-1 and IGFBP-3 levels. During IGF-I treatment, an inverse relationship between baseline IGF-I and GH levels was observed. The data suggest that total IGF-I and IGF-IL serum levels are determined mainly by IGFBP-3, even in extreme situations such as GHIS, while other IGFBPs are less important. The IGFBP-3 concentration seems to be a major regulator of the pharmacokinetics of exogenous IGF-I, which, in turn, influences IGFBP-3 levels. This effect of IGF-I on IGFBP-3 is not through induction of IGFBP-3 synthesis, but possibly by reduction of IGFBP-3 clearance. Finally, IGF-I administration suppresses GH secretion.     

The insulin–like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

Serum concentrations of growth hormone–dependent insulin–like growth factor I (IGF–I) and insulinlike growth factor binding protein–3 (IGFBP–3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross–linked telopeptide of type I collagen (ICTP) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double–blind treatment periods (200 and 800 μg) and one open, non–randomized treatment period (400 μg ). All periods were 18 days'duration. Budesonide treatment was associated with a dose–related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included (p < 0.01; z =–2.7) and when it was excluded from the calculations (p < 0.01; z =–2.6), indicating reduced synthesis of type III collagen. A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations (p = 0.05; z =–1.9). No other statistically significant variations were seen.     

Short stature and growth hormone

Normal growth and development is a prime concern during childhood. Accurate assessment is essential for differentiating between normal and abnormal growth. Increased accessibility to growth hormone has equipped the pediatrician and pediatric endocrinologist to treat and improve growth in many clinical scenarios. At the same time, there is added responsibility to use this tool judiciously. This review summarizes the basics of proper growth assessment, differentiation of normal and abnormal growth causes of and works up of short stature, and delineation of indications for growth hormone treatment.     

Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children

Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt.     

生长发育迟缓与胰岛素样生长因子的关系

目的提高由于生长激素－胰岛素样生长因子（ＧＨ－ＩＧＦ）轴异常引起的生长发育迟缓诊断的准确性。方法分别收集门诊６８例生长发育迟缓儿童运动激发试验前后２次血清和１４例住院患儿药物激发试验１０次血标本,用免疫放射计量（ＩＲＭＡ）方法测定ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３,放免方法（ＲＩＡ）测定ＧＨ。结果药物激发试验ＧＨ水平与ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３测定一致。运动激发试验根据运动后ＧＨ水平及身高百分位的情况将６８例分为３组：ＧＨ＜５０μｇ／Ｌ,５０～１００μｇ／Ｌ,＞１００μｇ／Ｌ。ＧＨ＜５０μｇ／Ｌ组１４例,其中１０例身高小于第３百分位,其ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３水平分别是（３９±２０）,（２７４±１２２）,（４２０±２１０）ｎｍｏｌ／Ｌ,低于正常值（Ｐ＜００１）,ＧＨ水平与ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３相符。结论用运动激发试验联合测定ＧＨ、ＩＧＦ－１和ＩＧＦＢＰ－３三项指标可以提高由于ＧＨ－ＩＧＦ轴异常所引起的生长发育迟缓诊断的准确性。     

Good growth despite very low levels of insulin-like growth factors

A 12.5-year-old girl presented with short stature. Insulin-like growth factor 1(IGF-I) and insulin- like growth factor binding protein (IGFBP-3) were below the 0.1 percentile. Growth hormone provocation tests disclosed normal responses to l-arginine and insulin-induced hypoglycaemia. A huge benign mesenteric cyst was discovered by abdominal ultrasound and completely removed. Subsequently, the girl showed a marked catch-up growth; however, IGF-I and IGFBP-3 remained below the 0.1 percentile. Conclusion These observations imply that growth may take place even with very low levels of insulin-like growth factors. The interpretation of low IGF-I and IGFBP-3 levels in short children still requires good clinical judgement and basic knowledge of their biological action. Received: 24 September 1997 / Accepted in revised form: 16 March 1998     

新生儿血清瘦素、生长激素、胰岛素样生长因子-1、胰岛素样生长因子结合蛋白-3水平与宫内发育的关系

目的 探讨瘦素(leptin)、生长激素(GH)、胰岛素样生长因子-1(IGF-1)、胰岛素样生长因子结合蛋白-3(IGFBP-3)在不同宫内发育状况胎儿中的变化,及对胎儿生长发育调控的作用.方法 2004年1月-2006年6月出生早产小于胎龄儿(A组)30例,早产适于胎龄儿(B组)36例,足月小于胎龄儿(C组)32例,足月适于胎龄儿(D组)37例.生后24 h内抽取患儿静脉血,用放射免疫法(RIA)检测其血清leptin、GH、IGF-1、IGFBP-3水平,组间比较采用及多元回归相关分析.结果 各组新生儿血清leptin、GH、IGF-1、IGFBP-3水平均存在明显差异(Pa<0.05,0.01),各指标基本呈C、A、B、D组次序由低到高,但A组IGF-1与C组差异无统计学意义(P>0.05);在A、B和C组,出生体质量与leptin、IGF-1、IGFBP-3呈正相关(Pa<0.01),而D组出生体质量与IGF-1呈正相关(P<0.01),与其他激素无相关性.结论 leptin、IGF-1、IGFBP-3参与宫内发育迟缓儿和早产儿宫内生长发育的调控.IGF-1在早产适于胎龄儿的宫内生长发育中也起调控作用,而leptin、GH、IGFBP-3均不是足月适于胎龄儿生长发育的主要调节因素.     

Insulin secretion in growth hormone-deficient children and the effect of the sulfonylurea drug glibenclamide on linear growth

The effect of glucose on insulin release and the influence of glibenclamide on linear growth were determined in five growth hormone (STH) deficient children who were treated with human growth hormone. It was found that the administration of 5 I.U. of human growth hormone twice a week improved the defective insulin secretion while prolongation of the interval between growth hormone injections to 7 days had no effect on -cell function. The addition of treatment with 5 mg/day glibenclamide to the regular human growth hormone injections resulted in an increased growth rate in four children while one patient developed hypoglycemic symptoms. The results show that STH-deficient children may benefit from combined treatment with human growth hormone plus glibenclamide.Presented in part at 13. Arbeitstagung für pädiatrische Forschung, Göttingen, 1977     

The effects of smoking in pregnancy on factors influencing fetal growth

AIM: To evaluate the influence of maternal smoking during pregnancy on factors influencing fetal growth. METHODS: Thirty newborns of smoking mothers were prospectively compared with 60 newborns of non-smoking mothers. Pre-albumin, albumin, triglycerides, glucose, insulin, insulin-like growth factor I, IGF binding protein 3, pH, lactic acid, erythropoietin and hemoglobin concentrations were measured in umbilical cord blood. RESULTS: Infants of smoking mothers had a significantly lower birth weight (3418 +/- 533 vs. 3863 +/- 503 g; p < 0.001), length (50.5 +/- 2,6 vs. 52.3 +/- 1.9 cm; p < 0.001) and head circumference (34.6 +/- 1.8 vs. 35.8 +/- 1.1 cm; p < 0.001) than controls. They also had significantly lower insulin (3.2 (2.0-4.9) vs. 5.8 (4.6-7.1) mU/L; p = 0.008), insulin-like growth factor I (54.4 +/- 32.5 vs. 93.8 +/- 54.5 microg/L; p = 0.001) and IGF binding protein 3 (1664 +/- 432 vs. 1943 +/- 421 microg/L; p = 0.01) concentrations, than controls. Infants of smoking mothers also had significantly higher hemoglobin (167 +/- 14 vs. 157 +/- 13 g/L; p = 0.002) and erythropoietin (42.3 (25.1-72.4) vs. 26.3 (21.9-30.9) U/L; p = 0.03) than controls, but not pH or lactate concentrations. There was no significant difference in pre-albumin, albumin, triglycerides and glucose concentrations. CONCLUSIONS: Smoking during pregnancy causes symmetrical fetal growth impairment, possibly due to decreased oxygen transport to the fetus and decreased concentrations of fetal insulin, insulin-like growth factor I and IGF binding protein 3.     

Effects of insulin-like growth factor I treatment on the molecular distribution of insulin-like growth factors among different binding proteins

The molecular distribution of insulin-like growth factor I (IGF-I) and IGF-II among the IGF binding proteins (IGFBPs) was studied before and during IGF-I therapy in Ecuadorean adults with growth hormone receptor deficiency (GHRD). Of the total circulating IGF-I and IGF-II, 70% was carried by the 150 kDa complex in normal subjects, while in patients with GHRD, 50% of serum IGF-I, but only 30–35% of serum IGF-II, was measured within the 150 kDa IGFBP-3 region. Administration of IGF-I altered the concentration of IGF-I and IGF-II, although the percentage of total IGF measured within each IGFBP region was not affected, as the increase in IGF-I and the decrease in IGF-II were proportional. Similarly, serum concentrations of IGFBP-3 and the acid-labile subunit, measured by radioimmunoassay, were unaltered. Thus, administration of IGF-I to patients with GHRD was unable to correct the aberrant distribution of IGFs among the IGFBPs.     

难治性肾病综合征患儿生长激素-胰岛素样生长因子轴的变化及意义

目的：观察难治性肾病综合征(RNS)患儿生长激素(GH)-胰岛素样生长因子(IGF)轴的变化及意义。方法：计算26例RNS患儿的身高标准差积分(HtSDS),以双抗放射免疫法和免疫放射法检测血、尿IGFI及其结合蛋白3(IGFBP3)水平和血GH基础值,以同年龄组正常儿童(NC组,n=18)作对照。结果：RNS组血IGFI(152.68±120.95) ng/ml,IGFBP3(2 183.33±1 711.33) ng/ml低于NC组(255.68±46.92) ng/ml,(4 333.87±1 122.00) ng/ml,(P<0.05),尿IGFI(5.32±2.84) ng/mg肌酐,IGFBP3(16.38±8.55) ng/mg肌酐高于NC组(0.90±0.37) ng/mg肌酐,(5.13±1.64) ng/mg肌酐,(P<0.05);RNS组的血GH水平虽低于NC组,但P>0.05。RNS组身高标准差积分(HtSDS)(-0.42±0.75)低于NC组(0.30±0.17),(P<0.05)。结论：RNS患儿存在GHIGF轴的变化,此变化为RNS患儿生长障碍的主要原因之一。     

母乳中胰岛素样生长因子1水平对新生儿生长发育的影响

目的　动态观察人类母乳中胰岛素样生长因子 1(IGF 1)在初乳及成熟乳中的变化及其与泌乳量的关系 ;探讨母乳中IGF 1水平对新生儿生长发育的影响。方法　监测 38名足月新生儿生后 6周身长、体重、头围的增长及其母亲体重指数。采用双抗放射免疫法测定初乳 (生后 3～ 5d)和成熟乳 (生后 4 2d)中IGF 1的浓度并测量同日母乳量 ,测量新生儿生后 3～ 5d血清IGF 1浓度 ,并分析两者之间的关系。结果　 (1)初乳中IGF 1浓度 [(6 3± 1 6 ) μg/L]显著高于成熟乳 [(4 7± 2 1) μg/L],差异有显著意义 (t=3 2 32 ,P <0 0 5 )。 (2 )初乳和成熟乳中IGF 1的浓度 [分别为 (6 3± 1 6 ) μg/L ,(4 7± 2 1) μg/L]均与同日母乳分泌量 [分别为 (380± 114 )ml/d ,(783± 199)ml/d]呈正相关 (r分别为 0 6 17,0 793) ;乳量绝对不足的母亲初乳中IGF 1浓度 [(4 1± 1 5 ) μg/L]明显低于能维持母乳喂养者 [(6 3± 1 6 ) μg/L],差异有显著意义 (t=4 4 5 4 ,P <0 0 0 1)。 (3)与新生儿体重、头围增长相关的因素按相关性大小依次为成熟乳量、初乳中IGF 1的浓度、新生儿生后早期血清IGF 1水平以及母亲哺乳期的体重指数。结论　初乳中足够的IGF 1浓度是启动泌乳并使之得以维持的重要条件 ,乳腺分泌的IGF 1可能通过促进     

Insulin-like growth factors in lysosomal storage disease

Recent data indicate that insulin-like growth factor II (IGF II) and lysosomal enzymes bind to a common receptor. We measured serum IGF I and II levels in 16 patients with various lysosomal storage disorders. The IGF serum concentrations were normal as long as no marked liver disease was present. Under these conditions no direct interconnection between the lysosomal system and the serum IGF levels was found.