Serum IGFBP-3 Research Articles

Effects Of Astragalus Extract Mixture HT042 On Height Growth In Children With Mild Short Stature: A Multicenter Randomized Controlled Trial

Astragalus extract mixture HT042 is a standardized functional food ingredient approved by Korean FDA with a claim “HT042 may help height growth of children”. We evaluated the safety and efficacy of HT042 on height growth in prepubertal children with mild short stature. A multicenter, randomized, double-blind, placebo-controlled parallel study was performed over 24 weeks on children aged 6-8 years with height ranked below the 25th percentile. Children were randomly assigned supplementation with either a placebo or HT042. In 129 children, whose height was measured at baseline and end point, height gain was significantly higher in HT042 group than placebo group after 24 weeks. The difference was elevated when the efficacy analysis was restricted to children whose height was below 10th percentile. Bone age advancement was lower in HT042 group. Height SDS gains for bone age was higher in HT042 group and the difference was significant in children below 10th percentile. Serum IGF-1 and IGFBP-3 levels were significantly increased compared with baseline only within HT042 group. HT042 supplementation increased growth rate in children without skeletal maturation, and it was more effective in much shorter children. The effects may be mediated by increases in serum IGF-1 and IGFBP-3 levels.

Serum IGF-I, IGFBP-3 and ALS concentrations and physical performance in young swimmers during a training season

IntroductionThe GH/IGF-I axis is a system of growth mediators, receptors, and binding proteins that regulate somatic and tissue growth; and it has been shown that exercise programs are related to the anabolic function of this axis. ObjectiveThe aim of this study was to analyse the changes of serum IGF-I concentration and that of its binding proteins IGFBP-3 and ALS in adolescent swimmers at different stages of a training season, and compare them with physical performance parameters and body composition of the athletes. Material and methodsNine male athletes, aged 16 to 19years and who trained regularly throughout the season, were included in this study. Serum IGF-I, IGFBP-3, and ALS concentrations were recorded before and after (pre×post) standardized training sessions during the different stages of a training season (extensive×intensive×tapering). Endurance in freestyle, anaerobic fitness in tied swimming (Peak Force and Average Force), body mass, fat percentage, and lean body mass were also analysed at the different stages of training in order to compare the changes of the IGF-I/IGFBP/ALS system with the physical performance and body composition of the athletes. Variations in the IGF-I/IGFBP-3-ALS system before and after a standardized training session, and at the different stages of training were analysed by the Wilcoxon and Friedman non-parametric tests, respectively. Significance was considered at 5%. ResultsThe results from this study demonstrate that IGF-I is sensitive to the acute and chronic effects of training, exhibiting biphasic behaviour throughout the season. The catabolic phase was characterized by a reduction in serum IGF-I concentrations during the intensive stage (∆IGF-I: - 43.33±47.32ng/ml; P<0.05) while the anabolic phase was marked by similar basal concentrations at the different stages of training and an increase in post-training serum IGF-I concentrations during the tapering stage (320±40; 298±36 and 359±94ng/ml; P<0.05). IGFBP-3 was only sensitive to the chronic effects of training, with a reduction in post-training serum concentrations during the intensive stage and an increase during the tapering stage (4.7±0.7, 4.6±0.4 and 5.0±0.7mg/l; P<0.05). No significant difference (P>0.05) was observed in pre- or post-training IGFBP-3 concentrations (∆IGFBP-3) at the different stages. ALS concentrations remained unchanged throughout the season, demonstrating that in adolescent athletes they are unaffected by the acute or chronic effects of swimming. Peak Force (25.0±6.3, 24.2±5.7 and 28.5±6.5N; P<0.05) and Average Force (10.3±3.6, 8.8±1.8 and 14.7±1.8N; P<0.05) followed IGF-I and IGFBP-3 variations, with a decrease during the intensive stage and a significant (P<0.05) increase during the tapering stage. The body composition and cardiorespiratory condition of the swimmers did not vary significantly throughout the season, exhibiting behaviour independent of IGF-I or IGFBP-3. ConclusionSerum IGF-I and IGFPB-3 concentrations have proven to be sensitive markers of training status and, thus, may be used as guides for coaches and athletes in the challenging task of modulating training intensity in young athletes.

Adipose Tissue-Derived IGFBP1 Facilitates Progression of Leukemia

We recently reported that adipose tissue functions as a reservoir for leukemia stem cells (LSCs) using a murine model of leukemia (Ye et al., Cell Stem Cell, 2016). Intriguingly, the presence of leukemic cells in adipose tissue induces increased lipolysis and the release of free fatty acids (FFA) which in turn fuels the growth of LSCs. Further, adipose tissue protects resident LSCs from chemotherapy. These findings indicate that the unique characteristics of adipose tissue may provide key insights on the growth and survival of leukemic cells. Thus, in the present study we focus on the endocrine function of adipose tissue and explore its role in leukemia development.First, to evaluate secreted factors, we applied adipokine arrays which detect 38 adipokines to leukemia serum collected at different stages of leukemia pathogenesis. Interestingly, we observed a significantly elevated level of serum IGFBP1 as soon as leukemic disease became evident at low levels (~0.5%) in marrow. IGFBP1 increased to levels approximate 200X normal at peak stages of disease burden. ELISA analyses further confirmed these observations.IGFBP1 is normally considered as a liver-derived protein. However, we did not find any changes of IGFBP1 expression in leukemic liver. Rather, we observed a significant increase in the expression of IGFBP1 in adipose tissue. IGFBP1 in conditioned medium (CM) from leukemic gonadal adipose tissue (GAT) is approximate 100X higher than naive GAT. Together, these findings suggest adipose tissue-derived IGFBP1 contributes to the increased serum IGFBP1 we detected in leukemic animals.We next examined the role of IGFBP1 in leukemia development using a neutralizing antibody. Treatment of experimental animals with anti-IGFBP1 antibody significantly decreased leukemic burden in GAT (~40% IgG treated VS. 20% Anti-IGFBP1 treated) while bone marrow (BM) and spleen leukemic engraftment remained unchanged (~40%). Further, less atrophy of adipose tissue as well as less body weight loss was seen in the IGFBP1 neutralizing antibody treated group. Consistent with this observation, serum FFA level was also reduced, suggesting less lipolysis in the IGFBP1 antagonized group. Together, these results indicate that IGFBP1 is involved in the regulation of leukemic cells homing to adipose tissue and consequently leukemia-induced lipolysis.Next we explored the mechanisms for the increased expression of IGFBP1 in adipose tissue. Studies have shown that both FGF21 and hypoxia induce IGFBP1 expression. We did not find any changes of FGF21 expression in adipose tissue or in liver, suggesting FGF21 was not involved in IGFBP1 regulation in our system. In contrast, we observed a five-fold elevation in IGFBP1 mRNA in primary adipose tissue cultured under hypoxic conditions. Studies have shown that both BM and spleen in leukemia mice are already hypoxic in early stages of leukemic development (Benito et al., Plos One, 2011). Thus, we hypothesize that tissue hypoxia may at least partially regulate IGFBP1 in leukemia. Ongoing experiments are testing this hypothesis. Additionally, inflammatory cytokines have been reported to increase IGFBP1 expression. We previously reported significantly increased levels of inflammatory cytokines in the adipose tissue of leukemic mice including TNF-α, IL1 and CSF2 (1.5X normal adipose tissue). Therefore, we hypothesize the local inflammatory cytokine production may also contribute to increased expression of IGFBP1, a theory that is also currently under investigation.IGFBP1 has recently been reported to activate osteoclasts and thus promotes bone metabolism (Wang et al., Cell Metabolism, 2015). Studies have found an increased number of osteoclasts and thus bone loss in our leukemic model (Frisch et al., Blood, 2012). We hypothesize that adipose tissue-derived IGFBP1 contributes to bone loss in leukemic mice. Ongoing experiments are testing whether antagonization of IGFBP1 in leukemic mice will rescue bone loss.Collectively, these findings suggest that adipose tissue-derived IGFBP1 facilitates progression of leukemia through regulation of adipose tissue lipolysis and may promote bone marrow colonization by leukemia cells through activation of osteoclasts. DisclosuresNo relevant conflicts of interest to declare.

IGFBP3 and MAPK/ERK signaling mediates melatonin-induced antitumor activity in prostate cancer.

Treatment of prostate cancer (PCa), a leading cause of cancer among males, lacks successful strategies especially in advanced, hormone-refractory stages. Some clinical studies have shown an increase in neuroendocrine-like cells parallel to the tumor progression but their exact role is a matter of debate. The prostate is a well-known target for melatonin, which reduces PCa cells proliferation and induces neuroendocrine differentiation. To evaluate the mechanisms underlying the indole effects on neuroendocrine differentiation and its impact on PCa progression, we used a cell culture model (LNCaP) and a murine model (TRAMP). Persistent ERK1/2 activation was found in both, melatonin and androgen-deprived cells. Melatonin blocked nuclear translocation of androgen receptor (AR), thus confirming anti-androgenic actions of the indole. However, using a comparative genome microarray to check the differentially expressed genes in control, melatonin, or androgen-deprived cells, some differences were found, suggesting a more complex role of the indole. By comparing control cells with those treated with melatonin or depleted of androgen, a cluster of 26 differentially expressed genes (±2.5-fold) was found. Kallikreins (KLK)2 and KLK3 (PSA) were dramatically downregulated by both treatments whereas IGFBP3 and IGF1R were up- and downregulated, respectively, in both experimental groups, thus showing a role for IGF in both scenarios. Finally, melatonin prolonged the survival of TRAMP mice by 33% when given at the beginning or at advances stages of the tumor. Serum IGFBP3 was significantly elevated by the indole in early stages of the tumor, confirming in vivo the role of the IGF signaling in the oncostatic action of the indole.

Human placental growth hormone is increased in maternal serum at 20 weeks of gestation in pregnancies with large-for-gestational-age babies

To investigate the relationship between maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF)-1 and 2, IGF binding proteins (IGFBP)-1 and 3 and birth weight in appropriate-for-gestational-age (AGA), large-for-gestational-age (LGA) and small-for-gestational-age (SGA) cases in a nested case-control study. Maternal serum samples were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Serum hormone concentrations were determined by ELISA. We found that maternal serum GH-V concentrations at 20 weeks of gestation in LGA pregnancies were significantly higher than in AGA and SGA pregnancies. Maternal GH-V concentrations were positively correlated to birth weights and customized birth weight centiles, while IGFBP-1 concentrations were inversely related to birth weights and customized birth weight centiles. Our findings suggest that maternal serum GH-V and IGFBP-1 concentrations at 20 weeks' gestation are associated with fetal growth.

Associations of IGFBP3 Gene Polymorphism and Gene Expression with the Risk of Osteonecrosis of the Femoral Head in a Han Population in Northern China.

The critical roles of IGFBP3 in regulating the osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells strongly indicate its potential effects on the pathogenesis of osteonecrosis of the femoral head (ONFH). In this study, we investigated the association of IGFBP3 gene polymorphism and its protein expression with the development of ONFH to further explore its molecular pathogenesis. Ligase detection reactions and enzyme-linked immunosorbent assay were used to detect the polymorphisms of rs2453839[C/T] and rs3110697[A/G] and the serum protein expression of IGFBP3 gene in 182 cases and 179 controls, respectively. The serum lipids level was also measured by automatic biochemistry analyzer. The results revealed that the recessive model of rs3110697 and the dominant model of rs2453839 were significantly associated with the increased risk of ONFH (p = 0.048, p = 0.047, respectively). The genotypes of rs2453839 were also significantly related to the clinical stages of ONFH (p = 0.017). More importantly, the serum protein expression of IGFBP3 and insulin-like growth factor 1 (IGF1) in the ONFH group were statistically increased compared with the control group (p = 0.044, p = 0.007). The serum triglyceride and low-density lipoprotein cholesterol level in the ONFH group were significantly higher than the control group (p = 0.01, p = 0.005, respectively), but the serum high-density lipoprotein cholesterol level of the ONFH group was dramatically lower than the control group (p = 0.0001). Our results showed that both the gene polymorphisms of IGFBP3 and the abnormal protein expression of serum IGFBP3 and IGF1 closely associated with the development of ONFH.

P.53 - Serum IGF1 and IGFBP3 levels in SMA patients

P.53 - Serum IGF1 and IGFBP3 levels in SMA patients

Antibody-Array-Based Proteomic Screening of Serum Markers in Systemic Lupus Erythematosus: A Discovery Study.

A discovery study was carried out where serum samples from 22 systemic lupus erythematosus (SLE) patients and matched healthy controls were hybridized to antibody-coated glass slide arrays that interrogated the level of 274 human proteins. On the basis of these screens, 48 proteins were selected for ELISA-based validation in an independent cohort of 28 SLE patients. Whereas AXL, ferritin, and sTNFRII were significantly elevated in patients with active lupus nephritis (LN) relative to SLE patients who were quiescent, other molecules such as OPN, sTNFRI, sTNFRII, IGFBP2, SIGLEC5, FAS, and MMP10 exhibited the capacity to distinguish SLE from healthy controls with ROC AUC exceeding 90%, all with p < 0.001 significance. These serum markers were next tested in a cohort of 45 LN patients, where serum was obtained at the time of renal biopsy. In these patients, sTNFRII exhibited the strongest correlation with eGFR (r = -0.50, p = 0.0014) and serum creatinine (r = 0.57, p = 0.0001), although AXL, FAS, and IGFBP2 also correlated with these clinical measures of renal function. When concurrent renal biopsies from these patients were examined, serum FAS, IGFBP2, and TNFRII showed significant positive correlations with renal pathology activity index, while sTNFRII displayed the highest correlation with concurrently scored renal pathology chronicity index (r = 0.57, p = 0.001). Finally, in a longitudinal cohort of seven SLE patients examined at ∼3 month intervals, AXL, ICAM-1, IGFBP2, SIGLEC5, sTNFRII, and VCAM-1 demonstrated the ability to track with concurrent disease flare, with significant subject to subject variation. In summary, serum proteins have the capacity to identify patients with active nephritis, flares, and renal pathology activity or chronicity changes, although larger longitudinal cohort studies are warranted.

Raised serum levels of IGFBP-1 and IGFBP-2 in idiopathic pulmonary fibrosis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic lung disorder of unknown origin, which ultimately leads to death. Several growth factors such as IGFs (insulin-like-growth factor) and IGFBPs (insulin like growth factor binding proteins) seem to take part to the pathogenesis. We evaluated IGFs and IGFBPs in serum from patients with IPF and healthy subjects including 24 untreated IPF and 26 IPF receiving anti-fibrotic therapy and to compare them with healthy subjects.MethodsSerum of 50 idiopathic pulmonary fibrosis and 55 healthy subjects (HS) were analysed by ELISA for IGFs and IGFBPs, TGF-β and KL-6, the latter being tested as positive control in IPF.ResultsSerum levels of IGFBP-1 and IGFBP-2 and KL-6 were significantly higher in the IPF group than in the healthy subjects (p < 0.05, p < 0.001 and p < 0.0001 respectively) while the picture was inversed regarding IGFs. By contrast there was no significant difference between the groups with respect to TGF-β. IGFBP-2 was significantly reduced in the patients with specific anti-fibrotic therapy pirfenidone and nintedanib compared to untreated patients (p < 0.05) but still significantly elevated in comparison to HS (p < 0.001).ConclusionSerum IGFBP-1 and −2 are increased in idiopathic pulmonary fibrosis and IGFBP-2 may be reduced by anti-fibrosing therapy. IGFBPs may be promising biomarkers in IPF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0249-6) contains supplementary material, which is available to authorized users.

Effect of insulin-like growth factor-I during the early postnatal period in intrauterine growth-restricted rats.

Insulin-like growth factor-I (IGF-I) is essential for perinatal growth and development; low serum IGF-I has been observed during intrauterine growth restriction (IUGR). We investigated the effects of recombinant human (rh) IGF-I in IUGR rats during the early postnatal period. Intrauterine growth restriction was induced by bilateral uterine artery ligation in pregnant rats. IUGR pups were divided into two groups injected daily with rhIGF-I (2 mg/kg; IUGR/IGF-I, n = 16) or saline (IUGR/physiologic saline solution (PSS), n = 16) from postnatal day (PND) 7 to 13. Maternal sham-operated pups injected with saline were used as controls (control, n = 16). Serum IGF-I and IGF binding proteins (IGFBP) 3 and 5 were measured on PND25. The expression of Igf-i, IGF-I receptor (Igf-ir), Igfbp3, and 5 mRNA in the liver and brain was measured using real-time polymerase chain reaction on PND25. Immunohistochemical staining of the liver for IGF expression was performed. Mean bodyweight on PND3 and PND25 in the IUGR pups (IUGR/IGF-I and IUGR/PSS) was significantly lower than that of the control pups. Serum IGF-I and hepatic Igf-ir mRNA in the IUGR pups were significantly lower than those in the control pups. In the IUGR/IGF-I group, hepatic Igfbp3 mRNA and liver immunohistochemical staining were increased. In the IUGR/PSS and control pups, there were no significant differences between these two groups in serum IGFBP3 and IGFBP5, hepatic Igf-i and Igfbp-5 mRNA, or brain Igf mRNA. No benefits on body and brain weight gain but an effective increase in hepatic IGFBP-3 was observed after treatment with 2 mg/kg rhIGF-I during the early postnatal period.

Impaired phosphorylation of JAK2-STAT5b signaling in fibroblasts from uremic children.

Chronic kidney disease (CKD) in children is characterized by severe growth failure. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in uremic animals shows a post-receptor impaired phosphorylation of Janus kinase 2/signal transducer and activator of transcription (JAK-STAT) proteins. The objective of our study was to characterize the intracellular phosphorylation of JAK-STAT signaling in fibroblasts from children with CKD on chronic peritoneal dialysis (PD). Serum GH-binding protein (GHBP), IGF-1 and IGFBP3 were measured in 15 prepubertal CKD stage-5 children on PD. Cytoplasmic JAK2, cytoplasmic/nuclear STAT5b and nuclear IGFBP3, acid-labile subunit (ALS) and IGF-1 mRNA expression were quantified in fibroblasts obtained from skin biopsies before and after stimulation with 200 ng/ml recombinant human growth hormone (rhGH). Phosphorylation activity at both the cytoplasmic and nuclear level was expressed as the ratio phosphorylated (p)/total (t) abundance of the product (p/t) at 30 and 60 min. Fifteen healthy children were recruited as the control group. Values were expressed in arbitrary units (AU) and normalized for comparison. Significance was defined as p < 0.05. Thirty minutes after rhGH stimulus, the cytoplasmic (p/t) JAK2 ratio was significantly lower in patients than in controls [median and interquartile range (IQR): 7.4 (4.56) vs. 20.5 (50.06) AU]. At 60 min after rhGH stimulation, median JAK2 phosphorylation activity was still significantly lower in the patients [7.14 (IQR 3.8) vs. 10.2 (IQR 29.8) AU; p < 0.05]. The increase in the cytoplasmic (p/t) STAT5b/β-actin ratio was lower at both measurement points in the patients compared to the controls, without reaching statistical significance between groups. Median IGFBP3 mRNA abundance was significantly decreased in fibroblasts from uremic patients 24 h after rhGH stimulation compared to the healthy controls [1.27 (IQR 0.83) vs. 2.37 (IQR 0.80) AU]. Median ALS and IGF-1 mRNA expression changed in response to rhGH stimuli at 24 and 48 h. In this study, children with CKD undergoing PD therapy showed an impaired phosphorylation of JAK2/STAT5b signaling in fibroblasts after GH stimulation, as well as impaired IGFBP3 mRNA abundance. Both impairments may be partially responsible for the observed resistance to the growth-promoting actions of GH in chronic kidney failure.

Serum Adiponectin And Insulin-Like Growth Factor 1 In Predominantly Female Patients With Thyroid Cancer: Association With The Histologic Characteristics Of The Tumor

Objective: Insulin-like growth factor (IGF)-1 and adiponectin have been proposed to contribute to the pathogenesis of different malignancies. However, data regarding their association with histologic characteristics of thyroid cancer are scarce. The main aims of the present study were the comparative evaluation of IGF-1, IGF-binding protein 3 (BP3), and adiponectin serum levels between different histologic types of thyroid cancer, as well as within specific histologic characteristics of the tumors.Methods: A total of 179 thyroid cancer patients (126 [70.4%] women) were recruited. A total of 129 (72.1%) had papillary thyroid carcinoma (including variants), 26 had follicular thyroid carcinoma (14.5%), and 24 had medullary thyroid carcinoma (13.4%). Parameters from history, physical examination, and thyroid histology were selected. Serum adiponectin, IGF-1, and IGF-BP3 were measured in fasting morning samples.Results: IGF-1, IGF-BP3, and adiponectin levels were similar among different histologic types of thyroid carcinoma, with a trend towards higher IGF-1 and IGF-BP3 levels in patients with intrathyroid invasion, compared to those without. In addition, ratios of IGF-1 to adiponectin (P = .012) and IGF-1 to (adiponectin × IGF-BP3) (P = .003), as well as type 2 diabetes (P = .001), were positively associated with tumor size.Conclusion: Although IGF-1, IGF-BP3, and adiponectin were not separately different between groups or within specific histologic lesions, when they were combined to produce IGF-1 to adiponectin and IGF-1 to (adiponectin × IGF-BP3) ratios, they were independently associated with tumor size. Future prospective studies are needed to evaluate whether these ratios could serve as prognostic markers of thyroid tumor aggressiveness.Abbreviations:CI = confidence intervalIGF-1 = insulin-like growth factor-1IGF-1R = insulin-like growth factor 1 receptorIGF-BP3 = insulin-like growth factor binding protein 3MTC = medullary thyroid carcinomaOR = odds ratioPTC = papillary thyroid carcinomaPTC-fv = papillary thyroid carcinoma-follicular variantT2DM = type 2 diabetes mellitus

Evaluation of Serum GH, IGF-1, and IGFBP-3 Levels as Biomarkers in The Diagnosis of Acute Myocardial Infarction

Evaluation of Serum GH, IGF-1, and IGFBP-3 Levels as Biomarkers in The Diagnosis of Acute Myocardial Infarction

Associations of serum carotenoid concentrations and fruit or vegetable consumption with serum insulin-like growth factor (IGF)-1 and IGF binding protein-3 concentrations in the Third National Health and Nutrition Examination Survey (NHANES III).

Dietary intervention may alter the insulin-like growth factor (IGF) system and thereby cancer risk. In a qualitative review, eleven of twenty studies showed a link between one or more carotenoids, vegetable or fruit intake and the IGF system, however, with partly contrary findings, such that no firm conclusion can be drawn. Therefore, we evaluated associations between serum carotenoid concentrations or the intake of fruits and vegetables with IGF-1, IGF binding protein (BP)-3 and their molar ratio (IGF-1:IGFBP-3) within the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). In our analysis, we included 6061 NHANES III participants and used multivariable-adjusted linear regression models. IGF-1 concentrations were significantly positively associated with serum concentrations of lycopene, β-carotene, α-carotene, β-cryptoxanthin and lutein/zeaxanthin in men and women. Statistically significant positive associations were observed for serum concentrations of α-carotene and lutein/zeaxanthin and intake of fruits with serum IGFBP-3 concentrations in women, but not in men. The IGF-1:IGFBP-3 molar ratio was significantly positively associated with serum concentrations of lycopene, β-carotene and α-carotene in men and with β-carotene in women. In conclusion, dietary interventions with carotenoids, fruits and vegetables may affect the IGF system, although the direction of these effects is currently unclear.

Agreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies

ObjectiveLevels of insulin-like growth factor (IGF) proteins are associated with the risk of cancer and mortality. IGF assays produced by Diagnostic Systems Laboratories (DSL) were widely used in epidemiological studies, were not calibrated against recommended standards and are no longer commercially available. DesignIn a split sample study among 1471 adults participating in the Cardiovascular Health Study, we compared values obtained using DSL assays with alternative assays for serum IGF-I (Immunodiagnostic Systems, IDS), IGFBP-1 (American Laboratory Products Company, ALPCO) and IGFBP-3 (IDS). ResultsResults were compared using kernel density estimation plots, quartile analysis with weighted kappa statistics and linear regression models to assess the concordance of data from the different assays. Participants had a mean age of 77years. Results between alternative assays were strongly correlated (IGF-I, r=0.93 for DSL versus IDS; log-IGFBP-1, r=0.90 for DSL versus ALPCO; IGFBP-3, r=0.92 for DSL versus IDS). Cross tabulations showed that participants were usually in the same quartile categories regardless of the assay used (overall agreement, 74% for IGF-I, 64% for IGFBP-1, 71% for IGFBP-3). Weighted kappa also showed substantial agreement between assays (kw, 0.78 for IGF-I, 0.69 for IGFBP-1, 0.76 for IGFBP-3). Regressions of levels obtained with DSL assays (denoted X) to alternative assays were, IGF-I: 0.52X+15.2ng/ml, log-IGFBP-1: 1.01X−1.73ng/ml IGFBP-3: 0.87X+791.1ng/ml. Serum values of IGF-I, IGFBP-1 and IGFBP-3 measured using alternative assays are moderately correlated. ConclusionsCare is needed in the interpretation of data sets involving IGF analytes if assay methodologies are not uniform.

Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: a randomized clinical trial.

Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anticancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and cortisol in humans. To test the sustained effects of CR on these key hormonal adaptations, we performed a multicenter randomized trial of a 2-year 25% CR intervention in 218 nonobese (body mass index between 22 and 27.8kgm(-2) ) young and middle-aged (20-50years age range) men and women. Average CR during the first 6months was 19.5±0.8% and 9.1±0.7% over the next 18months of the study. Weight loss averaged 7.6±0.3kg over the 2-years period of which 71% was fat mass loss (P<0.0001). Average CR during the CR caused a significant 21% increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2years (P<0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum cortisol concentrations were slightly but significantly increased by CR at 1year only (P=0.003). Calorie restriction had no effect on serum concentrations of PDGF-AB and TGFβ-1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF-1 concentration or with a sustained and biological relevant increase in serum cortisol. However, long-term CR in humans significantly and persistently increases serum IGFBP-1 concentration.

Is Serum Serotonin Involved in the Bone Loss of Young Females with Anorexia Nervosa?

Recent experimental data suggest that circulating serotonin interacts with bone metabolism, although this is less clear in humans. This study investigated whether serum serotonin interferes with bone metabolism in young women with anorexia nervosa (AN), a clinical model of energy deprivation. Serum serotonin, markers of bone turnover [osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), type I-C telopeptide breakdown products (CTX)], leptin, soluble leptin receptor (sOB-R), and insulin-like growth factor-1 (IGF-1) and its binding protein (IGFBP-3) were assessed. Whole body, spine, hip, and radius areal bone mineral density BMD (aBMD) were assessed by dual-energy X-ray absorptiometry in 21 patients with AN and 19 age-matched controls. Serum serotonin, leptin, IGF-1, IGFBP-3, OC, PINP, and aBMD at all sites, radius excepted, were significantly reduced in AN whereas CTX and sOB-R were increased compared with controls. Serum serotonin levels were positively correlated with weight, body mass index, whole body fat mass, leptin, and IGF-1, and negatively with CTX for the entire population. Low serum serotonin levels are observed in patients with AN. Although no direct link between low serum serotonin levels and bone mass was identified in these patients, the negative relationship between serotonin and markers of bone resorption found in all population nevertheless suggests the implication of serotonin in bone metabolism. Impact of low serum serotonin on bone in AN warrants further studies.

A 20-week program of resistance or concurrent exercise improves symptoms of schizophrenia: results of a blind, randomized controlled trial.

To evaluate the effects of 20 weeks of resistance and concurrent training on psychotic and depressive symptoms, quality of life outcomes, and serum IGF-1, IGFBP-3, and brain-derived neurotrophic factor (BDNF) concentrations in patients with schizophrenia. In this blind, randomized controlled clinical trial, 34 patients with schizophrenia were assigned to one of three groups: control (CTRL, n=13), resistance exercise (RESEX, n=12), or concurrent exercise (CONCEX, n=9). Symptoms, quality of life, strength, and other variables were assessed. A significant time-by-group interaction was found for the RESEX and CONCEX groups on the Positive and Negative Syndrome Scale (PANSS) total score for disease symptoms (p = 0.007), positive symptoms (p = 0.003), and on the arm extension one-repetition maximum (1RM) test (p = 0.016). In addition, significant improvements on negative symptoms (p = 0.027), on the role-physical domain of the Short Form-36 Health Survey (p = 0.019), and on the chest press 1RM test (p = 0.040) were observed in the RESEX group. No changes were observed for the other variables investigated. In this sample of patients with schizophrenia, 20 weeks of resistance or concurrent exercise program improved disease symptoms, strength, and quality of life. ClinicalTrials.gov: NCT01674543.

Abstract 1790: Caloric restriction can increase the efficacy of radiation in both hormone-sensitive and hormone-resistant prostate cancers by downregulating the IGF-1R pathway

Abstract Locally advanced prostate cancers (LAPC) are aggressive, have poor prognosis, and are associated with high recurrence rates and conversion to castrate resistance. The molecular underpinnings of LAPC are being investigated to identify novel therapeutics. Animal models have shown that caloric restriction (CR) can potentially prevent the initiation of prostate cancer. We propose that CR may be used as a novel therapeutic intervention to enhance outcomes of radiation treatment by altering the molecular profile of prostate tumors. To assess the effect of CR with radiation in vivo, eighty 6 week old male nude mice were injected with LNCaP (hormone sensitive) or PC3 (hormone refractory) tumor cells. Once tumors were palpable, mice were randomized to be treated with one of 4 conditions: ad libitum (AL) diet, 8Gy of radiation (RT), 30% reduction in caloric intake (CR), or CR+RT. CR was associated with significant reduction in tumors. After PC3 tumor injection, compared with AL, the mice had a 22% reduction in tumor size with radiation, 77% with CR (p&amp;lt;0.01 by Student's t-test) and an 80% reduction with CR+RT (p&amp;lt;0.01). After LNCaP tumor injection, compared with ad libitum, the mice had a 49% reduction in tumor size with CR and a 55% reduction with CR+RT (p&amp;lt;0.01). Tissue evaluation of mice treated with CR or CR+RT from both the LNCaP and PC3 models revealed decreased proliferation via Ki-67 and increased apoptosis with cleaved caspase-3 levels. In addition, significant downregulation of multiple members of the IGF-1R pathway was seen, including downregulation of IGF-1R, IRS-1, PI3K and pAKT. Serum evaluation revealed decreased IGF-1:IGF-BP3 in serum. For the first time, we have shown that the efficacy of radiation can be increased by decreasing calories by 30% in both hormone-sensitive and hormone-refractory prostate cancer models. Future clinical trials for both hormone-sensitive and hormone-resistant prostate cancers should consider the innovative use of CR to augment standard cancer therapy as it has the potential to change the biology of tumors and enhance the opportunity for clinical benefit. Citation Format: Sunny Y. Han, Tu D. Dan, Tiziana De Angelis, John Y. Han, Mak Sarich, Peter Carroll, Karen Knudsen, Adam Dicker, Nicole L. Simone. Caloric restriction can increase the efficacy of radiation in both hormone-sensitive and hormone-resistant prostate cancers by downregulating the IGF-1R pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1790. doi:10.1158/1538-7445.AM2015-1790

Igfbp2 Deletion in Ovariectomized Mice Enhances Energy Expenditure but Accelerates Bone Loss.

Previously, we reported sexually dimorphic bone mass and body composition phenotypes in Igfbp2(-/-) mice (-/-), where male mice exhibited decreased bone and increased fat mass, whereas female mice displayed increased bone but no changes in fat mass. To investigate the interaction between IGF-binding protein (IGFBP)-2 and estrogen, we subjected Igfbp2 -/- and +/+ female mice to ovariectomy (OVX) or sham surgery at 8 weeks of age. At 20 weeks of age, mice underwent metabolic cage analysis and insulin tolerance tests before killing. At harvest, femurs were collected for microcomputed tomography, serum for protein levels, brown adipose tissue (BAT) and inguinal white adipose tissue (IWAT) adipose depots for histology, gene expression, and mitochondrial respiration analysis of whole tissue. In +/+ mice, serum IGFBP-2 dropped 30% with OVX. In the absence of IGFBP-2, OVX had no effect on preformed BAT; however, there was significant "browning" of the IWAT depot coinciding with less weight gain, increased insulin sensitivity, lower intraabdominal fat, and increased bone loss due to higher resorption and lower formation. Likewise, after OVX, energy expenditure, physical activity and BAT mitochondrial respiration were decreased less in the OVX-/- compared with OVX+/+. Mitochondrial respiration of IWAT was reduced in OVX+/+ yet remained unchanged in OVX-/- mice. These changes were associated with significant increases in Fgf21 and Foxc2 expression, 2 proteins known for their insulin sensitizing and browning of WAT effects. We conclude that estrogen deficiency has a profound effect on body and bone composition in the absence of IGFBP-2 and may be related to changes in fibroblast growth factor 21.