Enterotrophic effect of insulin-like growth factor-I but not growth hormone and localized expression of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and -5 mRNAs in jejunum of parenterally fed rats

BACKGROUND: Administration of insulin-like growth factor (IGF)-I, but not growth hormone (GH), stimulates mucosal hyperplasia in surgically stressed rats with intestinal atrophy induced by hypocaloric total parenteral nutrition (TPN). Our aim was to characterize the basis for this disparity in enterotrophic action by assessing the relationships between stimulation of intestinal growth, nutritional adequacy, and localization of expression of IGF-I, insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5 mRNAs in jejunum. METHODS: Rats were maintained with TPN for 8 days and treated with IGF-I or GH and adequate nutrition for 5 days after recovery from surgery. Jejunal mass, morphology, and sucrase activity were assessed. Localization of expression of IGF-I, IGFBP-3, and IGFBP-5 mRNAs in jejunum was accomplished by in situ hybridization. RESULTS: Serum IGF-I and body weight gain were significantly increased by IGF-I or GH. Jejunal mucosal dry mass, morphology, and sucrase activity were improved with IGF-I but not GH. There were no differences in IGF-I mRNA. IGFBP-3 mRNA was localized in the lamina propria of the villi. IGF-I or GH stimulated IGFBP-3 expression. IGF-I strongly stimulated IGFBP-5 expression in the lamina propria and the muscularis and induced a twofold increase in IGFBP-5 mRNA based on RNase protection assay of intact jejunum total RNA. GH induced a modest increase in IGFBP-5 expression in the muscularis with no effect on intact jejunum total RNA. CONCLUSIONS: The GH resistance observed in the jejunal mucosa of TPN rats cannot be fully explained by inadequate nutrition. The expression of IGFBP-5 in the lamina propria suggests it may modulate the enterotrophic action of exogeneous IGF-I.     

Growth hormone and insulin-like growth factor-I as anabolic agents

The reduced growth hormone and insulin-like growth factor-I concentrations in growth hormone deficiency and normal ageing are associated with reduced muscle mass and strength, and slower muscle protein synthesis. Recent research has addressed the hypothesis that growth hormone and insulin-like growth factor-I have an anabolic effect in adults, including the elderly. These hormones stimulate whole-body and muscle protein synthesis, at least under some conditions. There is increasing evidence to justify long-term administration of growth hormone to promote muscle growth in growth hormone deficient adults. However, the long-term effects on muscle mass and function in the elderly do not seem beneficial enough to justify widespread hormone replacement therapy. These hormones may be useful anabolic agents to counteract muscle wasting under other conditions, including surgical stress, renal failure, muscular dystrophy, glucocorticoid administration and HIV infection, but more clinical trials are needed to determine the functional significance of the protein anabolic effects under these conditions.     

学龄前肥胖儿童血清IGF-I、IGF-BP3与其他激素相互关系的研究

[目的]研究学龄前肥胖儿童血清胰岛素样生长因子-I(IGF-I)、胰岛素样生长因子结合蛋白-3(IGF-BP3)与瘦素(Leptin)、胰岛素(Ins)、雌二醇(E2)及睾酮(T)的相互关系,探讨IGF-I在肥胖发病机制中的作用,为肥胖儿童的早期干预提供理论依据.[方法]对122例学龄前肥胖儿童及61例正常儿童血清IGF-I、IGF-BP3、LEI、in、Ins、E2和T水平进行测定,并分析IGF-I、IGF-BP3与其他激素的相互关系.[结果]学龄前肥胖儿童血清IGF-I、IGF-BP3、Lepfin、Ins和E2水平明显高于对照组(P值均＜O.001),两组间睾酮水平差异无显著性(P>O.05);血清IGF-I、IGF-BP3与Leptin、Ins、E2及睾酮水平显著正相关(P值均＜0.01),且Leptin与Ins、E2水平显著正相关(P值均＜0.001);多元线性回归分析显示IGF-BP3、Ins和E2是影响IGF-I的重要因素.[结论]学龄前肥胖儿童IGF-I、Leptin和Ins在调节机体能量代谢过程中不仅作为独立的外周因子发挥作用,同时提示IGF-I对儿童生长发育以及性发育的调控受Leptin、Ins及性激素多种激素水平的共同影响,IGF-I是儿童肥胖又一敏感检测指标.     

学龄前肥胖儿童血清IGF-Ⅰ、IGF-BP_3与其他激素相互关系的研究

【目的】研究学龄前肥胖儿童血清胰岛素样生长因子-Ⅰ（IGF-Ⅰ）、胰岛素样生长因子结合蛋白-3（IGF-BP3）与瘦素（Leptin）、胰岛素（Ins）、雌二醇（E2）及睾酮（T）的相互关系,探讨IGF-I在肥胖发病机制中的作用,为肥胖儿童的早期干预提供理论依据。【方法】对122例学龄前肥胖儿童及61例正常儿童血清IGF-Ⅰ、IGF-BP3、Leptin、Ins、E2和T水平进行测定,并分析IGF-Ⅰ、IGF-BP3与其他激素的相互关系。【结果】学龄前肥胖儿童血清IGF-Ⅰ、IGF-BP3、Leptin、Ins和E2水平明显高于对照组（P值均〈0.001）,两组间睾酮水平差异无显著性（P〉0.05）;血清IGF-Ⅰ、IGF-BP3与Leptin、Ins、E2及睾酮水平显著正相关（P值均〈0.01）,且Leptin与Ins、E2水平显著正相关（P值均〈0.001）;多元线性回归分析显示IGF-BP3、Ins和E2是影响IGF-Ⅰ的重要因素。【结论】学龄前肥胖儿童IGF-Ⅰ、Leptin和Ins在调节机体能量代谢过程中不仅作为独立的外周因子发挥作用,同时提示IGF-Ⅰ对儿童生长发育以及性发育的调控受Leptin、Ins及性激素多种激素水平的共同影响,IGF-Ⅰ是儿童肥胖又一敏感检测指标。     

Utility of insulin-like growth factor-I and its binding protein assays

Insulin-like growth factor-I circulates in serum either in free form or bound to insulin-like growth factor-binding proteins that modulate its bioavailability. Insulin-like growth factor-binding proteins interfere with insulin-like growth factor-I assay, which remains technically difficult. Many assays have been developed, but their results are somewhat discordant. The choice of separation method, standard and tracer considerably influences the results. The circulating concentration of insulin-like growth factor-I, however, is clearly dependent on nutritional status, and total levels are a valuable marker of nutritional status. The clinical utility of free insulin-like growth factor-I assay and simultaneous assay, in the same sample, of total insulin-like growth factor-I and its binding proteins (reflecting the bioavailable insulin-like growth factor-I fraction), remains to be evaluated.     

Relation of cord serum levels of growth hormone,insulin-like growth factors,insulin-like growth factor binding proteins,leptin, and interleukin-6 with birth weight,birth length,and head circumference in term and preterm neonates

OBJECTIVES: Fetal growth process is governed by multiple factors. We investigated the relation of insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), leptin, and interleukin-6 (IL-6) with intrauterine growth in preterm and term neonates. METHODS: Thirty-eight preterm and 43 term neonates were recruited. Anthropometric measures were recorded and umbilical cord blood samples were collected at birth. RESULTS: Birth weight (BW), birth length (BL), ponderal index, head circumference (HC), and cord serum levels of albumin, prealbumin, retinol-binding protein (RBP), total and free IGF-I, IGF-II, IGFBP-3, acid-labile subunit (ALS), and leptin were significantly lower, whereas levels of IGFBP-1, IGFBP-2, and IL-6 were significantly higher in preterm than in term neonates (P < 0.05). Total and free IGF-I, ALS, and leptin had significantly positive correlations, whereas IGFBP-2 had a significantly negative correlation, with BW and BL in preterm plus term neonates. Forward stepwise multivariate regression analysis showed that gestational age (GA), IGFBP-2, leptin, and free IGF-I are significant predictors of BW; GA, IGFBP-2, ALS, transferrin, and leptin are significant predictors of BL; and GA and free IGF-I are significant predictors of HC in preterm and term neonates. CONCLUSIONS: Our results suggest that IGF-I, IGF-II, IGFBP-2, ALS, and leptin play important roles in intrauterine growth.     

Effects of alcohol on insulin-like growth factor I and insulin-like growth factor binding protein 3 in postmenopausal women

BACKGROUND: Increased circulating insulin-like growth factor I (IGF-I) concentrations, frequently adjusted for IGF binding protein 3 (IGFBP-3), have been associated with increased risk of several types of cancer, including colon, prostate, and breast. Studies have suggested that alcohol may affect IGF-I or IGFBP-3; however, controlled feeding studies to assess alcohol's effects on IGF-I or IGFBP-3 have not been conducted. OBJECTIVE: To determine whether chronic, moderate alcohol intake affects serum IGF-I or IGFBP-3 concentrations, we performed a controlled, crossover feeding study. DESIGN: Fifty-three postmenopausal women were randomly assigned to consume 0 g (control), 15 g (one drink), or 30 g (2 drinks) alcohol daily for 8 wk and were rotated through the other 2 intake levels in random order. All foods and beverages were provided during the intervention. Individuals were monitored and calories adjusted to maintain constant weight, and serum was collected at the end of each diet period. RESULTS: Compared with the effects of 0 g alcohol/d, IGF-I concentrations were nearly unchanged by 15 g alcohol/d (0.8%; 95% CI: -3.2%, 3.5%) but decreased significantly by 4.9% (95% CI: -8.0%, -1.6%) with 30 g alcohol/d. IGFBP-3 concentrations significantly increased by 3.0% (95% CI: 0.4%, 5.6%) with 15 g alcohol/d but did not increase significantly with 30 g/d (1.8%; 95% CI: -0.9%, 4.5%). CONCLUSIONS: To our knowledge, this is the first published controlled diet study to find that in postmenopausal women, when weight is kept constant, alcohol consumption reduces the amount of serum IGF-I potentially available for receptor binding. These findings suggest that the effect of alcohol intake should be considered in studies of IGF-I, IGFBP-3, and cancer in postmenopausal women.     

Development of the insulin-like growth factor-I assay system

A high speed full automatic ELISA system for measurement of insulin-like growth factor-I (IGF-I) was established by using magnetic particle-linked monoclonal antibody and enzyme-labeled monoclonal antibody. A standard curve was obtained, and the effect of dilution on the assay system was investigated. An IGF-I spike recovery test of human serum samples and a study of the correlation with a radioimmunoassay system were performed, and good results were obtained from all studies. The assay range was 0.5-50 ng/ml, and the time required for the full automatic measurement was 15 minutes. This assay system will play a central role in the clinical approach to IGF-I.     

Body size in early life and adult levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3

Body size in early life has been associated with breast cancer risk. This may be partly mediated through the insulin-like growth factor (IGF) pathway. The authors assessed whether birth weight, body fatness at ages 5 and 10 years, and body mass index (BMI; weight (kg)/height (m)(2)) at age 18 years were associated with plasma concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 in 6,520 women aged 32-70 years at blood draw from the Nurses' Health Study (1990-2006) and Nurses' Health Study II (1997-2005). Birth weight, body fatness in childhood, and BMI at age 18 years were inversely associated with adult IGF-1 levels. For example, IGF-1 levels were 11.9% lower in women who reported being heaviest at age 10 years than in those who were leanest at age 10 (P-trend < 0.0001). Further, women who reported their birth weight as ≥10 pounds (≥4.5 kg) (vs. <5.5 pounds (<2.5 kg)) had 7.9% lower IGF-1 levels (P-trend = 0.002). Women whose BMI at age 18 years was ≥30 (vs. <20) had 14.1% lower IGF-1 levels (P-trend < 0.0001). Similar inverse associations were observed for insulin-like growth factor binding protein 3. These observations did not vary by adult BMI or menopausal status at blood draw. These findings suggest that altered IGF-1 levels in adulthood may be a mechanism through which early-life body size influences subsequent breast cancer risk.     

Anthropometric and behavioral correlates of insulin-like growth factor I and insulin-like growth factor binding protein 3 in middle-aged Japanese men

High levels of plasma insulin-like growth factor I (IGF-I) and low levels of insulin-like growth factor binding protein 3 (IGFBP-3) have been related to increased risk of several cancers. Little is known about the behavioral determinants of these biologic markers. The authors examined the relation of anthropometric and behavioral factors to plasma concentrations of IGF-I and IGFBP-3 in a cross-sectional study of 616 Japanese men aged 45-55 years in 1995-1996. In univariate analyses, body mass index was strongly, positively associated with both IGF-I and IGFBP-3. The waist/hip ratio was also linearly related to IGF-I and IGFBP-3 up to the third quartile level. Height was weakly, positively associated with IGF-I and IGFBP-3. Smoking was inversely associated with IGF-I and IGFBP-3. Alcohol use was associated inversely with IGF-I and positively with IGFBP-3. Neither IGF-I nor IGFBP-3 was related to physical activity. Results of the multivariate analysis were essentially the same as those of the univariate analyses. The findings regarding body mass index are in contrast to those of previous studies showing null or inverse associations, and they suggest that the relation of body mass index to IGF-I or IGFBP-3 may vary among populations. The study also indicates that smoking and alcohol use might affect plasma IGF-I and IGFBP-3.     

胰岛素样生长因子及其结合蛋白与妊娠期高血压疾病的相关性研究

目的:研究妊娠期高血压疾病患者血清胰岛素样生长因子-1(IGF-1)、胰岛素样生长因子结合蛋白-1(IGFBP-1)的水平与病情程度及新生儿出生体重之间的关系。方法:采用放射免疫方法测定并比较38例妊娠期高血压疾病患者与38例正常血压妊娠妇女的血清IGF-1、IGFBP-1的水平。结果:子痫前期组IGF-1显著低于妊娠期高血压组和正常组,而IGFBP-1水平显著高于妊娠期高血压组和正常组;妊娠期高血压组与正常组间IGF-1、IGFBP-1的水平比较,差异均无统计学意义。IGF-1水平与收缩压、舒张压及平均动脉压呈显著负相关,与新生儿出生体重呈显著正相关,而IGFBP-1与收缩压、舒张压及平均动脉压呈显著正相关,与新生儿出生体重呈显著负相关。结论:妊娠期高血压疾病患者的发病及严重程度与IGF-1、IGFBP-1有明显的关系,IGF-1、IGFBP-1与胎儿的发育及新生儿出生体重有明显的相关性。     

Insulin-like growth factor I,insulin-like growth factor binding protein 3, and urologic measures of benign prostatic hyperplasia

Laboratory studies suggest that insulin-like growth factor I (IGF-I) promotes prostatic growth. The authors evaluated the association between benign prostatic hyperplasia and IGF-I and its binding protein IGFBP-3 in community-dwelling men to determine whether this laboratory finding is manifest at the population level. Participants (n = 471) were Olmsted County, Minnesota, Caucasian males aged 40-79 years in 1990. Urologic measures were assessed from the International Prostate Symptom Score, peak urinary flow rates, prostate volume, and serum prostate-specific antigen (PSA), and serum IGF-I and IGFBP-3 levels were measured. After adjustment for age, the relative odds (odds ratios) of an abnormal urologic measure in men with high versus low serum IGF-I levels were 0.98 (95% confidence interval (CI): 0.66, 1.45) for a symptom score of >7, 1.14 (95% CI: 0.72, 1.80) for a peak urinary flow rate of <12 ml/second, 1.11 (95% CI: 0.72, 1.72) for a prostate volume of >30 ml, and 0.71 (95% CI: 0.46, 1.09) for a PSA level of >1.4 ng/ml. A low IGFBP-3 level was associated with an enlarged prostate (odds ratio = 1.72, 95% CI: 1.05, 2.82), after simultaneous adjustment for IGF-I and age, but not with other urologic measures. These data do not provide evidence for an association between benign prostatic hyperplasia and serum IGF-I.     

Levels of plasma insulin-like growth factor I (IGF I), IGF II,IGF binding proteins,type 1 IGF receptor and growth hormone binding protein in community-dwelling elderly subjects with no malnutrition and no inflammation

Plasma samples from community-dwelling subjects aged 65 to 92 presenting no malnutrition and no inflammation (as assessed by albumin, transthyretin, CRP, and orosomucoid levels and BMI) were compared to those of healthy controls aged 20 to 65 to determine the effect of aging on the IGF system. Concentrations of IGF I, IGF II and IGFBP3 significantly decreased, and those of GHBP slightly increased with age from 20 to 92 years (n=327 r=-0.64 p<0.0001; n=45 r=-0.44 p<0.003; n=91 r=-0.23 p<0.03 and n=61 r=0.26; p<0.05 respectively). Western immunoblotting showed that the proteolysis of IGFBP3 was not significantly different in elderly and younger subjects. The affinity of the IGF type 1 receptor for IGF I was moderately lower (Ki=0.56 0.2 vs 0.33 0.1, nM respectively; p<0.005) and the number of binding sites was moderately higher (10.4 1.5 vs 8.1 1.9 binding sites/cell, respectively; p<0.03) in the elderly than in the younger adults. Our results suggest that the age-related decline in plasma levels of IGF I, IGF II and IGFBP3 occurs independently from malnutrition and inflammation processes. GHBP plasma levels, which reflect the number of GH receptors at the level of the liver, do not decline in our malnutrition-free elderly population, and thus are not involved in the decline of IGF I plasma levels with age. In the elderly, affinity and number of type 1 IGF receptor were close to those of younger subjects; the decline in IGF I plasma levels may account for the small rise in the number of type 1 IGF receptors binding sites per cell.     

Maternal concentrations of insulin-like growth factor I and insulin-like growth factor binding protein 1 during pregnancy and birth weight of offspring

Maternal concentrations of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 1 (IGFBP-1) may influence fetal growth. Offspring birth weight related to maternal IGF-I and IGFBP-1 measured in pregnancy was studied in 368 randomly selected women without preeclampsia who delivered a singleton liveborn child in Norway between 1992 and 1994. Maternal IGF-I concentrations were not consistently associated with birth weight, but a 1-standard deviation stronger increase in IGF-I from the first to second trimester was associated with an 82-g (95% confidence interval (CI): 11, 153) higher birth weight. IGFBP-1 concentrations were inversely associated with birth weight: Birth weight was 71 g (95% CI: 14, 128) lower per 1-standard deviation higher IGFBP-1 in the second trimester, and an increase in IGFBP-1 from the first (below median) to second (above median) trimester was associated with a 342-g (95% CI: 124, 560) lower birth weight, compared with having low IGFBP-1 (below median) in both trimesters. Conversely, low IGFBP-1 in both trimesters was associated with a 200-350-g higher birth weight compared with other combinations of IGFBP-1. In conclusion, persistently low IGFBP-1 in pregnancy is associated with relatively higher birth weight. Maternal insulin resistance may provide a link between IGFBP-1 and offspring birth weight.     

Hyperinsulinemia,insulin-like growth factor-I,insulin-like growth factor-binding protein-1, and sex-hormone binding-globulin in prepubertal and pubertal girls with premature adrenarche

Precocious adrenarche is defined as the development of pubic hair before the age of 8 years in girls and 9 years in boys. Pubarche caused premature adrenarche in girls has been considered as a normal variant of pubertal development for years. Recently, it is cleared that premature pubarche can be considered as a marker of increased risk for endocrine and metabolic abnormalities. Precocious adrenarche in affected girls is associated with hyperinsulinaemia and functional ovarian hyperandrogenism during puberty. Authors investigated serum levels of insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein-1 (IGFBP-1), insulin-like growth factor-binding protein-3 (IGFBP-3), sex hormone binding-globulin (SHBG) and levels of insulin during oral glucose tolerance test in 34 girls with premature adrenarche in 38 age- and BMI-matched healthy controls. Affected girls were assigned into prepubertal and pubertal subgroups. It has been shown that hyperinsulinaemia, decrease in IGFBP-1 and increase IGF-I levels may be present in some affected prepubertal patients. In the pubertal group, in addition to hyprinsulinaemia, decreased IGFBP-1 and increased IGF-I levels an attenuated SHBG level was observed. According to the authors, these laboratory parameters may predict endocrine and metabolic abnormalities in later life. The observed correlations support the hypothesis that insulin/IGF system plays role in the pathogenesis of hyperandrogenism in premature adrenarche and in later hormonal and metabolic changes.     

Diet, serum insulin-like growth factor-I and IGF-binding protein-3 in European women

OBJECTIVE: The aim of this study was to examine the relationship of diet with serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in women. DESIGN: Cross-sectional study. SETTING AND SUBJECTS: The population are 2109 women who were control subjects in a case-control study of breast cancer nested in the European Prospective Investigation into Cancer and Nutrition. Control subjects were randomly chosen among risk sets consisting of female cohort members alive and free of cancer (except non-melanoma skin cancer) at the time of diagnosis of the index case. Matching criteria were age at enrolment, follow-up time, time of the day of blood collection and study centre. Diet was measured through validated questionnaires. Serum hormone concentrations were measured by enzyme-linked immunosorbent assays. The relationship between serum IGF-I, IGFBP-3, and intake of nutrients and foods was explored by linear regression in models adjusted for energy intake, age, body mass index, smoking, physical activity, centre and laboratory batch. RESULTS: Serum IGF-I levels were positively related to protein intake (P(trend)<0.001), but not related to energy, fat or carbohydrate intake. Positive relationships were observed with the intake of milk (P(trend)=0.007), calcium (P(trend)<0.001), magnesium (P(trend)=0.003), phosphorus (P(trend)<0.001), potassium (P(trend)=0.002), vitamin B6 (P(trend)=0.03), vitamin B2 (P(trend)=0.001) and inverse relationships with vegetables (P(trend)=0.02) and beta-carotene (P(trend)=0.02). IGFBP-3 was not related with most of the nutrients and foods in this study. CONCLUSIONS: In this population, circulating IGF-I is modestly related with the intake of protein and minerals, and with milk and cheese, while IGFBP-3 does not appear to be related with diet.     

血清IGF-1、IGFBP-3水平和大肠癌关系的Meta分析

目的综合评价血清胰岛素样生长因子-1(IGF-1)、胰岛素样生长因子结合蛋白-3(IGFBP-3)水平和大肠癌的关系。方法利用Meta分析法对6篇关于血清IGF-1、IGFBP-3水平与大肠癌关系的研究文献进行定量综合分析。结果对于IGF-1，合并OR=1．56(95％CI：1．14～2．13)；按实验方法不同分层，间接酶联免疫吸附试验(ELISA)合并OR=1．92(95％CI：1．26～2．93)，IRMA法合并OR=1．23(95％CI：0．78～1．94)；对于IGFBP-3，合并OR=0．78(95％CJ：0．43～1．44)；按实验方法不同分层，ELISA法合并OR=0．46(95％CI：0．29～0．74)，免疫放射测定法(IRMA)合并OR=1．44(95％CI：0．93～2．23)。结论血清IGF-1高水平为大肠癌的独立危险因子，IGFBP-3与大肠癌的关联不具有统计学意义；IGFBP-3与大肠癌关系的各研究之间异质性是由实验方法不同而引起，但该结论尚需大样本并同时进行两种方法的测量证实。