IGF-binding Protein-3 Concentrations Research Articles

Implication of Pappalysins and Stanniocalcins in the Bioavailability of IGF-I in Children With Type 1 Diabetes Mellitus.

Anomalies in the growth hormone (GH)/insulin-like growth factor (IGF) axis, are common in children with type 1 diabetes mellitus (T1DM), even in those reaching a normal or near-normal final height. However, concentrations of the IGF bioavailability regulatory factors (pappalysins [PAPP-As] and stanniocalcins [STCs]) have not been reported in children with T1DM. To determine serum concentrations of PAPP-As and STCs in children at diagnosis of T1DM and after insulin treatment and the correlation of these factors with other members of the GH/IGF axis, beta-cell insulin reserve, auxology, and nutritional status. A single-center prospective observational study including 47 patients (59.5% male), with T1DM onset at median age of 9.2 years (interquartile range: 6.3, 11.9) was performed. Blood and anthropometric data were collected at diagnosis and after 6 and 12 months of treatment. At 6 and 12 months after T1DM diagnosis, there was improvement in the metabolic control (decrease in glycated hemoglobin [HbA1c] at 12 months -3.66 [95% CI: -4.81, -2.05], P = .001), as well as in body mass index SD and height SD (not statistically significant). STC2 increased (P < .001) and PAPP-A2 decreased (P < .001) at 6 and 12 months of treatment onset (P < .001), which was concurrent with increased total IGF-I and IGF-binding protein concentrations, with no significant modification in free IGF-I concentrations. HbA1c correlated with PAPP-A2 (r = +0.41; P < .05) and STC2 (r = -0.32; P < .05). Implementation of insulin treatment after T1DM onset modifies various components of the circulating IGF system, including PAPP-A2 and STC2. How these modifications modulate linear growth remains unknown.

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 as early predictors of growth, body composition, and neurodevelopment in preterm infants.

To investigate the relationship between insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3) and long-term growth, body composition, and neurodevelopment in preterm infants. Prospective data were collected from ≤32 weeks gestational age infant cohort (N = 50). IGF-1 and IGFBP-3 concentrations were measured at 1 week (early) and 35 weeks (late) post-menstrual age (PMA). Growth, body composition, and neurodevelopment outcomes were measured at 4 and 12 months PMA. Relationships were measured by linear regression analysis. Early IGFBP-3 concentration was positively associated with neurodevelopment at 12 months PMA. Early IGF-1 concentration was positively associated with weight at 4 months PMA, head circumference at 12 months PMA, and body mass index at 12 months PMA. Late IGFBP-3 concentration was positively associated with weight at 4 months PMA. Further investigation of these associations may lead to novel biomarkers and/or treatments to optimize health outcomes in preterm infants.

Prognostic Value of Circulating Cytokines in Chemorefractory Colorectal Cancer.

Circulating cytokines could be optimal biomarkers for prognostication and management decisions in colorectal cancer (CRC). Chemorefractory CRC patients with available plasma samples were included in this study. In the discovery cohort (n = 85), 182 circulating cytokines were tested with a semi-quantitative multiplex assay, and prognostic cytokines were analyzed in the validation cohort (n = 111) by ELISA. Overall survival (OS) was the primary outcome measure, with the false discovery rate (FDR) method (significance level of <0.01) being used to correct for multiple comparisons. Four cytokines were associated with OS in the discovery cohort: insulin-like growth factor-binding protein 1 (IGFBP-1) (HR 2.1 [95%CI: 1.58-2.79], FDR < 0.001), insulin-like growth factor-binding protein 2 (IGFBP-2) (HR 1.65 [95%CI: 1.28-2.13], FDR = 0.006), serum amyloid A (SAA) (HR 1.84 [95%CI: 1.39-2.43], FDR < 0.001), and angiotensin II (HR 1.65 [95%CI: 1.29-2.1], FDR = 0.006). Of these, IGFBP-1 (HR 2.70 [95%CI: 1.56-4.76], FDR = 0.007) and IGFBP-2 (HR 3.33 [95%CI: 1.64-6.67], FDR = 0.008) were confirmed to be independently associated with OS in the validation cohort. Patients with high concentrations of IGFBP-1 and/or IGFBP-2 had a median OS of 3.0 months as compared with 6.9 months for those with low concentrations of both cytokines (HR 2.44 [95%CI: 1.52-4.0], FDR = 0.002) Validation of circulating IGFBP-1 and IGFBP-2 as independent prognostic biomarkers for chemorefractory CRC in larger, independent series is warranted.

Expression of insulin-like growth factor binding protein-3 in HELLP syndrome

ObjectiveTo investigate the expression of insulin-like growth factor binding protein-3(IGFBP-3) in HELLP syndrome and its possible role in the pathogenesis of this disease.Methods1) 87 subjects were enrolled, including 29 patients with HELLP syndrome, 29 patients with pre-eclampsia (PE), and 29 healthy gravidae as control. The levels of IGFBP-3, IGF-1, TGF-β1, and VEGF in maternal and umbilical blood of them were detected using ELISA. Correlation analysis was used to observe the correlation between IGFBP-3 and IGF-1/TGF-β1/VEGF in maternal and umbilical blood, as well as that between maternal serum IGFBP-3 and clinical diagnostic indicators of HELLP syndrome. 2) Human hepatic sinusoid endothelial cells (HLSEC) and human umbilical vein endothelial cells (HUVEC) were cultured with different concentrations of IGFBP-3. After 72 h of culture, cell apoptosis and the normal living cells rate were detected and compared.Results1) In both maternal and umbilical blood of HELLP group, levels of IGFBP-3 and TGF-β1 were higher than control and PE group, IGF-1was lower than control group, VEGF was lower than control and PE group. IGFBP-3 in maternal blood was correlated with IGF-1/TGF-β1/ VEGF, while IGFBP-3 in umbilical blood was linked to IGF-1/TGF-β1. In maternal blood, there was a negative correlation between PLT and IGFBP-3, and a positive correlation between ALT/AST/LDH and IGFBP-3. 2) After cultured with IGFBP-3, the total apoptosis rate of either HLSEC or HUVEC was considerably elevated, while the normal living rate was decreased.ConclusionThe expression of IGFBP-3 is elevated in HELLP syndrome, which may subsequently promote cell apoptosis by affecting the expression and function of IGF-1, VEGF, and TGFβ1 in the IGF/PI3K/Akt, TGF-β1/Smad3, and VEGF/eNOS/NO pathways. IGFBP-3 aggravates inflammatory reactions of the vascular endothelium and liver under hypoxia, affects the normal function of cells, and plays a role in the pathogenesis of diseases.

HIF-1α is positively associated with endometrial receptivity by regulating PKM2.

Numerous advancements have been introduced into the field of assisted reproductive technology (ART) in the past four decades. Nonetheless, implantation failure is still a key limiting step for a successful pregnancy. Building of endometrial receptivity (ER) is essential for successful implantation. However, the fundamental biological processes and mechanisms of ER remain elusive. Our study investigates the function of hypoxia inducible factor-1α (HIF-1α) during ER establishment and shed lights on the novel molecular mechanism by which HIF-1α regulates ER-related gene expression network. Levels of HIF-1α, homeobox A10 (HOXA10), insulin-like growth factor-binding protein 1 (IGFBP1), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) in endometrial tissues were measured via real-time PCR, immunoblotting and immunohistochemistry. The correlation between HIF-1α and HOXA10, IGFBP1, PKM2, LDHA were analyzed separately. Ishikawa cells were treated with vector HIF-1α, HIF-1α-siRNA, and PKM2-siRNA. After transfection, the levels of HOXA10, IGFBP1, LDHA, and PKM2 were measured via real-time PCR and immunoblotting, and the lactate concentrations and cell migration of Ishikawa cells were measured. Levels of HIF-1α, IGFBP1, HOXA10, LDHA, and PKM2 were significantly decreased in recurrent implantation failure (RIF) patients and levels of HOXA10, IGFBP1, PKM2, and LDHA were correlated with HIF-1α in endometrium. Then in a cellular model established by HIF-1α vector and HIF-1α-siRNA, the expression of HOXA10, IGFBP1, LDHA, PKM2, and lactate concentrations were dramatically upregulated and downregulated. And the expression of HOXA10, and IGFBP1 were dramatically decreased by PKM2-siRNA. HIF-1α plays a crucial role in the building of ER through regulating glycolysis.

134-OR: Associations of Growth Hormone (GH) Mediators with Loss of Glycemic Control in Youth with Type 2 Diabetes (T2D)

T2D in youth has a more severe phenotype than in adults, with puberty as a potential contributor to this difference. Pubertal changes in GH mediators (e.g., insulin-like growth factor 1 (IGF-1), growth hormone receptor (GHR), insulin-like growth factor binding protein 1 (IGFBP-1)) may impact insulin sensitivity and beta cell function. We examined associations of GH mediators with loss of glycemic control in youth with T2D using the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort (N= 310). We performed paired comparison of plasma concentrations of IGF-1, GHR, and IGFBP-1 (ELISA), between 0mo and 36mo based on TODAY primary outcome of loss of glycemic control vs. maintained glycemic control (LGC vs MGC), with LGC defined as HbA1c ≥ 8% for 6 months and/or insulin dependence. We studied associations of GH mediators with HbA1c, insulinogenic index, oral disposition index, and 1/fasting insulin. Models were adjusted for age, sex, race, treatment arm, and baseline HbA1c (linear regression). Mean plasma IGF-1 (ng/mL) was lower in LGC group at 0mo (LGC: 451 ± 141, MGC: 485 ± 155, p = 0.04), and at 36mo (LGC: 340 ± 117, MGC: 400 ± 136, p&amp;lt; 0.0001). Increase in IGF-1 between 0-36mo predicted lower HbA1c at 36mo (B = -3.2E-3, SE = 9.0E-4, p &amp;lt; 0.001). Higher GHR was associated with higher HbA1c (B = 1.2E-2, SE = 3.0E-3, p &amp;lt; 0.001) and lower 1/fasting insulin (B = -6.6E-4, SE = 2.1E-4, P &amp;lt; 0.01) at 0mo. Increase in GHR between 0-36mo predicted higher 36mo HbA1c (B = 3.0E-2, SE = 9.4E-3, p &amp;lt; 0.01). IGFBP-1 was positively associated with 1/fasting insulin at 0m (B = 1.1E-3, SE = 4.9E-4, p = 0.03). In exploratory analyses stratified by Tanner stage (TS) at study entry, GH mediators changed differentially between TS 1-3 (n = 31) vs TS 4-5 (n = 274). In conclusion, GH mediators differed based on primary outcome in TODAY, and were associated with HbA1c and insulin sensitivity. Whether changes in GH mediators contribute to, or are the result of, changes in glucose metabolism is a key area for future studies. Disclosure C.Lu: None. D.Wolfs: None. L.El ghormli: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. E.M.Isganaitis: None. Funding National Institutes of Health (2T32DK007260-46); National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK061230-16)

Associations of insulin-like growth factor binding protein-2 with metabolic profile and hepatic fat deposition in asymptomatic men and women.

Low circulating levels of insulin-like growth-factor binding protein-2 (IGFBP-2) have been associated with increased adiposity and metabolic alterations such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease in individuals with obesity. However, whether IGFBP-2 affects energy metabolism in the early stages of these disorders remains unclear. Herein, we hypothesized that plasma IGFBP-2 concentrations are inversely associated with early liver fat accumulation and alterations in lipid and glucose homeostasis in apparently healthy and asymptomatic men and women. Three hundred thirty-three middle-aged Caucasian men and women apparently healthy and without cardiovascular symptoms were enrolled for a cross-sectional cardiometabolic imaging study. Individuals with BMI ≥ 40 kg/m2, cardiovascular disease, dyslipidemia, hypertension, and diabetes were excluded. Fasting glucose and lipid profiles were measured and an oral glucose tolerance test was performed. Liver fat content was assessed by magnetic resonance spectroscopy. Volume of visceral adipose tissue (VAT) was evaluated by magnetic resonance imaging. Plasma IGFBP-2 levels were quantified by ELISA. Participants with low IGFBP-2 levels were characterized by a higher body fat mass (P < 0.0001), insulin resistance (P < 0.0001), higher plasma triglyceride (TG) (P < 0.0001), and lower HDL-cholesterol levels (P < 0.0001) in a sex-independent manner. IGFBP-2 levels were inversely correlated with hepatic fat fraction in both men (r = -0.36, P < 0.0001) and women (r = -0.40, P < 0.0001). IGFBP-2 concentrations were negatively associated with hepatic fat fraction independently of age and VAT in both men (R2 = 0.23, P = 0.012) and women (R2 = 0.27, P = 0.028). In conclusion, our findings show that even in asymptomatic, apparently healthy individuals, low IGFBP-2 levels are associated with a more deteriorated cardiometabolic risk profile and with a high hepatic fat content in a VAT-independent manner. However, IGFBP-2 does not appear to influence the established sexual dimorphism observed for metabolic variables and hepatic fat fraction. Additional studies are required to better understand the relationships between IGFBP-2 and liver fat content.NEW & NOTEWORTHY Faced with a paucity of reliable clinical etiologic markers for fatty liver, this research article demonstrates, for the first time, that low blood levels of the protein IGFBP-2 are associated with a more deteriorated cardiometabolic risk profile and with a high hepatic fat content independently of visceral fat volume and sex, even in asymptomatic, apparently healthy individuals.

Circulating IGF-1 and IGFBP-2 may be biomarkers for risk stratification in patients with acute coronary syndrome: A prospective cohort study

Background and aimThe involvement of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-2 (IGFBP-2) following acute coronary syndrome (ACS) is rarely studied in clinical practice. Therefore, we sought to evaluate the relationship between IGF-1 and IGFBP-2 concentrations at admission and risk stratification based on the Thrombolysis in Myocardial Infarction (TIMI) risk score in patients with ACS. Methods and resultsIn all, 304 patients diagnosed with ACS were included in this study. Plasma IGF-1 and IGFBP-2 were measured using commercially available ELISA kits. The TIMI risk score was calculated and the study population was stratified into high (n = 65), medium (n = 138), and low (n = 101) risk groups. Levels of IGF-1 and IGFBP-2 were analyzed for their predictive ability of risk stratification based on the TIMI risk scores. Correlation analysis showed that IGF-1 levels were negatively correlated with TIMI risk levels (r = −0.144, p = 0.012), while IGFBP-2 levels were significantly and positively correlated with TIMI risk levels (r = 0.309, p < 0.001). In multivariate logistic regression analysis, IGF-1 (odds ratio [OR]: 0.995; 95% confidence interval [CI]: 0.990–1.000; p = 0.043) and IGFBP-2 (OR: 1.002; 95%CI: 1.001–1.003; p < 0.001) were independent predictors of high TIMI risk levels. In receiver operating characteristic curves, the area under the curve values for IGF-1 and IGFBP-2 in the prediction of high TIMI risk levels were 0.605 and 0.723, respectively. ConclusionsIGF-1 and IGFBP-2 levels are excellent biomarkers for risk stratification in patients with ACS, which provides further guidance for clinicians to identify patients at high risk and to lower their risk.

Further Evidence that an Episode of Premature Labor Is a Pathologic State: Involvement of the Insulin-Like Growth Factor System

Introduction: Approximately 47% of women with an episode of preterm labor deliver at term; however, their infants are at greater risk of being small for gestational age and for neurodevelopmental disorders. In these cases, a pathologic insult may disrupt the homeostatic responses sustaining pregnancy. We tested the hypothesis of an involvement of components of the insulin-like growth factor (IGF) system. Methods: This is a cross-sectional study in which maternal plasma concentrations of pregnancy-associated plasma protease (PAPP)-A, PAPP-A2, insulin-like growth factor-binding protein 1 (IGFBP-1), and IGFBP-4 were determined in the following groups of women: (1) no episodes of preterm labor, term delivery (controls, n = 100); (2) episode of preterm labor, term delivery (n = 50); (3) episode of preterm labor, preterm delivery (n = 100); (4) pregnant women at term not in labor (n = 61); and (5) pregnant women at term in labor (n = 61). Pairwise differences in maternal plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 among study groups were assessed by fitting linear models on log-transformed data and included adjustment for relevant covariates. Significance of the group coefficient in the linear models was assessed via t-scores, with p < 0.05 deemed a significant result. Results: Compared to controls, (1) women with an episode of premature labor, regardless of a preterm or a term delivery, had higher mean plasma concentrations of PAPP-A2 and IGFBP-1 (each p < 0.05); (2) women with an episode of premature labor who delivered at term also had a higher mean concentration of PAPP-A (p < 0.05); and (3) acute histologic chorioamnionitis and spontaneous labor at term were not associated with significant changes in these analytes. Conclusion: An episode of preterm labor involves the IGF system, supporting the view that the premature activation of parturition is a pathologic state, even in those women who delivered at term.

Circulating Levels of Nesfatin-1 and Spexin in Children with Prader-Willi Syndrome during Growth Hormone Treatment and Dietary Intervention.

Despite observable improvement in the treatment outcomes of patients with Prader-Willi syndrome (PWS), adequate weight control is still a clinical problem. Therefore, the aim of this study was to analyze the profiles of neuroendocrine peptides regulating appetite-mainly nesfatin-1 and spexin-in children with PWS undergoing growth hormone treatment and reduced energy intake. Twenty-five non-obese children (aged 2-12 years) with PWS and 30 healthy children of the same age following an unrestricted age-appropriate diet were examined. Serum concentrations of nesfatin-1, spexin, leptin, leptin receptor, total adiponectin, high molecular weight adiponectin, proinsulin, insulin-like growth factor-I, and total and functional IGF-binding protein-3 concentrations were determined using immunoenzymatic methods. The daily energy intake in children with PWS was lower by about 30% (p < 0.001) compared with the controls. Daily protein intake was similar in both groups, but carbohydrate and fat intakes were significantly lower in the patient group than the controls (p < 0.001). Similar values for nesfatin-1 in the PWS subgroup with BMI Z-score < -0.5 and the control group, while higher values in the PWS subgroup with BMI Z-score ≥ -0.5 (p < 0.001) were found. Spexin concentrations were significantly lower in both subgroups with PWS than the controls (p < 0.001; p = 0.005). Significant differences in the lipid profile between the PWS subgroups and the controls were also observed. Nesfatin-1 and leptin were positively related with BMI (p = 0.018; p = 0.001, respectively) and BMI Z-score (p = 0.031; p = 0.027, respectively) in the whole group with PWS. Both neuropeptides also correlated positively in these patients (p = 0.042). Altered profiles of anorexigenic peptides-especially nesfatin-1 and spexin-in non-obese children with Prader-Willi syndrome during growth hormone treatment and reduced energy intake were found. These differences may play a role in the etiology of metabolic disorders in Prader-Willi syndrome despite the applied therapy.

Associations between insulin-like growth factor binding protein-2 and lipoprotein kinetics in men

Low circulating concentrations of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with dyslipidemia, notably with high triglyceride (TG) levels. However, the determinants by which IGFBP-2 influences lipoprotein metabolism, especially that of TG-rich lipoproteins (TRLs), are poorly understood. Here, we aimed to assess the relationships between IGFBP-2 levels and lipoprotein production and catabolism in human subjects. Fasting IGFBP-2 concentrations were measured in the plasma of 219 men pooled from previous lipoprotein kinetics studies. We analyzed production rate and fractional catabolic rates of TRLapoB-48, and LDL-, IDL-, and VLDLapoB-100 by multicompartmental modeling of l-[5,5,5-D3] leucine enrichment data after a 12 h primed constant infusion in individuals kept in a constant nutritional steady state. Subjects had an average BMI of 30 kg/m2, plasma IGFBP-2 levels of 157 ng/ml, and TG of 2.2 mmol/l. After adjustments for age and BMI, IGFBP-2 levels were negatively associated with plasma TG (r = −0.29; P < 0.0001) and positively associated with HDL-cholesterol (r = 0.26; P < 0.0001). In addition, IGFBP-2 levels were positively associated with the fractional catabolic rate of VLDLapoB-100 (r = 0.20; P < 0.01) and IDLapoB-100 (r = 0.19; P < 0.05) and inversely with the production rate of TRLapoB-48 (r = −0.28; P < 0.001). These correlations remained statistically significant after adjustments for age, BMI, and the amount of fat given during the tracer infusion. These findings show that the association between low plasma IGFBP-2 and high TG concentrations could be due to both an impaired clearance of apoB-100-containing VLDL and IDL particles and an increased production of apoB-48-containing chylomicrons. Additional studies are necessary to investigate whether and how IGFBP-2 directly impacts the kinetics of TRL.

The Value of IGF-1 and IGFBP-1 in Patients With Heart Failure With Reduced, Mid-range, and Preserved Ejection Fraction.

BackgroundPrevious studies have reported inconsistent results regarding the implications of deranged insulin-like growth factor 1 (IGF-1)/insulin-like growth factor-binding protein 1 (IGFBP-1) axis in patients with heart failure (HF). This study evaluates the roles of IGF1/IGFBP-1 axis in patients with HF with reduced ejection fraction (HFrEF), mid-range ejection fraction (HFmrEF), or preserved ejection fraction (HFpEF).MethodsConsecutive patients with HFrEF, HFmrEF, and HFpEF who underwent comprehensive cardiac assessment were included. The primary endpoint was the composite endpoint of all-cause death and HF rehospitalization at one year.ResultsA total of 151 patients with HF (HFrEF: n = 51; HFmrEF: n = 30; HFpEF: n = 70) and 50 control subjects were included. The concentrations of IGFBP-1 (p < 0.001) and IGFBP-1/IGF-1 ratio (p < 0.001) were significantly lower in patients with HF compared to controls and can readily distinguish patients with and without HF (IGFBP-1: areas under the curve (AUC): 0.725, p < 0.001; IGFBP-1/IGF-1 ratio: AUC:0.755, p < 0.001; respectively). The concentrations of IGF-1, IGFBP-1, and IGFBP-1/IGF-1 ratio were similar among HFpEF, HFmrEF, and HFrEF patients. IGFBP-1 and IGFBP-1/IGF-1 ratio positively correlated with N-terminal probrain natriuretic peptide (NT-proBNP) levels (r = 0.255, p = 0.002; r = 0.224, p = 0.007, respectively). IGF-1, IGFBP-1, and IGFBP-1/IGF-1 ratio did not predict the primary endpoint at 1 year for the whole patients with HF and HF subtypes on both univariable and multivariable Cox regression.ConclusionThe concentrations of plasma IGFBP-1 and IGFBP-1/IGF-1 ratio can distinguish patients with and without HF. In HF, IGFBP-1 and IGFBP-1/IGF-1 ratio positively correlated with NT-proBNP levels.

Evaluation of Serum Levels of Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor-Binding Protein 3 in Patients With Colorectal Cancer: A Case-Control Study.

Background/aim: Limited information is available about the relationship between colorectal cancer (CRC) and serum concentration of insulin-like growth factor 1 (IGF1) and insulin-like growth factor-binding protein 3 (IGFBP3). This study aims to compare the serum levels of IGF1and IGFBP3 in colorectal cancer cases and controls and to assess the relationship between their level and the demographic and histopathological characteristics.Methods: A case-control study in which 50 patients with colorectal cancer and 50 controls matched by gender and age were compared regarding the demographic characteristics and the level of both IGF1 and IGFBP3. The correlation with different clinicopathological features was assessed.Results: Levels of IGF1 were significantly higher while levels of IGFBP3 were significantly lower among cases compared to control. IGF1 was significantly higher among patients with liver metastasis, lymph node (LN) spread, and lymphovenous invasions and did not show significant association with gender, smoking status, family history, or primary site of colorectal cancer. Lower IGFBP3 was significantly high among patients with liver and lymph node metastasis, lymphovenous invasion, and patients with positive family history. This significant negative correlation was also detected between IGFBP3 levels and the size of the tumor.Conclusions: High IGF1 levels and low concentrations of IGFBP3 are related to colorectal cancer and were significantly associated with liver metastasis, lymph node spread, and lymphovenous invasions. Further research is recommended to investigate if circulating IGF1 and IGFBP3 levels can be used to identify people at high risk of colorectal cancer and to investigate potential lifestyle or pharmaceutical ways to lower IGF1 bioactivity as a risk reduction strategy.

Dynamic Changes in Serum IGF-I and Growth During Infancy: Associations to Body Fat, Target Height, and PAPPA2 Genotype

IGF-I is important for postnatal growth and may be of diagnostic value in infants suspected of pituitary disease; however, little is known about the impact of IGF-I and its determinants on infant growth. Importantly, detailed reference ranges for IGF-I and IGF binding protein-3 (IGFBP-3) concentrations during infancy are lacking. To evaluate the rapid changes in weight and length as well as their determinants in healthy infants, and to establish age- and sex-specific reference curves for IGF-I and IGFBP-3 in children aged 0 to 1 years. Prospective longitudinal study. Cohort study. A total of 233 healthy children (114 girls) with repeated blood samples during the first year of life. Serum concentrations of IGF-I and IGFBP-3, length velocity, weight velocity, and PAPPA2 (rs1325598) genotype. Individual trajectories of length and weight velocities were sex specific. We provide detailed reference curves based on longitudinal data for IGF-I and IGFBP-3 during infancy. In both girls and boys, IGF-I decreased during infancy, whereas IGFBP-3 remained stable. IGF-I and IGFBP-3, but not PAPPA2 genotype, were positively associated with weight gain, but not with longitudinal growth. When stratified by sex, the association between weight gain and IGF-I only remained significant in girls. Interestingly, we found a significant association between IGF-I and infant weight gain in girls, but not with longitudinal growth in the first year of life. Our findings highlight the role of IGF-I as an important anabolic hormone that is not limited to linear growth.

The High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Polymorphisms Are Differentially Associated With Growth and IGF-I Levels in Infancy: The Cambridge Baby Growth Study.

This study explored the link between HLA polymorphisms that predispose to type 1 diabetes and birth size, infancy growth, and/or circulating IGF-I in a general population-based birth cohort. The Cambridge Baby Growth Study is a prospective observational birth cohort study that recruited 2,229 newborns for follow-up in infancy. Of these, 612 children had DNA available for genotyping single nucleotide polymorphisms in the HLA region that capture the highest risk of type 1 diabetes: rs17426593 for DR4, rs2187668 for DR3, and rs7454108 for DQ8. Multivariate linear regression models at critical ages (cross-sectional) and mixed-effects models (longitudinal) were performed under additive genetic effects to test for associations between HLA polymorphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3). In longitudinal models, the minor allele of rs2187668 tagging DR3 was associated with faster linear growth (P = 0.007), which was more pronounced in boys (P = 3 × 10-7) than girls (P = 0.07), and was also associated with increasing IGF-I (P = 0.002) and IGFBP-3 (P = 0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging DQ8 and rs17426593 tagging DR4 were associated with lower IGF-I concentrations at age 12 months (P = 0.003) and greater skinfold thickness at age 24 months (P = 0.003), respectively. The variable associations of DR4, DR3, and DQ8 alleles with growth measures and IGF-I levels in infants from the general population could explain the heterogeneous growth trajectories observed in genetically at-risk cohorts. These findings could suggest distinct mechanisms involving endocrine pathways related to the HLA-conferred type 1 diabetes risk.

Wear of hip prostheses increases serum IGFBP-1 levels in patients with aseptic loosening

The biological mechanisms involved in aseptic loosening include inflammation-associated and bone resorption-associated processes. Coordinated cellular actions result in biochemical imbalances with devastating consequences for the joint. Given that this condition is not known for showing systemic signs, we investigated whether circulating levels of inflammation-related proteins are altered in patients with aseptic loosening. Our study included 37 patients who underwent revision surgery due to hip osteolysis and aseptic loosening and 31 patients who underwent primary total hip arthroplasty. Using antibody arrays, we evaluated the serum levels of 320 proteins in four patients from each group. The results showed differences in insulin-like growth factor-binding protein 1 (IGFBP-1) concentrations, which we then quantified using enzyme-linked immunosorbent assay tests in all study patients. The results confirmed that serum IGFBP-1 concentrations were higher in the revision surgery patients than in the hip arthroplasty patients. In vitro studies showed that exposure of human osteoblasts to titanium particles induced an IGFBP-1 release that further increased when exposure to particles was performed in media conditioned by human M1 macrophages. These findings suggest that elevated serum IGFBP-1 levels in patients with aseptic loosening can arise from increased local IGFBP-1 production in the inflammatory environment of the periprosthetic bed.

Evaluation of circulating IGF-I and IGFBP-3 as biomarkers for tumors in dogs.

BackgroundSerum-based parameters are considered non-invasive biomarkers for cancer detection. In human studies, insulin-like growth factor-I and II (IGF-I and IGF-II) and insulin-like growth factor binding protein-3 (IGFBP-3) are useful as diagnostic or prognostic markers and potential therapeutic targets.ObjectivesThis study examined the diagnostic utility of circulating IGF-I, IGF-II, and IGFBP-3 levels in healthy dogs and dogs with tumors.MethodsThe serum concentrations of these biomarkers in 86 dogs with tumors were compared with those in 30 healthy dogs using an enzyme-linked immunosorbent assay (ELISA).ResultsThe ELISA results showed no difference between healthy dogs and dogs with tumors in the serum IGF-II concentrations. On the other hand, there was a significant difference in the circulating IGF-I and IGFBP-3 levels between healthy dogs and dogs with tumors. The concentrations of serum IGF-I (median [interquartile range], 103.4 [59.5–175] ng/mL) in dogs with epithelial tumors were higher than those (58.4 ng/mL [43.5–79.9]) in healthy dogs. Thus, the concentrations of serum IGFBP-3 (43.4 ng/mL [33.2–57.2]) in dogs with malignant mesenchymal tumors were lower than those (60.8 ng/mL [47.6–70.5]) in healthy dogs.ConclusionsThe serum IGF-I and IGFBP-3 levels can be used as diagnostic biomarkers in dogs with tumors.

Metformin and insulin treatment of gestational diabetes: effects on inflammatory markers and IGF-binding protein-1 \u2013 secondary analysis of a randomized controlled trial

BackgroundGestational diabetes mellitus (GDM) is characterized by disturbed glucose metabolism and activation of low-grade inflammation. We studied whether metformin treatment has favorable or unfavorable effects on inflammatory markers and insulin-like growth factor-binding protein 1 (IGFBP-1) in GDM patients compared with insulin, and whether these markers associate with major maternal or fetal clinical outcomes.MethodsThis is a secondary analysis of a previous randomized controlled trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum samples were collected at the time of diagnosis (baseline, mean 30 gestational weeks [gw]) and at 36 gw. Inflammatory markers serum high-sensitivity CRP (hsCRP), interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glycoprotein acetylation (GlycA) as well as three IGFBP-1 phosphoisoform concentrations were determined.ResultsIn the metformin and insulin groups combined, hsCRP decreased (p = 0.01), whereas IL-6 (p = 0.002), GlycA (p < 0.0001) and all IGFBP-1 phosphoisoforms (p < 0.0001) increased from baseline to 36 gw. GlycA (p = 0.02) and non-phosphorylated IGFBP-1 (p = 0.008) increased more in patients treated with metformin than those treated with insulin. Inflammatory markers did not clearly associate with pregnancy outcomes but non-phosphorylated IGFBP-1 was inversely associated with gestational weight gain.ConclusionsMetformin had beneficial effects on maternal serum IGFBP-1 concentrations compared to insulin, as increased IGFBP-1 related to lower total and late pregnancy maternal weight gain. GlycA increased more during metformin treatment compared to insulin. The significance of this observation needs to be more profoundly examined in further studies. There were no evident clinically relevant relations between inflammatory markers and pregnancy outcome measures.Trial registrationThe trial comparing metformin and insulin treatment was registered in ClinicalTrials.gov (NCT01240785) November 3, 2010. Retrospectively registered.

Associations between Maternal and Fetal Levels of Total Adiponectin, High Molecular Weight Adiponectin, Selected Somatomedins, and Birth Weight of Infants of Smoking and Non-Smoking Mothers.

The aim of the study was to determine the relationships between maternal smoking, total adiponectin, high molecular weight adiponectin (HMW adiponectin), selected somatomedins, and the birth weight of newborns. A total of 78 women with a healthy, singleton pregnancy, 41 active smokers and 37 non-smokers, and their offspring were studied. Total and HMW adiponectin, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1) and 2 (IGFBP-2) were determined in maternal and cord blood by enzyme-link immunosorbent assay. Serum levels of total and HMW adiponectin were lower in smokers compared to the tobacco abstinent in both the mothers (p = 0.013; p = 0.006) and the infants (p = 0.001; p = 0.047). In smoking women and their children, serum concentrations of IGF-I were significantly lower (p = 0.014; p = 0.042), IGFBP-1 significantly higher (p = 0.009; p = 0.039), and IGFBP-2 did not differ from that observed in the non-smoking group. In multivariate analysis performed on the whole group of mothers, the highest impact of serum cotinine and IGFBP-2 levels were indicated for adiponectin and cotinine and the number of cigarettes/day for HMW adiponectin concentration. In correlation analysis estimated separately for smokers and non-smokers, neonatal birth weight was positively associated with total and HMW adiponectin concentrations in umbilical cord blood. Birth weight was also inversely associated with IGFBP-1 and positively correlated with IGF-I levels in maternal serum as well as in cord blood (r = −0.317, p = 0.005; r = −0.294, p = 0.004; r = 0.245, p = 0.031; r = 0.271, p = 0.009, respectively). The present study showed the levels of total and HMW adiponectin in umbilical cord blood may have a significant effect on fetal development. Both IGF-I and IGFBP-1 concentrations also play an essential role in fetal growth, which is an important predictor of birth weight. Cigarette smoking during pregnancy negatively affected adiponectin and the insulin growth factor profile in the serum of women and the cord blood and may be the reason for the lower birth weight of the smokers newborns compared with the nonsmokers offspring.

Insulin-Like Growth Factor Binding Protein-2 Promotes Proliferation and Predicts Poor Prognosis in Hepatocellular Carcinoma.

BackgroundInsulin-like growth factor binding protein-2 (IGFBP2) levels are significantly increased in the plasma of hepatocellular carcinoma (HCC) patients. However, the correlation between IGFBP2 levels and clinical parameters and the exact role of IGFBP2 in HCC are unclear. In this study, we identified the role and potential molecular mechanisms of IGFBP2 in HCC.Materials and MethodsELISA assays were used to detect plasma IGFBP2 levels in HCC patients and healthy controls, and the correlations with patients’ clinicopathological data were analyzed. The CCK8 assay was used to explore cell proliferation. Luciferase reporter, co-immunoprecipitation, and immunofluorescence assays were used to demonstrate the molecular mechanism of IGFBP2 in HCC.ResultsPlasma IGFBP2 levels were determined blindly in 37 HCC patients and 37 matched healthy controls. The mean plasma IGFBP2 concentrations in HCC patients were higher than in healthy controls, and IGFBP2 levels in HCC were positively correlated with the degree of differentiation, tumor size, metastasis, and portal venous invasion. Exogenous IGFBP2 activated integrin β1 and thus induced the combination and colocalization of activated integrin β1 and p-FAK, which promoted the phosphorylation of FAK, Erk, and Elk1, eventually inducing EGR1-mediated proliferation of the HCC cell lines HepG2 and HCCLM3. Meanwhile, neutralization of integrin β1 inhibited IGFBP2-induced FAK, Erk, Elk1, and EGR1 activation.ConclusionTaken together, these results indicated that exogenous IGFBP2 promoted the integrin β1/FAK/Erk/Elk1/EGR1 pathway, which stimulated the proliferation of HCC cells. Plasma IGFBP2 could be a novel prognostic biomarker for HCC patients.