IGFs) And Their Binding Proteins Research Articles

Nutritional Modulation of the Somatotropin/Insulin-Like Growth Factor System: Response to Feed Deprivation in Lactating Cows

Mid-lactation Holstein cows (n = 4) were used to evaluate the effects of complete feed deprivation on circulating insulin-like growth factors (IGF) and their binding proteins (IGFBP). Comparisons were made between cows in fed and unfed conditions and included response to a single injection of bovine somatotropin (bST). Two days of feed deprivation decreased milk yield 66%. Concentrations of bST nearly doubled during feed deprivation, whereas glucose and insulin steadily decreased. Circulating concentrations of IGF-I decreased nearly 50%, IGF-II decreased 28% and IGFBP-2 increased 49% during the 2 d of feed deprivation. In contrast, IGFBP-3 was not affected. Eighteen to 24 h after the bST challenge, circulating concentrations of IGF-I rose 100% during the fed period, but there was no response during the unfed period. Blood concentrations of IGF-II decreased 17% after bST challenge in the fed period but were unchanged in the unfed period. More moderate undernutrition (80% of requirements) did not affect circulating IGFBP-2 but did alter the response of IGFBP-2 to bST. A conceptual model was developed that illustrates that nutritional regulation of the ST/IGF system represents a key component signaling the appropriate use of nutrients. Overall, results demonstrate that nutritional modulation of the ST/IGF system plays a key role in animal performance and well-being over a wide range of physiological situations.

THE ROLE OF THE SYSTEM OF INSULIN-LIKE GROWTH FACTORS IN BLOOD IN SOFT TISSUE SARCOMAS

Although soft tissue sarcomas (STS) belong to a group of rare diseases of mesenchymal origin, their characteristic tendency to recurrence and high mortality necessitates the search for some prognostic bio-markers to identify patients at risk of their recurrence [1]. In this regard, the system of insulinlike growth factors (IGF) and their binding proteins (IGFBP) is of interest, since it has been established that dysregulation of the IGF system leads to the proliferation of cancer cells, migration and resistance to chemotherapy.

Pediatric pulmonary hypertension: insulin-like growth factor-binding protein 2 is a novel marker associated with disease severity and survival.

Background:Insulin like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH.Methods:Serum was analyzed by ELISA for IGF1, and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n=175), and a cohort of asthmatic subjects (n=46, age 0-21) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic, and clinical variables for PAH severity.Results:Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output, and 6 minute-walk-distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p<0.001.), but not IGF1 (p=0.13).Conclusion:Circulating IGFBP2 is a novel marker for pediatric PAH which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension.

The insulin-like growth factor family and breast cancer prognosis: A prospective cohort study among postmenopausal women in Denmark

ObjectiveCirculating levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with breast cancer (BC) risk. The evidence in relation to BC prognosis is limited. We aimed to evaluate the association between pre-diagnostic serum levels of IGF-I, IGF-II, IGFBP-2, IGFBP-3 and BC prognosis (i.e. recurrence, BC specific mortality and all-cause mortality) among women diagnosed with BC. We hypothesized that higher serum levels of IGFs and IGFBPs were associated with poor BC prognosis and that the associations were modified by estrogen receptor (ER) status. DesignFrom the Danish Diet, Cancer and Health cohort, 412 postmenopausal women diagnosed with incident BC within 5 years of cohort baseline (1993–1997) were identified. Baseline serum samples were analyzed for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Follow-up was carried out through 2014 by linkage to national Danish registries. Exposures were related to BC prognosis by Cox Proportional Hazard models; effect modification by ER status was investigated and sensitivity analyses by follow-up time were made. ResultsDuring a median of 15 years, 106 women experienced recurrence and 172 died (118 due to BC). Overall, no associations were observed between IGF-I, IGF-II, IGFBP-2, IGFBP-3 and BC prognosis and no effect modification by ER status was observed. However, higher levels of IGF-II were associated with higher BC specific mortality [Hazard Ratio (HR) (95% Confidence Intervals (CI)): 1.43 (1.01–2.04)] within 10 years of follow-up. Likewise, higher levels of IGFBP-2 were associated with higher BC specific mortality [HR (95% CI): 1.87 (1.19–2.94)] within 5 years of follow-up. In contrast, higher levels of IGFBP-3 were associated with lower risk of recurrence [HR (95% CI): 0.76 (0.60–0.97)] at 5 years of follow-up and BC specific mortality [HR (95% CI): 0.80 (0.65–0.98)] within 10 years of follow-up. ConclusionsThe present study did not support an association between higher serum levels of IGFs, IGFBPs and adverse BC prognosis. However, it is possible that the role of the IGF family in the etiology of the 5–10 year BC prognosis is different from that of longer-term BC prognosis.

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.

Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

Loss of Igfbp7 Causes Precocious Involution in Lactating Mouse Mammary Gland

BackgroundInsulin like growth factors (IGFs) and their binding proteins (IGFBPs) are secreted peptides that play major roles in regulating the normal development and maturation of mammary gland. While Igfbp7 has been shown to decrease breast tumor growth, its role in regulating the normal mammary gland development has not been studied. To this end, we generated Igfbp7-null mice and examined the development and maturation of mammary glands in the virgin, pregnant and lactating animals.ResultsWe report here that loss of Igfbp7 significantly retards mammary gland development in the virgin animals. More significantly, the pregnant Igfpb7-null glands contained fewer alveolar structures and that during lactation these glands exhibit the morphological changes that are associated with involution. The transcriptome profile of the Igfbp7-null glands on the lactation day 3 revealed a distinct involution-related gene signature compared to the lactating WT glands. Interestingly, we found that the lactating Igfbp7-null glands exhibit increased expression of Stat3 and enhanced activation of (phosphorylated) Stat3, combined with decreased expression of Stat5 suggesting that the absence of Igfbp7 accelerates the onset of involution. We also found that in absence of Igfpb7, the lactating glands contain increased Igfbp5 protein along with decreased expression of IGF-1 Receptor and Akt activation. Finally, we show that during the normal course of involution, Igfbp7 expression is significantly decreased in the mammary gland.ConclusionOur data suggest that loss of Igfbp7 induces precocious involution possibly through diminished cell survival signals. Our findings identify Igfbp7 as major regulator of involution in the mammary gland.

Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2

Clinically relevant prostate cancer (PCa) is more frequent in Westernised societies and increasingly men have co-morbidities associated with a Western lifestyle, primarily diabetes, characterised by hyperinsulinaemia and hyperglycaemia. IGFs and their binding proteins (IGFBPs) are important mediators of the effects of nutrition on growth and play a key role in the development of PCa. We used DU145, PC3 and LNCaP PCa cell lines to examine how hyperglycaemia altered their response to docetaxel. Trypan Blue dye-exclusion assay was used to determine the percentage of cell death. Protein abundance was determined using western immunoblotting. Levels of IGFBP2 were measured using an ELISA. IGFBP2 gene silencing was achieved using siRNA technology. DNA methylation was assessed using combined bisulphide restriction analysis. Acetylation status of histones H3 and H4 associated with IGFBP2 gene was assessed using chromatin immunoprecipitation assay. Hyperglycaemia reduced docetaxel-induced apoptosis by 40% for DU145 cells and by 88% for LNCaP cells. This reduced cell death was mediated by a glucose-induced up-regulation of IGFBP2, as silencing IGFBP2 negated the survival effect of high glucose. Glucose increased IGFBP2 via increasing the acetylation of histones associated with the IGFBP2 gene promoter. This finding could have important implications in relation to therapeutic strategies as epigenetic modulation could be reversible.

Fetal growth in relation to maternal and fetal IGF‐axes: a systematic review and meta‐analysis

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are key regulators of fetal growth. However, the literature is inconsistent. Our objective was to systematically and objectively evaluate the available literature and to develop a balanced opinion on the relation between maternal and fetal IGF-axes and birthweight. A systematic review and a meta-analysis were conducted according to the published Moose (Meta-analysis of Observational Studies in Epidemiology) guidelines. A robust recognized systematic methodology was used in the literature search and analysis to avoid bias. Weighted mean difference and 95% confidence intervals of cord/maternal IGFs and IGFBP-1 and -3 were calculated. Eleven observational studies were included. Cord IGF-I (p < 0.0001) and IGFBP-3 (p = 0.003) were significantly higher in large-for-gestational age (LGA) than appropriate-for-gestational age (AGA) babies. Cord IGFBP-1 was significantly higher in small-for-gestational age (SGA) than AGA babies (p < 0.0001). LGA and AGA babies had similar IGF-II levels, whereas SGA and AGA babies had comparable IGF-I levels. IGF-I was significantly higher in mothers of AGA than SGA babies (p < 0.0001). The assay methods and background population marginally affect the overall homogeneity and the direction of the primary analysis. Fetal IGFs and their binding proteins play different roles in fetal growth at either end of the growth spectrum. Fetal IGF-I and IGFBP-3 may be influential in LGA. However, fetal IGFBP-1 has a more prominent role in SGA.

Cord blood level of insulin-like growth factor-1 and IGF binding protein-3 in monochorionic twins.

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are known to modulate fetal growth but their role in intrauterine growth of monochorionic twins (MCT) has not been studied. Cord venous blood was collected directly after birth. IGF-1 and IGFBP-3 in the cord venous blood were quantified by radioimmunoassay. Birth weights (BWs) were obtained electronically. Placentas were examined for chorionicity. Cord blood was collected in 37 pairs of MCT (15 pairs were males). BWs ranged from 564 to 3240 g, and gestational ages (GAs) were between 24 weeks and 39 weeks. There was a correlation between BW and cord venous blood IGFBP-3 concentration (r = 0.28, p = 0.015), but not between BW and cord venous blood IGF-1 level. There was no difference in IGF-1 between the heavier twins (30.8 ± 61.8 ng/mL) and lighter twins (33.2 ± 63.7 ng/mL), but a trend (p = 0.096) of higher IGFBP-3 level was demonstrated in heavier twins (3.14 ± 1.23 μg/mL) than in lighter twins (2.71 ± 1.19 μg/mL). The IGFBP-3 levels were higher (p = 0.042) in female twins (3.20 ± 1.33 μg/mL) than in male twins (2.64 ± 1.04 μg/mL). The IGF-1 level of the heavier twins correlated significantly to their lighter co-twin (r = 0.73, p < 0.001). Our data showed that cord venous blood IGF-1 level might be controlled mainly by genetic factors. IGFBP-3 might play an important role in fetal growth.

Abstract B93: Racial differences in plasma and breast tissue IGF-1 and IGFBP-3 levels in premenopausal women

Abstract Background: Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs), specifically IGF-1 and IGFBP-3 have been extensively studied regarding their role in breast cancer risk. Several studies have shown that higher circulating IGF-1 and IGFBP-3 concentrations in premenopausal women increases breast cancer risk. However, the data have been inconsistent. This may be due to misclassification of tissue levels where blood testing is not an adequate surrogate marker. In this study, we hypothesized that there is a wide interindividual variation in IGF-1 and IGFBP3 breast tissue levels, there will be a low correlation with breast tissue levels and there will be differences between European Americans and African Americans. Methods: Plasma and breast tissues collected from sixty nine premenopausal European American and African American women, without breast cancer, undergoing reduction mammoplasty surgery were analyzed for IGF-1 and IGFBP-3 concentrations. IGF-1 and IGFBP-3 concentrations were quantified using the Immulite 1000 system (Siemens Healthcare Diagnostics, Inc., Los Angeles, CA). Tissue IGF-1 and IGFBP-3 concentrations were adjusted by total protein concentration and are reported as nanograms of hormone per milligram of protein (ng/mg of protein). Assays were highly reproducible and all CVs were ≤9.3%. Spearman rank correlation coefficients were used to describe the associations between plasma and breast tissue IGF-1 and IGFBP-3 concentrations as well as the associations among IGF levels and selected breast cancer risk variables. Wilcoxon Rank-Sum, Kruskal-Wallis, Chi square and Fisher's exact tests were used to describe racial differences. Results: The mean breast tissue levels of IGF-1 in European Americans and African Americans were 21.8±14.2 and 28.5±14.2, respectively. For IGFBP-3 it was 35.0±25.1 and 28.8±26.1. For the IGF-1:IGFBP-3 ratio it was 0.9±0.6 and 1.6±1.0. In European Americans, plasma IGF-1 positively correlated with plasma and tissue IGFBP-3 concentrations (r=0.32; p ≤0.05 and r=0.42; p≤0.05, respectively) and tissue IGF-1 positively correlated with tissue IGFBP-3 concentrations (r= 0.46; p ≤0.05), but in African Americans none of these correlations were significant. Plasma IGFs did not predict tissue level, however several significant associations were observed between the IGFs (particularly the IGF-1:IGFBP-3 ratio) and factors related to body mass, reproductive history and alcohol consumption. Conclusions: Our data show that it is possible to assess endogenous IGFs within the breast tissue microenvironment and that these levels are not well correlated with plasma concentration. There is a wide interindividual variation in tissue levels, only partially predicted by measuring blood levels. Also, African Americans had higher levels than European Americans and so this might be an explanation for some of the differences in breast cancer risk, where African Americans tend to get breast cancer at a younger age. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B93.

Nutrient intake in the bovine during early and mid-gestation causes sex-specific changes in progeny plasma IGF-I, liveweight, height and carcass traits

Fetal and postnatal growth are mediated by insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Maternal nutrient intake during gestation can program the postnatal IGF-axis. This may have significant economic implications for beef cattle production. We investigated the effect of high ( H = 240%) and low ( L = 70%) levels of recommended daily crude protein (CP) intake for heifers during the first and second trimesters of gestation in a two-by-two factorial design on progeny ( n = 68) plasma IGF-I, IGF-II, total IGFBP (tIGFBP), postnatal growth and carcass traits. Calves were heavier at birth following high CP diets during the second trimester ( P = 0.03) and this persisted to 29 d. Plasma IGF-I concentrations of males were greater for HL compared to LL ( P < 0.01) and HH ( P > 0.04) from 29 to 657 d, and for LH compared to LL from 29 until 379 d ( P = 0.02). Exposure to low CP diets during the first trimester resulted in heavier males from 191 d onwards ( P = 0.04) but a tendency for lighter females from 552 d onwards ( P = 0.07) that had lighter carcass weights ( P = 0.04). Longissimus dorsi cross-sectional area of all carcasses was greater following exposure to low CP diets during the second trimester ( P = 0.04). Heifer nutrient intake during the first and second trimesters causes persistent and sex-specific programming of progeny plasma IGF-I, postnatal liveweight and carcass weight. Refining heifer nutritional programs during early gestation may optimize production objectives in progeny.

Insulin-Like Growth Factor-II Is Increased in Systemic Sclerosis-Associated Pulmonary Fibrosis and Contributes to the Fibrotic Process via Jun N-Terminal Kinase- and Phosphatidylinositol-3 Kinase-Dependent Pathways

Systemic sclerosis (SSc)-related pulmonary fibrosis, for which there are few effective therapies, is the most common cause of SSc-related mortality. We examined insulin-like growth factor (IGF)-II expression in explanted lung tissues from control and SSc patients to determine its role in the pathogenesis of fibrosis. IGF-II levels in vivo were detected using immunohistochemistry. Primary lung fibroblasts were cultured from lung tissues, and IGF-II mRNA was measured using reverse transcriptase-polymerase chain reaction. Western blot analysis measured extracellular matrix (ECM) production and phosphorylated signaling molecules. Immunostaining revealed increased IGF-II expression in fibroblastic foci of SSc lungs. Furthermore, primary SSc lung fibroblasts had a fourfold increase in IGF-II mRNA and a twofold increase in IGF-II protein compared with normal lung fibroblasts. IGF-II mRNA in SSc lung fibroblasts was expressed primarily from the P3 promoter of the IGF-II gene, and IGF-II induced both a dose- and time-dependent increase in collagen type I and fibronectin production. IGF-II triggered the activation of both phosphatidylinositol-3 kinase and Jun N-terminal kinase signaling cascades, the inhibition of which diminished IGF-II-induced ECM production. Our study demonstrates increased local IGF-II expression in SSc-associated pulmonary fibrosis both in vitro and in vivo as well as IGF-II-induced ECM production through both phosphatidylinositol-3 kinase- and Jun N-terminal kinase-dependent pathways. Our results provide novel insights into the role of IGF-II in the pathogenesis of SSc-associated pulmonary fibrosis.

Temporal Changes in Insulin-Like Growth Factors I and II and in Insulin-Like Growth Factor Binding Proteins 1, 2, and 3 in Human Milk

Aim: To evaluate the postpartum time course of changes in insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Methods: Breast milk IGF-I and IGF-II and IGFBP-1, IGFBP-2, and IGFBP-3 levels were determined in 23 women with babies born at term, from day 4 until up to 9 months after birth. Results: The IGFBP-3 levels were highest from day 4 to day 6 and then decreased by days 10–12. In contrast, IGF-I and IGF-II and IGFBP-1 and IGFBP-2 showed little change over the first 2 weeks after birth. Subsequently, all the IGF components showed a moderate decline over approximately the first 1–3 months and then stable levels up to 9 months after birth. Conclusion: Although the possibility cannot be excluded that these changes in levels of IGFs and their binding proteins in human milk represent passive loss from the mammary gland, we speculate that higher early levels of the human milk IGF system contribute to maturation of the infant gut.

Insulin-like Growth Factors, Their Binding Proteins, and Prostate Cancer Risk: Analysis of Individual Patient Data from 12 Prospective Studies

Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. Studies identified in PubMed, Web of Science, and CancerLit. The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.

High Serum IGFBP-2 Is Predictive of Increased Bone Turnover in Aging Men and Women

Elevated serum IGFBP-2 is associated with lower BMD in men and women. It is unknown whether IGFBP-2 serves as a negative regulator of bone metabolism by decreasing bone formation or increasing bone resorption. Studying an age-stratified community-based sample of 344 men and 276 women, IGFBP-2 was the strongest predictor of increased bone resorption among the IGF/IGFBPs studied. Serum insulin-like growth factor binding protein-2 (IGFBP-2), which increases with age, is a predictor of low BMD among aging men and women. However, it is unknown whether IGFBP-2 negatively influences bone metabolism by decreasing bone formation or increasing bone resorption. Few have examined the relation between the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) with bone turnover markers. In an age-stratified, random sample of the community, we examined the association between serum IGF-I, IGF-II, IGFBP-1, -2, and -3, and bone turnover markers before and after adjustment for potential confounders (age, body mass index, bioavailable estradiol and testosterone, and sex hormone binding globulin). Analyses were stratified by sex and menopausal status. We studied 344 men (age range, 23-90 yr) and 276 women (age range, 21-93 yr; 166 postmenopausal) not on oral contraceptives or hormone replacement. Among the IGF/IGFBPs assessed, IGFBP-2 was the strongest and most consistent predictor of bone turnover in men and women. After adjustment for potential confounders, IGFBP-2 was positively associated with osteocalcin (OC) and urine and serum N-teleopeptide (NTX) in men (r = 0.20, 0.26, and 0.23, respectively; p < 0.001), serum C-telopeptide (CTX) in premenopausal women (r = 0.28; p < 0.01), and OC, urine NTX, and serum CTX in postmenopausal women (r = 0.24, 0.33, and 0.19, respectively; p < 0.05). Higher serum IGFBP-2, which is predictive of lower BMD, is associated with increased markers of bone resorption, independent of age, body mass, and sex hormones. The association between IGFBP-2 and markers of bone formation may reflect coupling with increased bone resorption, which is not adequate to maintain BMD.

Insulin-Like Growth Factors and Binding Proteins in Early Milk from Mothers of Preterm and Term Infants

Breast-fed preterm infants often show a better outcome, partly ascribed to the benefit of insulin-like growth factors (IGFs) and their binding proteins (IGFBP). We compared IGF-I, IGF-II, IGFBP-2 and IGFBP-3 levels, measured by radioimmunoassays in milk samples from 30 mothers of preterm (<31 weeks) and from 19 mothers of term (>37 weeks) infants at days 7 and 21 postpartum. Proteolysis of IGFBP-2 within mother’s milk and digestion of ¹²⁵I-IGF-II and ¹²⁵I-IGFBP-2 by gastric juice from neonates were assessed by electrophoretic techniques. Mean concentrations did not differ between preterm and term milk: IGF-I (2.8 ± 0.2 vs. 2.3 ± 0.1 ng/ml), IGF-II (12.0 ± 0.4 vs. 12.2 ± 0.5 ng/ml), IGFBP-3 (100.0 ± 5.1 vs. 80.0 ± 5.8 ng/ml), but did so for IGFBP-2 (3,144 ± 172 vs. 2,428 ± 188 ng/ml, p < 0.02). Immunoblots revealed 42% (p < 0.05) more IGFBP-2 fragments of 14 and 25 kDa in preterm milk. Incubation with gastric juice caused cleavage of ¹²⁵I-IGFBP-2 and partial cleavage of ¹²⁵I-IGF-II. Mutual complexation protected IGF-II and IGFBP-2 from cleavage, suggesting that both are likely to arrive in the bowel in an intact form to exert promotive effects. The results provide further evidence that IGFBP-2 and IGF-II in breast milk are relevant factors for the early development of preterm infants.

Serum levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs), -1, -2, -3, in oral cancer

Introduction Insulin-like growth factor (IGF) possesses mitogenic properties promoting cellular proliferation and inhibiting cellular apoptosis. Reported evidence suggests that cancer (non-oral) is associated with high circulating levels of IGF-1 and low levels of IGFBP-3. Aims This study measured circulating levels of IFG-1 and IGFBPs -1, -2 and -3 in oral cancer patients. Methodology Blood was collected from surgical patients and controls. Samples were assayed for IGF-1 and IGFBPs -1, -2, -3, using commercially available enzyme-linked immunosorbant assays (ELISA; R&D Systems Europe, Oxon, UK). Results Twenty-seven oral cancer and 31 age- and sex-matched patients were recruited. Mean IGF-1 and IGFBP-3 levels were significantly lower in cancer patients than controls (85.3 ng/ml and 2008 ng/ml versus 191 ng/ml and 2935 ng/ml, P < 0.001). In contrast, levels of IGFBPs 1 and 2 were significantly higher in cancer patients than in controls. No significant association was demonstrated with tumour size or nodal metastases. Discussion This study has shown that in contrast to other cancers, circulating levels of IGF-1 and IGFBP-3 may both be lowered in patients with head and neck cancer.

Comparison of follicular fluid IGF-I, IGF-II, IGFBP-3, IGFBP-4 and PAPP-A concentrations and their ratios between GnRH agonist and GnRH antagonist protocols for controlled ovarian stimulation in IVF-embryo transfer patients

Insulin-like growth factors (IGF) and their binding proteins (IGFBP) play a major role in the autocrine and paracrine regulation of folliculogenesis. This is the first study that has compared follicular fluid (FF) IGF-I, IGF-II, IGFBP-3, IGFBP-4 and pregnancy-associated plasma protein (PAPP)-A concentrations, and their ratios, to investigate whether there was any difference in the intrafollicular microenvironment between the GnRH agonist (GnRHa) and antagonist (GnRHant) protocols for controlled ovarian stimulation (COS). A total of 68 IVF cycles were included in this study; two groups were studied: GnRHa long protocol group (n = 36) and the flexible GnRHant multiple-dose protocol group (n = 32). FF was obtained from dominant follicles during oocyte retrieval and stored at -70 degrees C until assayed. IGF-I, IGF-II and IGFBP-3 concentrations were measured by radioimmunoassay and IGFBP-4 and PAPP-A by enzyme-linked immunosorbent assay. The duration of COS was significantly longer, and total dose of gonadotrophins used, serum estradiol (E(2)) levels on hCG day and the number of oocytes retrieved were significantly higher in the GnRHa long protocol group. The concentrations of FF IGF-II and IGFBP-4 were significantly higher, and the ratio of IGF-I/IGFBP-4 was significantly lower in the GnRHa long protocol group. Serum E(2) levels per mature follicle were not different between the two groups. Our data may indicate a difference of intrafollicular microenvironment between cycles using GnRHa long protocols and those using GnRHant protocols. However, the difference in microenvironment does not appear to result in a difference in clinical outcome.

Best Timing of Birth in Placental Insufficiency

After completing this article, readers should be able to: 1. Explain the pathophysiology of fetal hypoxemia during uteroplacental circulatory insufficiency (UPI). 2. Describe the effect of UPI on nutritional substrates. 3. Delineate the potential and limitations of using Doppler flow velocity waveforms to guide delivery decisions in the presence of intrauterine growth restriction. Uteroplacental circulatory insufficiency (UPI) accounts for more than 70% of intrauterine growth restriction (IUGR) (1) and is associated with an increased risk of hypoxemic stress and nutritional deficiency. Both of these threats are concomitant and, to some extent, interrelated, but more importantly, both could lead to the feared complication of UPI—cerebral damage and secondary neurodevelopmental disabilities. To better appreciate the challenge involved in establishing the best time to deliver fetuses that have placental insufficiency, this article is divided in two parts. In the first section, present knowledge of the pathophysiology of fetal hypoxemia and nutritional deficiency in the context of UPI is reviewed briefly. The second section is devoted to a critical appraisal of the criteria currently applied to reach the decision that a fetus that has IUGR should be delivered. Fetal arterial oxygen (O2) concentrations are the result of relative proportions of blood that has different O2 saturations from various venous channels (the two venae cavae, the pulmonary veins, the coronary sinus, and the umbilical vein) draining into the cardiac cavities. Final arterial O2 saturation, therefore, predominantly is dictated by the volume of better-oxygenated blood arriving from the umbilical circulation. Normally, because of its low vascular resistance, the placenta accommodates 50% of the fetal combined cardiac output. Any change in this determinant part of venous return necessarily has a significant impact on intrauterine O2 delivery, even if Po2 in the umbilical vein is within normal range. Experimental (2)(3) and clinical (4 …

Gastrointestinal Inflammation and the Circulating IGF System in Humans

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have important anabolic functions in normal tissue growth, which in excess may lead to tumorigenesis. In the present study, circulating IGF-I, IGF-II and their binding proteins (IGFBP-3, IGFBP-2 and IGFBP-1) were determined in 92 adult patients with gastrointestinal inflammation (Crohn's disease, colitis ulcerosa, gastritis, duodenitis errosiva, gastrointestinal candidiasis, and rotaviral and adenoviral enteritis). Serum IGF concentrations were measured by radioimmunoassay, while IGFBP profiles and IGFBP proteolytic patterns were characterized by immunoblotting. Concentrations of both IGF-I and IGF-II were significantly (p < 0.001) lower in patients than in healthy subjects. Immunoblotting demonstrated a decreased amount of intact IGFBP-3 (by approximately 60%), whereas IGFBP-2 and IGFBP-1 were increased (approximately 1.7 and 3.5-fold, respectively). No alteration in either fragmentation pattern or relative degree of proteolysis was detected in patients compared to the control group. It may be concluded that the IGF system is seriously imbalanced in patients with gastrointestinal inflammation, regardless of primary cause. These findings may help towards a better understanding of the metabolic outcome of the inflammatory process, and possibly in predicting the efficiency of patient recovery.