Diagnostic Significance of Hypomethylated IGFBP3 and TWIST1 Genes in Patients with Colorectal Cancer.

Background: Colorectal cancer (CRC) has been often the main reason for dying worldwide. Many factors are implicated in the progress of colorectal carcinoma, one of the chiefs of which is DNA methylation. Insulin-like growth factor-binding protein 3 (IGFBP3) and twist homolog 1 (TWIST1) genes have already been studied and are potential biomarkers for early colorectal diagnosis. Therefore, we designed this research to assess the levels of methylation of these genes in stool specimens of patients with CRC. Materials and Methods: A whole of 80 specimens containing 40 stool specimens from CRC patients and 40 specimens from healthy individuals as a control group was investigated. DNA was extracted using the bisulfate method and methylation of the candidate genes was assessed using methylation-sensitive high-resolution melting method. Differences in the methylation levels between CRC patients and controls were assessed by statistical analysis. Results: Our study showed significant hypomethylation in both IGFBP3 and TWIST1 promoters in patients' samples compared with normal individuals and notably the promoter hypomethylation found in these genes appeared to occur simultaneously (P < 0.0001 and P < 0.0025, respectively). Meantime, hypomethylation of these genes had not any significant connection with medical results. Conclusion: Our results propose that the IGFBP3 and TWIST1 genes' methylation status can serve as potential biomarkers for early CRC diagnosis. However, more studies are still necessary to better appreciate the methylation pattern of these two genes in CRC and to prove their effects on protein levels.

Doxorubicin induced ROS-dependent HIF1α activation mediates blockage of IGF1R survival signaling by IGFBP3 promotes cardiac apoptosis.

Doxorubicin (Dox) causes the generation of intracellular reactive oxygen species (ROS) and inactivates insulin-like growth factor 1 (IGF1) signaling, leading to cardiomyocyte apoptosis. IGF-binding protein 3 (IGFBP3) is the most abundant circulating IGF1 carrier protein with high affinity, which has been reported to mediate ROS-induced apoptosis. Hypoxia-inducible factor 1α (HIF1A), an upstream protein of IGFBP3 is regulated by prolyl hydroxylase domain (PHD) through hydroxylation. In this study, we investigated the role of IGFBP3, HIF1A, and PHD in Dox-induced cardiac apoptosis.Cells challenged with 1 µM Dox for 24 h increased ROS generation, augmented intracellular and secreted IGFBP3 levels, and reduced IGF1 signaling. Further, we showed that Dox enhanced the extracellular association of IGF1 with IGFBP3. Moreover, echocardiography parameters, especially ejection fraction (EF) and fractional shortening (FS) were significantly reduced in ventricle tissue of Dox challenged rats. Notably, siRNA approach against IGFBP3 or an anti-IGFBP3 antibody rescued Dox-induced cardiac apoptosis, mitochondrial ROS, and the decrease in the IGF1 signaling activity. Furthermore, silencing HIF1A either using siRNA or inhibitor downregulated intracellular IGFBP3, rescued apoptosis, mitochondrial generation, and reduction in IGF1 signaling. Finally, western blot data revealed that ROS scavenger reversed Dox-induced cardiac apoptosis, increased levels of HIF1A and secreted IGFBP3, and decreased IGF1 survival signaling and PHD expression.These findings suggest that Dox-induced ROS generation suppressed PHD, which might stabilize nuclear HIF1A protein, leading to increased IGFBP3 expression and secretion. This in turn results in enhanced extracellular association of the latter with IGF1 and blocks IGF1 pro-survival signaling and may result in inducing cardiac apoptosis.

Association between Chronological Age and IGF-1, IGFBP-3, and CTX Levels in Saliva of Children through Younger Adult Population with Varying Periodontal Status.

The quest for the most precise and non-invasive technology to monitor the pubertal growth spurt is driven by the role of growth determination in orthodontics. The objective of this study was to estimate the levels of salivary insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), and cross-linked C-terminal telopeptide of type I collagen (CTX1), and to analyze whether the levels of these biomarkers vary among different chronological age groups with and without periodontal disease. Eighty participants were divided into three groups based on their chronological age: group 1: 6−12 years; group 2: 13−19 years; and group 3: 20−30 years. The assessed clinical parameters included the simplified oral hygiene index (OHI-S), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment loss (CAL), and community periodontal index (CPI). Using ELISA kits, the IGF-1, IGFBP-3, and CTX1 levels in the saliva samples were estimated. The salivary concentration of IGFBP-3 was significantly associated with age and gender (p < 0.01). However, no significance was observed between subjects with and without periodontal disease. Significant associations existed between the values of IGF-1, IGFBP-3, and CTX1 in saliva among subjects from the various chronological age groups. Estimation of salivary IGF-1 and IGFBP-3 could serve as a useful tool in the assessment of growth maturity and bone remodeling patterns during orthodontic treatment planning.

Comparison of Salivary IGF-1, IGFBP-3, and CTX with Periodontal Status among Patients Belonging to Various Skeletal Maturity Groups.

PURPOSE: To compare the levels of salivary IGF-1, IGFBP-3, and CTX with periodontal status among patients belonging to various skeletal maturity groups. MATERIALS AND METHODS: This cross-sectional study was conducted on 80 participants 6 to 25 years of age. Based on skeletal maturity, the participants were categorised into 3 different stages: prepubertal, pubertal, and post-pubertal stages. The periodontal status of the participants was assessed using the simplified oral hygiene index (OHI-S), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment loss (CAL), and community periodontal index (CPI). The saliva samples were examined for IGF-1, IGFBP-3, and CTX using the respective ELISA kits. One-way ANOVA was used to determine statistically significant differences of means across the study groups for continuous variables. RESULTS: The study demonstrated statistically significant differences for the parameters OHI-S, bleeding on probing, PPD, CPI, and CAL (p < 0.05) depending on skeletal maturity stage. ANOVA test showed a statistically significant difference by stage in IGF-1, IGFPB3, and CTX (p < 0.01). CONCLUSION: An association exists between periodontal status and levels of salivary IGF-1, IGFBP-3, and CTX in patients belonging to various skeletal maturity groups.

Diagnostic Value of Serum Acid-Labile Subunit Alone and in combination with IGF-I and IGFBP-3 in the Diagnosis of Growth Hormone Deficiency.

BACKGROUND: The acid-labile subunit (ALS) is a crucial factor in the tertiary complex. IGF-I and IGFBP-3 are routinely measured during the diagnostic work-up for growth hormone deficiency (GHD). The aim of the study is to evaluate the relevance of serum ALS as an additional biomarker in the diagnosis of GHD. METHODS: Ninety-one children undergoing standard diagnostic work-up for GHD were included in this retrospective study. Inclusion criteria were evidence-based auxological cutoffs, IGF-I and IGFBP-3 <-2 SDS at first presentation, at least 1 growth hormone (GH) stimulation test, and IGF-I, IGFBP-3, and ALS measurements on the same day. Statistical analysis was performed by ROC as well as by odds ratio calculations. RESULTS: Forty-seven of 90 participants presented with peak GH values under the cutoff of 7 ng/mL. AUC from a model containing only IGF-I was 0.76 and 0.68 when using only ALS. A model containing IGF-I, IGFBP-3, and ALS (AUC = 0.77) did not improve the result compared to the combination of IGF-I/IGFBP-3 (0.77) or IGF-I/ALS (0.76). Furthermore, the variation in the outcome (GH peak

Insulin-Like Growth Factor 1 Related to Chronic Low-Grade Inflammation in Patients with Obesity and Early Change of its Levels After Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein (IGFBP) have an influence on metabolism. However, changes in metabolism after sleeve gastrectomy (SG) are not clearly known. This study investigated the change in IGFBP3 levels in obesity after bariatric surgery. METHODS: We evaluated 36 patients with obesity (14 males, aged 31.36 ± 7.06 years and 22 females, aged 32.55 ± 11.40 years) at baseline and 3 months after SG. Changes in their IGF1, IGFBP3, and IGF1/IGFBP3 ratios and glucose-lipid metabolic, inflammation, and oxidative stress parameters were measured. Enzyme-linked immunosorbent assay was used to measure their IGF1 and IGFBP3 levels. RESULTS: (1) IGFBP3 levels were negatively associated with waist circumference (WC) and waist-to-hip ratio (r = - 0.482, P = 0.043; r = - 0.503, P = 0.033); total IGF1 levels were negatively associated with body mass index and WC (r = - 0.569, P = 0.014; r = - 0.470, P = 0.048); and free IGF1 levels were negatively related to tumor necrosis factor (TNF)-α level independent of age (r = - 0.544, P = 0.020). Free IGF1 levels were negatively associated with uric acid, interleukin-6 (IL-6), IL-8, and TNF-α levels (r = - 0.646, P = 0.032; r = - 0.667, P = 0.025; r = - 0.641, P = 0.033; r = - 0.733, P = 0.010) and positively associated with superoxide dismutase activity (r = 0.635, P = 0.036) in females; this relation was not significant in males (all P > 0.05). Total IGF1 was also negatively associated with C-reactive protein (CRP) level in females (r = - 0.671, P = 0.024). (2) IGFBP3 level significantly decreased at 3 months after bariatric surgery in females (P < 0.001) but not in males (P = 0.815). Total IGF1 level significantly decreased after bariatric surgery (P = 0.048); the change was also significant in females (P = 0.014) but not in males (P = 0.626). Free IGF1 level after bariatric surgery was not statistically different between males (P = 0.605) and females (P = 0.628). (3) In females, the change in IGFBP3 level was associated with a change in high-density lipoprotein cholesterol and free fatty acid levels (r = 0.607, P = 0.003; r = 0.546, P = 0.016), and a change in total IGF1 level was associated with a change in CRP level (r = 0.664, P = 0.009). CONCLUSION: IGF1 level was related to chronic low-grade inflammation and oxidative stress in obesity, especially in females. IGFBP3 and IGF1 levels decreased in obesity after SG, especially in females. Changes in IGF/IGFBP3 levels were associated with a change in the inflammatory state after surgery.

Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma.

OBJECTIVE: Despite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment. METHODS: IGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models. RESULTS: We demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice. CONCLUSIONS: Our findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.

Insulin-Like Growth Factor Axis Expression in Dental Pulp Cells Derived From Carious Teeth.

The insulin-like growth factor (IGF) axis plays an important role in dental tissue regeneration and most components of this axis are expressed in human dental pulp cells (DPCs). In our previous study, we analyzed IGF axis gene expression in DPCs and demonstrated a novel role of IGF binding protein (IGFBP)-2 and -3 in coordinating mineralized matrix formation in differentiating DPCs. A more recent study from our laboratory partially characterized dental pulp stem cells from teeth with superficial caries (cDPCs) and showed that their potential to differentiate odontoblasts and/or into osteoblasts is enhanced by exposure to the mild inflammatory conditions characteristic of superficial caries. In the present study, we examine whether changes apparent in IGF axis expression during osteogenic differentiation of healthy DPCs are also apparent in DPCs derived from carious affected teeth.

An update on the diagnosis of growth hormone deficiency.

Growth hormone deficiency (GHD) is an endocrine disorder, which may be either isolated or associated with other pituitary hormone deficiencies. In children, short stature is a useful clinical marker for GHD. In contrast, symptomatology is not always so obvious in adults, and the existing methods of testing might be inaccurate and imprecise, especially in the lack of a suggestive clinical profile. Since the quality of life of patients diagnosed with GHD could also be significantly affected, in both children and adults, a correct and accurate diagnosis is therefore tremendously important to select those patients that can benefit from the GH treatment. In general, the endocrine diseases are challenging in terms of diagnosis, the simple measurement of the basal level of hormones is not sufficient for distinguishing between the physiological and pathological conditions. Traditionally, several stimulation tests have been considered by professional clinical guidelines, such as insulin tolerance test (ITT), GHRH-arginine stimulation test and the glucagon stimulation test, and all of them have both advantages and limitations. More recently (December 2017), FDA approved a growth hormone secretagogue receptor agonist, macimorelin, for the diagnosis of adults with GHD. The obvious advantage for macimorelin is the simple oral administration and the high level of agreement with the insulin tolerance test for those patients with organic disease and low levels of insulin-like growth factor (IGF-I). However, the safety profile and the diagnostic value was not yet established for the pediatric population and for those adults with extreme or morbid obesity. In addition, administration of macimorelin with drugs that prolong QT interval and CYP3A4 inducers should be avoided. Genetic screening could obviously bring a great insight in the GHD pathology. However, it remains an open question if it would be also cost effective to include it in the routine evaluation of the patients with GHD. Although major progresses have been made in this area, genetic testing continues to be difficult to access, mostly because of its high costs, especially in the low-income and middle-income countries.

High serum levels of IGF-I and IGFBP3 may increase comorbidity risk for asthmatic patients.

OBJECTIVE: Asthma is known as a chronic inflammatory lung disease which has also systemic features. Insulin-like growth factor I (IGF-I) plays a role for asthma pathogenesis. Controversially, IGF-binding protein 3 (IGFBP3) blocks asthma development. That is why IGF-I and IGFBP3 are targeted for future therapeutic treatments of asthma. We aimed to investigate serum level of IGF-I and IGFBP3 in patients with asthma. This study was performed in 27 asthma and 23 healthy individuals. Serum levels of IGF-I and IGFBP3 were measured by human ELISA assay kits. Serum levels of IGF-I and IGFBP3 were significanlty higher in the asthma group than the control group. Significant negative correlation was found between IGF-I and asthma control test (ACT) puan, O2 saturation, Forced Expiratory Volume in 1 second/ Forced Vital Capacity (FEV1/FVC), Forced Expiratory Flow 25 second/75 second (FEF2575) (%). Significant positive correlation was found between IGFBP3 and IGF-I, systolic blood pressure. Significant negative correlation was found between IGF-I and FEV1 (ml). RESULTS: Our results indicate that the serum levels of IGF-I and IGFBP3 are significanlty elevated in the asthma group. We assume that current treatment strategies are not really good enough for asthma. We suppose further strategies which are seeking to balance IGF-I and IGFBP3 should be developed for more effective and curative treatment of asthma (Tab. 2, Fig. 2, Ref. 22).

Serum insulin-like growth factor-1 and its binding protein 3 as prognostic factors for the incidence, progression, and outcome of hepatocellular carcinoma: a systematic review and meta-analysis.

PURPOSE: Previous studies have supported an association between serum insulin-like growth factor-1 (IGF1) and IGF-binding protein 3 (IGFBP3) levels and hepatocellular carcinoma (HCC), but the results were inaccurate. It has recently been proposed that IGF1 and IGFBP3 play roles in the time-to-progression (TTP) and overall survival (OS) of HCC patients. Our results revealed that serum IGF1 level is predictive of the progression and survival of HCC patients. RESULTS: HCC was associated with a significant reduction in serum IGF-1 and IGFBP-3 levels compared to cirrhosis (p = 0.037). Low serum IGF1 levels were predictive of a shorter TTP (OR, 2.74; 95% confidence interval [CI], 1.92-3.90) and poorer OS (odds ratio [OR], 2.20; 95% CI, 1.81-2.68) in HCC patients. The IGF1/IGFBP3 molar ratio was not significantly associated with the risk of HCC (OR, 1.311; 95% CI, 0.761-2.260). MATERIALS AND METHODS: We conducted a comprehensive literature search in PubMed, EMBASE, and the Cochrane Library. Twenty studies met the inclusion criteria and were subjected to statistical analysis. The geometric mean and standard deviation (SD) of serum IGF1 and IGFBP3 levels in the healthy, cirrhosis, and HCC groups were calculated. Pooled odds ratios (ORs) were calculated using a fixed-effects model to analyse the association of serum IGF1 level with the progression and survival of HCC patients. CONCLUSIONS: Serum IGF1 and IGFBP3 levels were positively associated with the incidence of HCC. Serum IGF1 level is an independent prognostic factor for the progression and survival of HCC patients.

Assessment of insulin like growth factor-1 and IGF binding protein-3 in healthy Indian girls from Delhi and their correlation with age, pubertal status, obesity and thyroid hormonal status.

BACKGROUND: Population specific data and influence of sub-clinical hypothyroidism on insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3) in Indian children is lacking. This study was undertaken to evaluate serum IGF-1 and IGFBP-3 and their correlation with age, gender, pubertal status and thyroid functions. METHODS: A total of 840 apparently healthy school girls aged 6-18 years, were recruited for the study and underwent assessment of height, weight, body mass index, pubertal status and serum T3, T4, TSH, IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio. RESULTS: The mean serum levels of IGF-1, IGFBP-3 levels and IGF-1/IGFBP-3 molar ratio were 381.8±240.5 ng/mL, 4.19±2.08 µg/mL and 40.5±37.2%, respectively. The serum IGF-1 and IGF-1/IGFBP-3 molar ratio increased significantly (p<0.0001) at 11 years followed by a steady yet non-significant rise till 16 years of age. A similar pattern was observed for IGFBP-3 showing a steep rise at 12 years and peaking at 16 years. Likewise, serum levels of IGF-1 and molar ratio of IGF-1/IGFBP-3 increased significantly with pubertal maturation from stage 1 to 3 and were higher in overweight girls compared to normal weight and obese girls. The growth factors were no different in girls with or without subclinical hypothyroidism. CONCLUSIONS: There was no significant impact of age on IGF-1 and IGFBP-3 in pre-pubertal girls. A sudden marked increase at 11 years followed by a gradual rise in growth factors till 16 years is indicative of pubertal initiation and maturation. Subclinical hypothyroidism did not influence growth factors in girls.

Serum IGF-1, IGFBP-3 levels and circulating tumor cells (CTCs) in early breast cancer patients.

OBJECTIVE: Insulin-like growth factor (IGF)-axis is involved in human oncogenesis and metastasis development for various solid tumors including breast cancer. Aim of this study was to assess the association between IGF-1, IGF-binding protein-3 (IGFBP-3) serum levels and the presence of circulating tumor cells (CTCs) in the peripheral blood of women diagnosed with early breast cancer (EBC), before and after adjuvant chemotherapy. DESIGN: 171 patients with early-stage breast adenocarcinomas were retrospectively evaluated. Immunoradiometric (IRMA) assays were employed for the in-vitro determination of IGF-1 and IGFBP-3 serum levels in blood samples collected after surgical treatment and before initiation of adjuvant chemotherapy. CTCs' presence was assessed through detection of cytokeratin-19 (CK-19) mRNA transcripts using quantitative real time reverse transcription polymerase chain reaction (RT-PCR). IGF-1, IGFBP-3 serum levels were correlated with CTCs' presence before and after adjuvant chemotherapy as well as with tumor characteristics including tumor size, axillary lymph node status, oestrogen (ER)/progestorene (PR) and human epidermural growth factor receptor 2 (HER2) receptor status. Log-rank test was applied to investigate possible association between IGF-1, IGFBP-3 serum levels and disease-free interval (DFI) and overall survival (OS). RESULTS: Before initiation of adjuvant therapy IGF-1, IGFBP-3 serum levels were moderately associated (Spearman's rho=0.361, p<0.001) with each other, while presenting significant differences across age groups (all p values<0.05). IGF-1 serum levels did not correlate with the presence of CTCs before initiation (p=0.558) or after completion (p=0.474) of adjuvant chemotherapy. Similarly, IGFBP-3 serum levels did not show significant association with detectable CTCs either before (p=0.487) or after (p=0.134) completion of adjuvant chemotherapy. There was no statistically significant association between the clinical outcome of patients in terms of DFI, OS and IGF-1(DFI: p=0.499; OS: p=0.220) or IGFBP-3 (DFI: p=0.900; OS: p=0.406) serum levels. CONCLUSIONS: IGF-1 and IGFBP-3 serum levels before initiation of adjuvant chemotherapy are not indicative of CTCs' presence in the blood and do not correlate with clinical outcome of women with early-stage breast cancer.

Tribulus terrestris extracts alleviate muscle damage and promote anaerobic performance of trained male boxers and its mechanisms: Roles of androgen, IGF-1, and IGF binding protein-3.

PURPOSE: To investigate the effects of Tribulus terrestris (TT) extracts on muscle mass, muscle damage, and anaerobic performances of trained male boxers and its mechanisms: roles of plasma androgen, insulin growth factor 1 (IGF-1), and IGF-1 binding protein-3 (IGFBP-3). METHODS: Fifteen male boxers were divided into exercise group (E, n = 7) and exercise plus TT group (E + TT, n = 8). The 2 groups both undertook 3-week high-intensity and 3-week high-volume trainings separated by a 4-week rest. TT extracts (1250 mg/day) were orally administered by boxers in E + TT group. TT extract compositions were detected by UHPLC-Q-TOF/MS. Before and at the end of the 2 trainings, muscle mass, anaerobic performance, and blood indicators were explored. RESULTS: Compared with E group, decreases of plasma CK (1591.5 ± 909.6 U/L vs. 2719.9 ± 832.5 U/L) and IGFBP-3 (3075.5 ± 1072.5 ng/mL vs. 3950.8 ± 479.3 ng/mL) as well as increases of mean power (MP, 459.4 ± 122.3 W vs. 434.6 ± 69.5 W) and MP/body weight (MP/BW, 7.5 ± 0.9 W/kg vs. 7.1 ± 1.1 W/kg) were detected in E + TT group after a high-intensity training. For high-volume training, reduction of IGFBP-3 (2946.4 ± 974.1 ng/mL vs. 3632.7 ± 470.1 ng/mL) and increases of MP (508.7 ± 103.2 W vs. 477.8 ± 49.9 W) and MP/BW (8.2 ± 0.3 W/kg vs. 7.5 ± 0.9 W/kg) were detected in E + TT group, compared with E group. Muscle mass, blood levels of testosterone, dihydrotestosterone (DHT), and IGF-1 were not signifiantly changed between the 2 groups. CONCLUSION: Taking 1250 mg capsules containing TT extracts did not change muscle mass and plasma levels of testosterone, DHT, and IGF-1 but significantly alleviated muscle damage and promoted anaerobic performance of trained male boxers, which may be related to the decrease of plasma IGFBP-3 rather than androgen in plasma.

Association of serum components of GH axis with GHR exon 3 polymorphism in idiopathic short stature children / 天津医药

Objective To investigate the possible association of circulating components of GH-IGFs-IGFBPs system with the GHR-exon 3 genotype in idiopathic short stature (ISS) children. Methods Genomic DNA was extracted and isolat-ed from peripheral leukocytes in 108 ISS children. GHR-exon 3 polymorphism was analyzed with multiplex poly-merase chain reactions (PCR) assay. According to the results of genotype, ISS children were divided into GHRfl group and GHRd 3 group. The height and weight were recorded in two groups. The body mass index (BMI) and BMI standard deviation score (SDS) were measured. The serum levels of insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGF-1 SDS and IGFBP3 SDS were calculated. GH stimulation test was used to measure the serum GH peak value. Fifty-five ISS chil-dren were treated with recombine human GH [0.15 IU/(kg·d)] for three months to analyse the association of IGF-1 response of GH treatment and genotypes. Results There were 63 GHRfl and 45 GHRd3 in 108 ISS children. There were no signifi-cant differences in BMI, IGF-1, IGFBP3, GH peak, IGF-1 SDS and IGFBP3 SDS between two groups (P>0.05). Multiple stepwise regression analysis showed that age, IGFBP3, lg (BMI) and lg (GH peak) were influencing factors of lgIGF-1 (P<0.05). In 55 ISS children treated with rhGH, there were 34 cases of GHRd3. The differences of △IGF-1 and △IGF-1 SDS were higher in GHRd3 group than those of GHRfl group (n=21). Conclusion The GH sensitivity may be a risk factor in ISS children, which may not be related with GHR polymorphism.

Low-fat diet with omega-3 fatty acids increases plasma insulin-like growth factor concentration in healthy postmenopausal women.

The insulin-like growth factor pathway plays a central role in the normal and abnormal growth of tissues; however, nutritional determinants of insulin-like growth factor I (IGF-I) and its binding proteins in healthy individuals are not well defined. Three test diets-high-fat diet (40% energy as fat), low-fat diet (LF; 20% energy as fat), and a diet with low fat and high omega-3 fatty acid (LFn3; 23% energy as fat)--were tested in a randomized crossover designed controlled feeding trial in healthy postmenopausal women. Plasma IGF-I, IGF binding protein-3 (IGFBP-3), insulin, glucose, and ratio of IGF-I/IGFBP-3 concentrations were measured in response to diets. Insulin sensitivity was calculated using the homeostatic model assessment of insulin resistance We hypothesized that IGF-I, insulin, and glucose concentrations would decrease and IGFBP-3 concentration would increase in response to the low-fat diets. Eight weeks of the LFn3 diet increased circulating IGF-I (P < .001) and IGFBP-3 (P = .01) and the LF diet increased IGFBP-3 (P = .04), resulting in trends toward an increased IGF-I/IGFBP-3 ratio with the LFn3 diet and a decreased IGF-I/IGFBP-3 ratio with the LF diet (P = .13 for both comparisons). No statistically significant differences were detected between treatments at baseline or 8 weeks for IGF-1, IGFBP-3, or the ratio of IGF-1/IGFBP-3. Insulin, glucose, and the homeostatic model assessment of insulin resistance were not altered by the interventions. Low-fat diet with high n-3 fatty acids may increase circulating IGF-I concentrations without adversely affecting insulin sensitivity in healthy individuals.

TGF-ß-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells.

Signaling pathways initiated by transforming growth factor-ß (TGF-ß) and insulin-like growth factors (IGFs) are important in osteosarcoma cell growth. We have investigated a role for endogenous IGF binding protein-3 (IGFBP-3) in mediating cross-talk between TGF-ß receptor and type I IGF receptor (IGF1R) signaling pathways in MG-63 osteosarcoma cells. TGF-ß1 indirectly activated the Ras/Raf/MAPK pathway and induced the expression of IGFBP-3, an important regulator of IGF1R activity. IGFBP-3 attenuated TGF-ß1 activation of ERK1/2 and Akt in MG-63 cells, and inhibited TGF-ß1-induced cell cycle progression and proliferation. This effect of IGFBP-3 was blocked by inhibiting IGF1R signaling. TGF-ß1 phosphorylated Smad2 on the non-receptor substrate sites (Ser245/250/255). Blocking the TGF-ß1-induced expression of IGFBP-3 enhanced pSmad2(Ser245/250/255) and increased its nuclear accumulation. These results suggest an important role for TGF-ß1 in osteosarcoma cell growth, with the induction of IGFBP-3 by TGF-ß1 serving in a negative-feedback loop to control cell growth by preventing activation of the IGF1R.

Downregulation of Signaling-active IGF-1 by Dipeptidyl Peptidase IV (DPP-IV).

Functioning as an extracellular protease, dipeptidyl peptidase IV (DPP-IV) preferentially cleaves the peptide bond after the penultimate proline residue. We report here that DPP-IV cleaves the first two amino acids from insulin-like growth factor 1 (IGF-1), revealed by mass spectrometry. The kinetic parameters of the proteolytic cleavage indicate that this reaction is physiologically relevant. Interestingly, truncated IGF-1 is less potent than the full-length protein in activating the IGF-1R, but binds more readily to IGF-binding protein 3 (IGFBP3). Quantitative RT-PCR showed that the level of DPP-IV mRNA is dramatically lower in lung squamous cell carcinoma tissues than in adjacent nonneoplastic lung tissues. However, this reduction was not observed in lung adenocarcinoma tissues. Our study suggests a possible link between IGF-1 and DPP-IV in cancer development in a specific tumor niche. A DPP-IV-related pathway may be important in mitigating IGF-1 signaling. Consequently, a robust IGF signaling pathway may accelerate early carcinogenesis in environments lacking DPP-IV.

Insulin-like Growth Factor(IGF)-I and IGF-Binding Protein-3 in Relation to Hemoglobin Concentration in Healthy Infants

PURPOSE: Insulin-like growth factor(IGF-I) and IGF binding protein(IGFBP)-3 is thought to play an important role in fetal erythropoiesis. The objective of this study was to establish a relation between IGF-I, free IGF-I, IGFBP-1, and -3 with hemoglobin level in healthy term, 3-month, and 12-month old infants. METHODS: Healthy term infants(n=20)were enrolled at birth, as well as 3 months