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Noninvasive methods for liver disease diagnoses offer great advantages over biopsy, but they cannot be utilized in all cases. Therefore, specific indicators for chronic liver disease management are necessary. The aim was to assess the production of insulin-like growth factor-binding proteins (IGFBPs) 1–7 and their correlation with the different stages of fibrosis in chronic hepatitis C (CHC). A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized by FibroTest® and/or FibroScan®. Serum concentrations of IGFBPs 1–7 were determined through multiple suspension arrangement array technology. Significant differences were validated by the Kruskal–Wallis and Mann–Whitney U tests. Logistic regression models were performed to assess the association between the IGFBPs and fibrosis stages. The association was determined utilizing odds ratios (ORs), and receiver operating characteristic (ROC) curves were constructed to distinguish the IGFBPs in relation to the diagnosis of fibrosis. IGFBP-1 and IGFBP-7 concentrations were higher in CHC than in the healthy individuals, whereas IGFBP-3, IGFBP-5, and IGFBP-6 were downregulated in the patients. An apparent increase of all the IGFBPs was found at fibrosis stage F4, but with different regulations. IGFBP-2, -4, -6, and -7 had the best OR, showing the relation to fibrosis progression. The ROC curves showed that IGFBP-7 was the only protein that distinguished F1 from F3 and F2 from F3. IGFBPs participate in liver fibrosis progression and could be employed as circulating novel protein panels for diagnosis and as possible therapeutic targets in liver fibrosis progression.

Abstract Context Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. Objective We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment. Methods Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at 6 months of treatment in 11 children. Results Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. Conclusion The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

Longitudinal bone growth, which is regulated by endocrine and paracrine factors, is a critical determinant of linear growth during childhood. This study investigated the effects of an aqueous extract of Phyllostachyos Caulis in Taeniam (PCE) on longitudinal bone growth and its regulatory effects on circulating insulin-like growth factor-1 (IGF-1) in rats. Twenty-eight adolescent rats were randomly assigned to four groups (n = 7 per group): control, recombinant human growth hormone (rhGH) 20 μg/kg, PCE 200 mg/kg, and 400 mg/kg. After 10 days of administration, the serum levels of growth hormone (GH), IGF-1, IGF binding protein 3 (IGFBP3), and osteocalcin, as well as tibial length, were measured. In addition, the mRNA expression levels of IGF-1 and IGFBP3 in liver tissue were quantified via real-time polymerase chain reaction (qRT-PCR), and the protein expression levels of Janus kinase 2 (JAK2), signal transducer and activator of transcription 5 (STAT5), and IGF-1 were assessed via western blotting. Compared with the control, 400 mg/kg PCE significantly increased the serum levels of GH, IGF-1, IGFBP3, and osteocalcin in rats by 486.6%, 73.7%, 22.5%, and 27.8%, respectively ( P < 0.01), and increased the tibial length by 7.4% ( P < 0.01). Compared with the control, 400 mg/kg PCE also increased the mRNA expression of IGF-1 and IGFBP3 in the liver by 5.2-fold ( P < 0.01) and 7.3-fold ( P < 0.05), respectively. Moreover, compared with the control, 400 mg/kg PCE increased hepatic IGF-1 protein expression by 2.76-fold ( P < 0.01) and promoted the phosphorylation of JAK2 and STAT5 by 1.13-fold ( P < 0.05) and 2.82-fold ( P < 0.01), respectively. These findings suggest that PCE promotes longitudinal bone growth in rats, potentially through GH-mediated IGF-1 regulation via the JAK2/STAT5 pathway.

Objective: To examine the relationship between body mass index (BMI) and waist-hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3. Design: Cross-sectional study on 2139 women participating in a case-control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3. Results: Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m2 or BMI>29.2 kg/m2 compared to women with BMI within this range (Pheterogeneity<0.0001, Ptrend=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P trend=0.005). Conclusions: Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.

Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Among the 260 genes, we focused on 130 encoded proteins with known function for which antibodies were available. Twenty-three proteins showed values of the area under the curve (AUC) of more than 0.8 in receiver operating characteristic (ROC) analysis of reverse-phase protein array (RPPA) data of IDACP patients compared with healthy controls, and these proteins were selected as biomarker candidates. We then used our high-throughput selected reaction monitoring or multiple reaction monitoring (SRM/MRM) methodology, together with an automated sample preparation system, micro LC and auto analysis system, to quantify these candidate proteins in plasma from healthy controls and IDACP patients on a large scale. The results revealed that insulin-like growth factor-binding protein (IGFBP)2 and IGFBP3 have the ability to discriminate IDACP patients at an early stage from healthy controls, and IGFBP2 appeared to be increased in risk diseases of pancreatic malignancy, such as intraductal papillary mucinous neoplasms (IPMNs). Furthermore, diagnosis of IDACP using the combination of carbohydrate antigen 19-9 (CA19-9), IGFBP2 and IGFBP3 is significantly more effective than CA19-9 alone. This suggests that IGFBP2 and IGFBP3 may serve as compensatory biomarkers for CA19-9. Early diagnosis with this marker combination may improve the prognosis of IDACP patients.

Abstract Background The insulin/insulin-like signaling (IIS) pathways, including insulin-like growth factors (IGFs), vary with age. However, their association with late-life cognition and neuroimaging parameters is not well characterized. Methods Using data from the British 1946 birth cohort, we investigated associations of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3; measured at 53 and 60-64 years of age) with cognitive performance [word-learning test (WLT) and visual letter search (VLS) at 60-64 years and 69 years of age] and cognitive state [Addenbrooke’s Cognitive Exam III (ACE-III) at 69-71 years of age], and in a proportion, quantified neuroimaging measures [whole brain volume (WBV), white matter hyperintensity volume (WMHV), hippocampal volume (HV)]. Regression models included adjustments for demographic, lifestyle, and health factors. Results Higher IGF-I and IGF-II at 53 years of age was associated with higher ACE-III scores [ß 0.07 95% confidence interval (CI) (0.02, 0.12); scoreACE-III 89.48 (88.86, 90.1), respectively). IGF-II at 53 years of age was additionally associated with higher WLT scores [scoreWLT 20 (19.35, 20.65)]. IGFBP-3 at 60 to 64 years of age was associated with favorable VLS score at 60 to 64 and 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.02, 0.12), respectively], higher memory and cognitive state at 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.01, 0.13), respectively], and reduced WMHV [ß −0.1 (−0.21, −0.00)]. IGF-I/IGFBP-3 at 60 to 64 years of was associated with lower VLS scores at 69 years of age [ß −0.08 (−0.15, −0.02)]. Conclusions Increased measure in IIS parameters (IGF-I, IGF-II, and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 relating to memory, processing speed, and WMHV; and IGF-I/IGFBP-3 molar ratio related to slower processing speed). IGFs and IGFBP-3 are associated with favorable cognitive function outcomes.

Breast cancer is the most common diagnosed cancer and the leading cause of cancer-related deaths among women globally. This study examined the impact of insulin-like growth factor binding protein-3 (IGFBP-3) A-202C polymorphism (rs2854744) on breast cancer risk and its association with insulin-like growth factor-1 (IGF-1) and IGFBP-3 serum levels among Palestinian women in the Gaza Strip. Understanding these genetic variants could guide the development of early detection strategies and personalized interventions for breast cancer in underrepresented populations. A case-control study involved 112 women with newly diagnosed breast cancer and 222 healthy controls. Genotyping of the IGFBP-3 A-202C polymorphism was performed using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), and serum IGFBP-3 and IGF-1 levels were measured. The CC genotype of IGFBP-3 A-202C was observed in 70.5% of cases and 20.7% of controls, conferring a 16-fold increased breast cancer risk (OR=16.237; 95%CI 7.904, 33.356, p ≤ 0.001). The AC genotype was found in 19.6% of cases and 32.4% of controls, also associated with ~ 3-fold increased risk (OR=2.889; 95%CI 1.319, 6.325, p = 0.008). The CC genotype conferred a 28-fold increased risk in premenopausal women (OR=28.050; 95%CI 10.281, 76.527, p ≤ 0.001) and 5-fold in postmenopausal women (OR=5.333; 95%CI 1.711, 16.620, p = 0.004). Women with the CC genotype had the highest mean serum IGF-1 levels (116.49 ng/mL, p ≤ 0.001) and IGFBP-3 levels (3.76 µg/mL, p = 0.006) compared to those with the AA genotype. Positive correlations were observed between IGFBP-3 polymorphism and serum IGF-1 ( r s = 0.175, p ≤ 0.001) and IGFBP-3 levels ( r s = 0.164, p = 0.003). The IGFBP-3 A-202C polymorphism, especially the CC genotype, is strongly associated with elevated serum IGFBP-3 and IGF-1 levels and increased breast cancer risk, highlighting its potential as a biomarker for breast cancer screening and risk stratification. Further studies are needed to validate these findings in diverse populations.

The identification of novel screening tools is imperative to empower the early detection of colorectal cancer (CRC). The influence of the long non-coding RNA maternally expressed gene 3 (MEG3) rs941576 single nucleotide polymorphism on CRC susceptibility remains uninvestigated. This research appraised MEG3 rs941576 association with the risk and clinical features of CRC and obesity-related CRC and its impact on serum MEG3 expression and its targets miR-27a/insulin-like growth factor 1 (IGF1)/IGF binding protein 3 (IGFBP3) and miR-181a/sirtuin 1 (SIRT1), along with the potential of these markers in obesity-related CRC diagnosis. 130 CRC patients (60 non-obese and 70 obese) and 120 cancer-free controls (64 non-obese and 56 obese) were enrolled. MEG3 targets were selected using bioinformatics analysis. MEG3 rs941576 was associated with magnified CRC risk in overall (OR (95% CI) 4.69(1.51–14.57), P  = 0.0018) and stratified age and gender groups, but not with obesity-related CRC risk or MEG3/downstream targets’ expression. Escalated miR-27a and IGFBP3 and reduced IGF1 serum levels were concomitant with MEG3 downregulation in overall CRC patients versus controls and obese versus non-obese CRC patients. Serum miR-181a and SIRT1 were upregulated in CRC patients versus controls but weren’t altered in the obese versus non-obese comparison. Serum miR-181a and miR-27a were superior in overall and obesity-related CRC diagnosis, respectively; meanwhile, IGF1 was superior in distinguishing obese from non-obese CRC patients. Only serum miR-27a was associated with obesity-related CRC risk in multivariate logistic analysis. Among overall CRC patients, MEG3 rs941576 was associated with lymph node (LN) metastasis and tumor stage, serum MEG3 was negatively correlated with tumor stage, while SIRT1 was correlated with the anatomical site. Significant correlations were recorded between MEG3 and anatomical site, SIRT1 and tumor stage, and miR-27a/IGFBP3 and LN metastasis among obese CRC patients, while IGF1 was correlated with tumor stage and LN metastasis among non-obese CRC patients. Conclusively, this study advocates MEG3 rs941576 as a novel genetic marker of CRC susceptibility and prognosis. Our findings accentuate circulating MEG3/miR-27a/IGF1/IGFBP3, especially miR-27a as valuable markers for the early detection of obesity-related CRC. This axis along with SIRT1 could benefit obesity-related CRC prognosis.

Objective The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are thought to play a significant role in metabolic pathways and glucose metabolism. Unregulated levels of IGFs/IGFBPs have been associated with the development of glucose intolerance and metabolic syndrome X (MSx). We hypothesized that change of IGFs/IGFBPs levels could increase the risk of MSx; thus, this study aimed to evaluate the serostatus of IGFs/IGFBPs in individuals with MSx. Results After adjustment for metabolic parameters, MSx patients had a lower level of IGF-1, IGFBP-1, and IGFBP-2 compared with subjects in the control group. Further analysis revealed a positive correlation between serum levels of IGF-1 and IGF-2 (p < 0.05), as well as serum IGFBP-3 and IGF-2 (p < 0.05). Also, the statistical analysis showed a negative association of serum IGF-1 with plasma glucose and total cholesterol levels (p < 0.05). Besides, a negative relationship was found between serum concentrations of IGF-1/IGF-2 and the risk of developing MSx. These data indicated that some components of IGFs/IGFBPs are linked with the pathogenesis of MSx. In conclusion, these inverse associations showed a possible linkage between the IGF/IGFBP signaling pathway and the development of MSx. It seems the decreased concentrations of IGFs edmay be regarded as a potential biomarker for early diagnosis or even prognosis of MSx but need more systematic studies to confirmed it.

Obesity is associated with alterations in circulating IGF1, IGF1-binding proteins (IGFBPs), insulin, inflammatory markers, and hormones implicated in cardiovascular disease, diabetes, cancer, and aging. However, the effects of 4 and 6 h time-restricted eating (TRE) on circulating IGF1 and IGFBPs is uncertain. Objective: This study aimed to investigate the effects of TRE on plasma IGF1, IGFBP1, IGFBP2, and IGFBP3, and whether these effects were mediated by weight loss or body composition changes. Insulin sensitivity, glucose control, adipokines, and inflammatory markers were also examined. Design: An exploratory analysis of an 8-week randomized controlled trial implementing a daily TRE intervention was carried out. Participants/Setting: This study was conducted at the University of Illinois at Chicago in 2019. Participants with obesity were randomized to 4 or 6 h TRE (n = 35) or a control (n = 14) group. Plasma biomarkers were measured by ELISA at baseline and week 8. In a sub-analysis, participants were stratified into higher- (>3.5%) and lower- (≤3.5%) weight-loss groups. Intervention: Participants fasted daily from 7 p.m. to 3 p.m. in the 4 h TRE group (20 h) and from 7 p.m. to 1 p.m. in the 6 h TRE group (18 h), followed by ad libitum eating for the remainder of the day. Controls received no dietary recommendations. Main outcome measures: IGF1, IGFBPs, hsCRP, and adipokines were the main outcome measures of this analysis. Statistical Analysis: Repeated measures ANOVA and mediation analysis were conducted. Results: Body weight significantly decreased with TRE (−3.6 ± 0.3%), contrasting with controls (+0.2 ± 0.5%, p < 0.001). Significant effects of TRE over time were observed on plasma IGFBP2, insulin, HOMA-IR, and 8-isoprostane levels, without affecting other biomarkers. In the sub-analysis, IGFBP2 increased while leptin and 8-isoprostane decreased significantly only in the “higher weight loss” subgroup. Changes in insulin and HOMA-IR were related to TRE adherence. Conclusions: Eight-week daily 4 to 6 h TRE did not affect IGF1, IGFBP1, or IGFBP3 levels but improved insulin, HOMA-IR, and 8-isoprostane. IGFBP2 increased and leptin decreased when weight loss exceeded 3.5% of baseline.