IGF-binding Protein-3 Concentrations Research Articles

Effect of feeding level on serum IGF1 response to GH injection

This study was conducted to further understand the mechanism by which nutrition modulates GH-induced changes in serum IGF1 concentration in cattle. Cows were fed hay only or corn-based concentrates in addition to hay for 8 weeks. At week 8, serum concentrations of IGF1, IGF-binding protein 3 (IGFBP3), and acid-labile subunit (ALS) as well as their mRNA levels in liver were determined immediately before and 7 days after an injection of GH formulated for sustained release. GH injection caused greater increases in both serum IGF1 concentration and liver IGF1 mRNA expression in the cows fed concentrates than in those fed hay. In the cows fed concentrates, the magnitude of the GH-induced increase in serum IGF1 concentration was, however, much greater than that in liver IGF1 mRNA expression. This difference was not due to GH-induced IGF1 mRNA being translated more efficiently. GH injection also induced greater increases in serum IGFBP3 and ALS concentrations in the cows fed concentrates than fed hay. The injection, however, did not induce a greater increase in IGFBP3 or ALS mRNA in the cows fed concentrates than fed hay. These data and the fact that the ternary complex of IGF1/IGFBP3/ALS stabilizes each of the components in the blood suggest that in cows, increased nutrition enhances serum IGF1 response to GH not only by increasing IGF1 mRNA response to GH in the liver, but also by elevating IGFBP3 and ALS concentrations in the blood.

Abstract 2795: Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract Experimental evidence suggests that an overexpression of insulin-like growth factor-I (IGF-I) is implicated in human pancreatic tumors. Moreover, increased IGF-II and decreased insulin-like growth factor binding protein-3 (IGFBP-3) concentrations are found in a number of cancers. We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55-74 years of age at baseline, to test whether pre-diagnostic circulating IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk. Between 1994 and 2006, 187 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n=374),who were alive at the time the case was diagnosed, were selected for each case and matched by age, race, sex and date of blood draw. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for smoking. In the multivariable adjusted model, IGF-I, IGF-II, and IGFBP-3 concentrations were not associated with pancreatic cancer (highest compared with lowest quintile, OR=1.23, 95% CI 0.67-2.25, p-trend=0.12; OR=0.98, 95% CI 0.52-1.85, p-trend=0.52; and OR=1.15, 95% CI 0.62-2.16, p-trend=0.90). However, a significant positive trend was observed with high IGF-I/IGFBP-3 molar ratio levels in the smoking-adjusted model (OR=1.46, 95% CI 0.78-2.74, p-trend=0.04). A higher IGF-I/IGFBP-3 molar ratio may represent increased free IGF-I and be a risk factor for pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2795.

Elevated levels of decidual insulin‐like growth factor binding protein‐1 in cervical fluid in early and mid‐pregnancy are associated with an increased risk of spontaneous preterm delivery

To study whether elevated levels of decidual insulin-like growth factor binding protein-1 (IGFBP-1) in the cervical fluid of unselected asymptomatic women in early or mid-pregnancy are associated with spontaneous preterm delivery (PTD). Prospective population-based cohort study. Maternity Clinics, University Central Hospital, Helsinki, Finland. A total of 5180 unselected pregnant women. Cervical swab samples were collected during the first and second trimester ultrasound screening. The concentration of IGFBP-1 was measured by immunoenzymometric assay, which detects the decidual phosphoisoforms of IGFBP-1 (phIGFBP-1). Concentrations of 10 micrograms/l or more were considered to be elevated. Spontaneous PTD. Results In the first trimester, 24.5% of women, and in the mid-second trimester, 20.2% of women, had an elevated cervical fluid phIGFBP-1 level. The rates of spontaneous PTD before 32 and before 37 weeks of gestation were higher in women with an elevated cervical fluid phIGFBP-1 level, compared with women who had cervical phIGFBP-1 of <10 micrograms/l (1.1% versus 0.3% and 5.7% versus 3.2%, respectively). An elevated phIGFBP-1 level in the first trimester was an independent predictor for PTD before 32 and before 37 weeks of gestation, with odds ratios of 3.0 (95% CI 1.3-7.0) and 1.6 (95% CI 1.2-2.3), respectively. Cervical phIGFBP-1 levels of 10 micrograms/l or more in the first trimester predicted PTD before 32 and before 37 weeks of gestation, with sensitivities of 53.8% and 37.0%, respectively. The negative predictive values were 99.7% and 96.8%. Elevated cervical fluid phIGFBP-1 levels in the first trimester were associated with an increased risk of spontaneous PTD.

Alterations of insulin-like growth factor binding protein 3 (IGFBP-3) glycosylation in patients with breast tumours

ObjectivesInsulin-like growth factor binding protein-3 (IGFBP-3) is an important modulator of development and progression of breast cancer as it regulates the amount of free, physiologically active IGF-I and IGF-II. Changes in the glycosylation pattern within IGFBP-3 may affect its interaction with ligands. The aim of this study was to investigate whether such changes occur during disease progression. Design and methodsIGFBP-3 in serum samples from healthy women and from women with breast tumours was characterised in terms of its concentration (IRMA), glycosylation moiety (lectin-affinity chromatography) and distribution of molecular species (immunoblotting). ResultsIn patients with benign tumours the concentration and carbohydrate content of IGFBP-3 was unaltered compared to healthy women. In patients with malignant tumours in most cases these two parameters were unchanged, but there were women whose concentration of IGFBP-3 was reduced and its structure was altered. In non-surviving cancer patients the concentration of IGFBP-3 was significantly reduced and these molecules contained a greater amount of biantennary complex type N-glycans having more mannose, fucose, bisecting GlcNAc and terminal sialic acid residues. ConclusionOur results showed that breast cancer progression causes alterations of IGFBP-3 glycosylation. The extent of changes increases with breast cancer severity.

Characterization of the specific and sustained GH1 expression induced by rAAV2/1 in normal adult male rats

Our aim was to investigate the long-term effects of intramuscular injection of rAAV2/1-CMV-GH1 viral particles on GH1 expression in normal adult male rats. We found that specific and sustained GH1 expression did not improve muscle exercise performance despite inducing local muscle hypertrophy. Injection of rAAV2/1-CMV-GH1 had some systemic effects on the liver and heart and on lipid metabolism in the healthy rats. Serum levels of hGH (human growth hormone), insulin, glucose and leptin increased significantly, which might induce insulin resistance. The serum concentration of IGF-1 (insulin-like growth factor 1), IGF-BP3 (insulin-like growth factor binding protein 3) and PIIINP (N-terminal propeptide of type III procollagen) markedly increased at 24 weeks after injection of GH1. In conclusion, GH1 expression driven by AAV2/1 in normal animals did not improve muscle strength but did increase muscle mass and may have systemic effects in healthy animals.

Low-intensity exercise training maintains adipokines in obese children

AbstractThe aim of the present study is to investigate the effects of a 12 weeks low-intensity exercise training on body composition, adipokines, and growth factors in normal (NG) and obese (OG) children. Maximal oxygen uptake (VO2max); body composition; adipokines consisting of adiponectin, retinol binding protein-4 (RBP4), and interleukin-6 (IL-6); and growth factors including insulin like growth factor-1 (IGF-1) and insulin like growth factor binding protein-3 (IGF-BP3) were measured before and after low-intensity exercise training program. Body composition parameters such as body weight, body mass index, body fat (%) and VO2 max were significantly different between NG and OG. Adiponectin levels in NG were increased after 12 weeks exercise training. In addition, our results showed that the concentrations of adiponectin, RBP4, IGF-1, and IGF-BP3 in OG were higher than those of NG. Adiponectin levels were significantly correlated with body fat (r = −0.545, p = 0.001) and VO2max (r = 0.368, p = 0.032) and RBP4 levels were significantly correlated with body fat (r = 0.371, p = 0.031) in all subjects. Exercise training improved adiponectin levels in NG subjects and maintained the levels of body fat, adipokines (adiponectin, RBP4), and growth factors (IGF-1, IGF-BP3) in OG subjects. The present study revealed that regular low-intensity exercise training is strongly associated with high adiponectin levels in healthy children. However, obese children did not exhibit any changes in the levels of adipokines and maintained body composition and growth factors.

Expression of insulin-like growth factor-1 and insulin-like growth factor binding proteins in the serum and cerebrospinal fluid of patients with Parkinson’s disease

Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra. Insulin like growth factor-1 (IGF-1) promotes the survival of dopaminergic neurons and protects them from toxin-induced damage in vitro. IGF-1 is produced by a wide variety of cells and is found in many physiological fluids, including cerebrospinal fluid (CSF). IGFs in physiological fluids are associated with insulin-like growth factor binding proteins (IGFBPs), which bind to them and modulate their bioactivity at the cellular level. Since the CSF is in contact with the extracellular space of the brain, biochemical brain modifications are, to some extent, reflected in the CSF, and peptides and growth factors in the CSF can be used as biomarkers of PD. The aim of this study was to determine the concentrations of IGF-1 and IGFBPs in the serum and CSF of patients with PD. Concentrations were measured in a total of 76 CSF samples from patients with PD ( n = 38) and controls ( n = 38). Serum and CSF IGF-1 and IGFBP concentrations were higher in patients with PD than in controls ( p < 0.001). We conclude that IGF-1 and IGFBPs are always present in human serum and CSF, and may be involved in the pathophysiology of PD.

Effects of Volatile Fatty Acids on IGF-I, IGFBP-3, GH, Insulin and Glucagon in Plasma, and IGF-I and IGFBP-3 in Different Tissues of Growing Sheep Nourished by Total Intragastric Infusions

Twelve SuffolkxSmall-tail-Han male sheep (body weight 21-26 kg), aged four months, were used to study the effects of volatile fatty acids (VFA) on IGF-I (insulin-like growth factor-I), IGFBP-3 (insulin-like growth factor binding protein-3), GH (growth hormone), insulin and glucagon in plasma, and IGF-I and IGFBP-3 in different tissues. The sheep were randomly divided into four groups with 3 sheep in each group. The sheep were sustained by total intragastric infusions and four levels of mixed VFA (the molar proportion of acetic acid, propionic acid and butyric acid was 65:25:10), which supplied 333, 378, 423 and 468 KJ energy/kg W 0.75 /d, were infused into the rumen as experimental Treatments I, II, III and IV, respectively. The experiment lasted 12 days, of which the first 8 days were for pretreatment and the last 4 days for collection of samples. At the end of the experiment, blood samples were taken and then the sheep were slaughtered and tissue samples from the rumen ventral sac, rumen dorsal sac, liver, duodenum and Longissimus dorsi muscle were obtained. IGF-I, IGFBP-3, GH, insulin and glucagon in plasma and IGF-I and IGFBP-3 in different tissues were analysed. Results showed that the concentration of IGF-I, IGFBP-3, GH, insulin or glucagon in plasma and the content of IGF-I and IGFBP-3 in the rumen dorsal sac, rumen ventral sac, liver or Longissimus dorsi muscle were increased with VFA infusion level (p 0.05). It was concluded that IGF-I, IGFBP-3, GH, insulin and glucagon in plasma and IGF-I and IGFBP-3 in rumen dorsal sac, rumen ventral sac, liver and Longissimus dorsi muscle were increased significantly with increasing level of ruminal infusion of mixed VFA.

Androgens, growth factors, and risk of prostate cancer: The Multiethnic Cohort

Androgens and growth factors are thought to be associated with prostate cancer risk, although past research has produced mixed results. We conducted a nested case-control study of biomarkers of prostate cancer risk within the Multiethnic Cohort. We compared prediagnostic levels of testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), 3alpha-androstanediol glucuronide (3alpha-diol G), insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein 1 (IGFBP-1), and IGFBP-3 in serum from 467 incident prostate cancer cases and 934 cancer-free controls. Controls were matched to the cases on geographic site (HI, LA), ethnicity, age at specimen collection (+/-1 year), date (+/-1 month) and time of day (+/-2 hr) of sample collection, and fasting status (<6, 6-7, 8-9, >10 hr). Multivariate conditional logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Serum concentrations of testosterone, DHT, SHBG, 3alpha-diol G, IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were not associated with risk of prostate cancer. Tests for trend of quartiles of serum concentrations also did not show any association. Results were relatively unchanged for men with advanced prostate cancer and their matched controls. However, the follow-up period was relatively short (mean of 1.9 years). Analysis by ethnic group showed an increased risk for Latino men in the second (OR = 3.67, 95% CI: 1.63-8.24) and third (OR = 2.96, 95% CI: 1.19-7.40) tertiles of IGF-I serum levels compared with the first tertile. The suggested increased risk for IGF-I in Latino men merits further study, with greater statistical power.

The common exon 3 polymorphism of the growth hormone receptor gene and the effect of growth hormone therapy on growth in Korean patients with Turner syndrome

Recombinant human growth hormone (GH) can achieve final adult height gain in girls with Turner syndrome (TS), but its efficacy varies widely across individuals. The exon 3-deleted polymorphism of growth hormone receptor (d3-GHR) has been reported to be associated with responsiveness to GH therapy. The short-term growth response of Turner patients to GH therapy was analysed according to their GHR-exon 3 polymorphism genotype. This was a retrospective study of 175 TS patients. Auxological and endocrine parameters were measured, and the GHR-exon 3 genotype was analysed. Allelic frequencies of GHR-exon 3 genotype were compared between patients with TS and control individuals. GH had been administered to 147 patients, 115 of which remained pre-pubertal after the first follow-up year. Changes in height standard deviation score (SDS), height velocity (HV), body mass index (BMI), IGF-1 and IGF binding protein-3 (IGFBP-3) concentrations were compared between these patients, grouped according to genotype, after the first follow-up year. There was no difference in GHR-exon 3 genotype frequency between the TS and control groups of Koreans. According to the GHR-exon 3 genotype (fl/fl group vs. d3/fl and d3/d3 group), HV gain and height SDS gain did not differ significantly at the first year of GH therapy. Moreover, changes in IGF-1, IGFBP-3 concentration and BMI showed no significant difference between the groups with and without d3-GHR after 1 year of GH therapy. The distribution of the GHR-exon 3 genotype was similar in the TS and control groups in a Korean population. The growth promotion efficacy of GH therapy did not differ significantly between TS patients with and without the d3-GHR allele. These findings indicate that the GHR-exon 3 genotype may not be a major factor to affect the GH response in Korean Turner patients.

Investigation of different molecular forms of IGFBP-1 using immobilised metal-, immuno- and lectin-affinity chromatography

Insulin-like growth factor-binding protein 1 (IGFBP-1) is a member of a family of six homologous proteins that regulate the action of the insulin-like growth factors. IGFBP-1 is a 25 kDa protein that beside its native form, may exist in several phosphoforms (30 kDa), which are predominant in the circulation of humans. Phosphorylation of IGFBP-1 is a post-translational modification that has a great influence on the IGF-I action. IGFBP-1 forms multimers and complexes with ?2-macroglobulin (?2M). Polymerisation of IGFBP-1 was also reported. In order to analyse and separate these IGFBP-1 molecular species, affinity chromatography methods were used in this study. The results demonstrated that most of the IGFBP-1 circulates in complexes with ?2M, which can be isolated by affinity chromatography using immobilised anti-?2M antibodies. IGFBP- 1/?2M complexes may be differentiated from IGFBP-1 dimer and multimers using lectin-affinity chromatography, since the latter do not interact with lectins. It seems that the complexes contain not only monomeric IGFBP-1, but also its multimers. Dimer and multimers are stable under reducing conditions, suggesting covalent linkage between units. Free IGFBP-1 monomer can be separated from multimers using Con A-affinity chromatography. The concentration of free IGFBP-1 is relatively low in the circulation.

Age- and gender-specific reference ranges for serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 concentrations on the Immulite 2500: results of the Study of Health in Pomerania (SHIP)

The objective of the present study was to calculate age- and gender-specific reference ranges for serum insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) concentrations using quantile regression. From the Study of Health in Pomerania (SHIP), 1798 men and women aged 25-85 years were recruited. Serum IGF-I and IGFBP-3 concentrations were determined using a chemiluminescent immunometric assay on an Immulite 2500 analyzer. Quantile regressions were performed to calculate the 2.5th and 97.5th percentiles. The reference ranges identified 43 (4.6%) women and 41 (4.8%) men with serum IGF-I concentrations, and 47 (5.0%) women and 42 (5.0%) men with serum IGFBP-3 concentrations outside the reference range. The use of quantile regression results in accurate calculation of age- and gender-specific reference ranges for serum IGF-I and IGFBP-3.

IGF-1, IGFBP-3 and ALS in adult patients with chronic kidney disease

Background Insulin-like growth factor I (IGF-1) is for the most part bound in a ternary complex with IGF-binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). This ternary complex is a storage form of IGF-1 in blood and passes not through the renal glomerulus. Little information is available in regard to the components of the ternary complex in adult renal disease. Objective To investigate levels of serum IGF-1, IGFBP-3 and ALS in relation to renal function and extent of proteinuria. Design and patients We measured IGF-1, IGFBP-3 and ALS concentrations in 137 patients who were investigated due to proteinuria and/or haematuria and/or renal impairment. The patients received renal biopsies and the histological diagnosis was documented. Urinary albumin excretion and relevant clinical parameter were evaluated. Results IGF-1 showed a highly positive correlation to IGFBP-3 and ALS, and the latter to IGFBP-3. IGF-1, IGFBP-3 and ALS decreased with increasing age. IGF-1 and IGFBP-3 showed no significant change depending on the creatinine clearance. However, ALS decreased with decreasing renal function. In patients with heavy proteinuria ALS levels, but not IGF-1 and IGFBP-3 levels, decreased significantly. Patients with chronic ischaemic renal damage and diabetic glomerulopathy showed higher IGF-1 and IGFBP-3 levels compared to patients with thin glomerular basement membrane disease despite their older age. Conclusions IGF-1 and IGFBP-3 levels seem to be independent of renal function and severity of proteinuria. However, ALS levels are altered in renal failure and nephrotic syndrome, which may be due to increased renal loss or diminished hepatic production or both.

The effect of hysteroscopic polypectomy on the concentrations of endometrial implantation factors in uterine flushings

Endometrial polyps have been associated with infertility and early pregnancy loss. The aim of this study was to investigate the effect of hysteroscopic polypectomy on the concentrations of endometrial implantation factors in uterine flushings. Pre-menopausal women with a certain diagnosis of endometrial polyp on contrast-enhanced transvaginal ultrasound scan were recruited into this prospective study. In all women, paired samples of uterine flushings were obtained on the same day of the menstrual cycle prior to and post hysteroscopic polypectomy. Enzyme-linked immunoassays were performed to analyse glycodelin, interleukin-6 (IL-6), interleukin-10 (IL-10), tumour necrosis factor alpha (TNFalpha) and osteopontin, whilst immunoradiometric assay was used to analyse insulin-like growth factor binding protein-1 (IGFBP-1). Concentrations of IGFBP-1, TNFalpha and osteopontin in uterine flushings were significantly lower in the mid-secretory phase prior to polypectomy in comparison to the measurements obtained after complete surgical removal of the polyp (P < 0.05). There were no differences in the concentrations of glycodelin, IL-6 and IL-10 in paired samples prior to and post-polypectomy. The presence of endometrial polyps is associated with decreased mid-secretory concentrations of IGFBP-1, TNFalpha and osteopontin, which are reversed following surgical polypectomy.

Perturbed Insulin-like Growth Factor-1 (IGF-1) and IGF Binding Protein-3 Are Not Associated with Chronic Widespread Pain in Men: Results from the European Male Ageing Study

To determine whether perturbations of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) were associated with the presence of chronic widespread pain (CWP) in men. The European Male Ageing Study (EMAS) is an 8-center population-based study of men aged 40-79 years recruited from population registers. A questionnaire asked about the presence and duration of musculoskeletal pain, from which subjects reporting CWP were identified. Subjects also had an interviewer-assisted questionnaire: levels of physical activity and mood were assessed, and height and weight were measured. IGF-1 and IGFBP-3 were assayed from a fasting blood sample. Logistic regression models were used to determine the association between IGF measures and CWP. Results were expressed as odds ratios or relative risk ratios. A total of 3206 subjects provided full data. Of those, 1314 (39.0%) reported no pain in the past month and 278 (8.3%) reported pain that satisfied criteria for CWP. IGF-1 concentrations were similar among subjects who reported no pain and those with CWP: 131.5 mg/l and 128.4 mg/l, respectively. This was true also for IGFBP-3 (4.3 and 4.3 mg/l). Obesity was associated with low IGF-1 and a high IGFBP-3/IGF-1 ratio, indicating less bioavailable IGF-1, irrespective of pain status. This relationship persisted after adjustment for comorbidities, depression, smoking, alcohol consumption, and quality of life. Overall CWP was not associated with perturbations in IGF-1 and IGFBP-3 concentrations. Hypofunctioning of the axis was noted among subjects who were obese and this was not specific to CWP. These data suggest that IGF-1 is unlikely to be etiologically important in relation to CWP, although the relationship with growth hormone remains to be elucidated.

Insulin-like growth factor binding protein-3 levels during early and late follow-up after surgery in acromegalic patients.

Disease activity in acromegaly is accurately reflected by growth hormone (GH) concentration during oral glucose tolerance test (OGTT) and insulin-like growth factor-I (IGF-I) levels, representing an integrated index of GH activity. This prospective study was performed to evaluate whether plasma IGF binding protein 3 (IGFBP-3) might also reflect the hormonal disease activity in pituitary acromegaly after operative treatment during early and late follow-up. Twenty-two acromegalic patients were studied. Data were obtained pre-, intra- and post-operatively in 13 cases. In 9 patients the acromegalic activity was studied only after treatment. The hormonal assessment included repeated blood samples for estimation of IGF-I, IGFBP-3 and repeated OGTTs. In each case 100 sigma g octreotide (Sandostatin lambda, Sandoz, Basel) was injected to test the acute response of GH, IGF-I and IGFBP-3. Intraoperatively, GH levels were estimated to examine acutely the influence of tumour reduction on GH levels. Patients were considered cured when GH levels (GH60min) were less than 2 ng/ml during OGTT 4 weeks after surgery. The data outlined that in patients with normalized GH60min levels, normalized IGFBP-3 levels were noticed 4 weeks and 12 months post-operatively. In non-cured patients normalized IGFBP-3 concentrations were found in 11 out of 15 cases in the late post-treatment phase. In contrast only 1 of 7 cured patients had persistently elevated IGF-I levels within the first month post-operatively, whereas no case of the non-cured patients had IGF-I values in the normal range. Despite these observations a strong correlation of IGF-I and IGFBP-3 did not exist before one year post-operatively -- either in the cured or in the non-cured patients. Serum IGFBP-3 in patients with pituitary acromegaly does not provide a predictive value of appreciable magnitude concerning cure or non-cure from the disease- whether examined early or late in the post-operative period. Absolute levels of IGFBP-3 may thus cause misinterpretation concerning cure of acromegalics after surgery.

Short-term growth hormone treatment and microcirculation: Effects in patients with chronic kidney disease

Endothelial dysfunction is common in patients with chronic kidney disease (CKD) and contributes significantly to the high long-term cardiovascular morbidity and mortality. The short-term cardiovascular effects of recombinant human growth hormone (rhGH) in CKD patients (stages III–V) and healthy controls ( n = 15 each) were explored in a single-center, non-randomized pilot study. Subjects were investigated before, after a 7 day treatment with rhGH, and after a 7 day wash-out period. Microcirculation was assessed by nailfold capillaroscopy and leg strain gauge plethysmography. Echocardiography was performed and serum concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3) were determined. Before the start of rhGH therapy, mean post-ischemic maximum flow velocity of erythrocytes ( V RBC) and leg blood flow (LBF) in CKD patients were significantly reduced to 68% and 75% of that seen in controls, whereas V RBC and LBF under resting conditions were comparable. Treatment with rhGH significantly increased V RBC and LBF under resting conditions. Whereas maximum post-ischemic V RBC was improved by rhGH in patients and controls, maximum post-ischemic LBF increased in controls only. This was paralleled by a non-significant reduction of total vascular resistance, and increased heart rate and cardiac index. In conclusion, CKD patients respond to short-term rhGH treatment with significantly improved capillary blood flow, whereas only minor effects on total peripheral resistance and cardiac output were noted.

Phenotypes and genotypes of insulin-like growth factor 1, IGF-binding protein-3 and cancer risk: evidence from 96 studies

Insulin-like growth factor 1 (IGF1) and its main binding protein, IGF-binding protein 3 (IGFBP3), play an important role in cancer development. Circulating levels and functional polymorphisms of IGF1 and IGFBP3 may be biomarkers of cancer development. However, the results of published studies remain conflicting rather than conclusive. We searched MEDLINE and EMBASE databases for all published studies related to circulating levels and polymorphisms of IGF1 and IGFBP3 and cancer risk. In all, 96 studies and over 110,000 subjects were available for this meta-analysis. Higher IGF1 circulating levels significantly increased 15% of cancer risk (odds ratio (OR), 1.15, 95% confidence interval (CI), 1.03-1.29), especially among prostate, pre-menopausal breast and colorectal cancer patients, whereas higher concentrations of IGFBP3 significantly decreased the risk of advanced prostate cancer by 56% (OR, 0.44, 95% CI, 0.25-0.77). Meanwhile, IGFBP3 -202CC genotype was associated with an increased risk of prostate cancer with borderline significance (OR, 1.18, 95% CI, 0.99-1.41). Genotype-phenotype correlation analyses showed that circulating levels of IGFBP3 could be modified by its promoter polymorphism A-202C (P < 0.001). In conclusion, circulating levels of IGF1, IGFBP3 and IGFBP3 A-202C play a crucial role in carcinogenesis and could serve as susceptibility biomarkers for cancer development.

The chronic oral administration of arginine aspartate decreases secretion of IGF‐1 and IGFBP‐3 in healthy volunteers

To investigate the effect of chronic oral arginine aspartate on the growth hormone (GH), GH-releasing hormone (GHRH), insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) secretions in healthy volunteers. Twenty-three healthy non-athlete volunteer males were administered arginine aspartate (30 g) orally once daily at 21:00 h for 21 consecutive days. Subjects were hospitalized on days 0, 1, 3, 5, 7, 14 and 21 of treatment. At each hospitalization, concentrations of GHRH, GH, IGF-1 and IGFBP-3 were measured over 4 h after arginine aspartate intake. GH, IGF-1 and IGFBP-3 concentrations were also determined over 12 h at days 0, 1 and 21. Compared with day 1, 4 h GH levels dropped at day 5 and subsequently rose to levels not significantly different from initial ones. The latter was substantiated by 12 h GH levels that did not significantly change from days 1 to 21. GHRH levels were not statistically different, although there was a trend in median values that seemed to inversely mirror those of GH. This dynamic over the course of the study for GH and GHRH was accompanied by a general decrease in IGF-1 and IGFBP-3. In healthy volunteers, a chronic oral treatment with 30 g/day arginine aspartate is followed by a decrease in IGF-1 and IGFBP-3 secretions.

Ligands of EGFR and the insulin-like growth factor family as serum biomarkers for response to EGFR-inhibitors in patients with advanced NSCLC

8100 Background: To determine whether concentrations of transforming growth factor α (TGFa), amphiregulin (ARG), both ligands of the epidermal growth factor receptor (EGFR), insulin-like growth factor 1(IGF1) or IGF-binding protein 3 (IGFBP3) measured in serum of advanced non-small cell lung cancer (NSCLC) patients are predictive of EGFR-inhibitors (EGFRi) response. Methods: We assessed serum levels of marker candidates using ELISA (TGA and ARG) and chemiluminescent (IGF1 and IGFBP3) assays. Sixty-one advanced NSCLC patients treated with EGFRi (gefitinib or erlotinib, &gt;14 days) were matched for gender, age and histology to a control group of 63 EGFRi-untreated advanced NSCLC patients. We dichotomized marker levels at the 20th, 50th or 80th percentile and evaluated whether the effect of EGFRi treatment on overall survival (OS) differed by marker level based on multivariate proportional hazards regression with an interaction term. We adjusted for gender, smoking, stage, histology and prior chemotherapy. Results: While 6-months OS did not appreciably differ between 50 EGFRi treated and 50 control patients whose TGFa levels were below the 80th percentile (39% vs. 54%, multivariate HR 0.78, 95% CI 0.45–1.34, p=0.359), it was substantially worse for 11 EGFRi treated patients compared with 13 control patients whose TGFa levels were high (9% vs. 42%, multivariate HR 2.38, 95% CI 0.87–6.52, p=0.092). The difference of EGFRi effects by TGFa level was statistically significant (interaction p=0.033). There was no evidence that EGFRi treatment effects differed by levels of ARG, IGF1 and IGFBP3. Patients with high concentrations of IGFBP3 (above the median) had significantly longer OS than patients with low IGFBP3 concentrations, independent of treatment (HR 0.46, 95% CI 0.29–0.73, p=0.001). Conclusions: This is the first study in NSCLC patients of Caucasian origin in which serum concentrations of TGFa are predictive for EGFR-inhibitor response, suggesting this is a potential predictive marker for EGFRi treatment. Furthermore, we coincidentally found that levels of IGFBP3 are predictive for overall survival, indicating this might be a prognostic factor in advanced NSCLC patients. [Table: see text]