Search

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D. [ABSTRACT FROM AUTHOR]

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D.

Objective: To investigate the relationship between serum 25-hydroxyvitamin D [25 (OH)D], insulin growth factor binding protein 1 (IGFBP-1), signal transducer and activator of transcription 4 (STAT4) and spontaneous abortion in patients with severe preeclampsia (PE). Methods: 150 severe PE patients who were treated in the Affiliated Hospital of Xuzhou Medical University from January 2020 to December 2022 were selected. Patients were divided into occurrence group (n=41) and non-occurrence group (n=109) according to whether spontaneous abortion occurred within 28 weeks of pregnancy. The levels of serum 25 (OH)D, IGFBP-1 and STAT4were compared between two groups. The clinical data in two groups were collected, and the influencing factors of spontaneous abortion in severe PE patients were analyzed by multivariate Logistic regression. The predictive value of serum 25 (OH)D, IGFBP-1 and STAT4 levels for spontaneous abortion in severe PE patients were analyzed by receiver operating characteristic (ROC) curve. Results: The levels of 25 (OH)D and IGFBP-1 in occurrence group were lower than those in non-occurrence group, and the level of STAT4 was higher than that in non-occurrence group (P＜0.05). Spontaneous abortion in severe PE patients was not related to age, gestational age of PE onset, pre-pregnancy body mass index (BMI), delivery history, systolic blood pressure (SBP), diastolic blood pressure (DBP), platelet count (PLT) and creatinine (Scr) (P＞0.05), but was related to abortion history, D-dimer (D-D), albumin (ALB), homocysteine (Hcy) and fibrinogen (P＜0.05). Multivariate logistic regression analysis showed that, the decrease of 25 (OH)D, the decrease of IGFBP-1, the increase of STAT4, abortion history, the increase of D-D, the decrease of ALB and the increase of Hcy were the risk factors of spontaneous abortion in severe PE patients, while the increase of fibrinogen was the protective factor of spontaneous abortion in severe PE patients (P＜0.05). The area under the curve (AUC) of combined detection of serum 25 (OH)D, IGFBP-1 and STAT4 in predicting spontaneous abortion was 0.960, which was higher than that of single index prediction. Conclusion: The decrease of serum 25 (OH)D and IGFBP-1 and the increase of STAT4 level in severe PE patients are likely to lead to spontaneous abortion, the occurrence of spontaneous abortion is also relate to abortion history, D-D, ALB, Hcy, fibrinogen level and other factors. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of metastatic colorectal cancer patients remains poor despite the increased number of active treatments. This particularly applies to patients with chemorefractory disease. Biomarkers that could help prognostication and management decisions in this setting are lacking. This is the study with the largest panel (n = 182) of circulating cytokines ever assessed in metastatic colorectal cancer. By analyzing 196 chemorefractory colorectal cancer patients with available plasma samples, we showed that high concentrations of IGFBP-1 and/or IGFBP-2 were associated with shorter overall survival. These results are consistent with the extensive literature supporting an association between the IGF pathway and colorectal cancer. Further research is needed to validate our findings in larger independent series, and to elucidate the biological mechanisms underlying the prognostic effect of these cytokines. 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. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor binding proteins (IGFBPs) play crucial roles in regulating biological activities of insulin-like growth factors (IGFs) and growth performance in vertebrates. IGFBP is a six-member protein family (IGFBP1–6) with a high affinity for IGF. It affects the distribution, stability, and biological activity of IGF by regulating the interaction between IGF ligands and receptors. Recently, IGFBP-1 was identified as a regulator of growth, reproduction, and development in bony fish, such as juvenile Atlantic salmon, where IGFBP-1 interacts with cortisol to regulate growth. IGFBP-1 regulates cell metabolism and growth through interaction with insulin in primary hepatocytes incubated in vitro in orange-spotted grouper (Epinephelus coioides). IGFBP-2 has a wide range of tissue expression characteristics in bony fish, and IGF regulation may occur through autocrine or paracrine pathways. For example, long-term fasting induced increased igfbp-2 mRNA expression in the liver of zebrafish. In addition, IGFBP-2 can inhibit the activity of IGF ligand through its high affinity with IGF to play an inhibitory and regulatory role in zebrafish growth. igfbp-2 mRNA expression was significantly up-regulated in Carassius auratus (goldfish) liver after fasting, and quickly recovered to normal levels after feeding. This indicated that igfbp-2 mRNA expression may be related to the anabolism and catabolism of goldfish, and is regulated by metabolic factors.Yellowtail kingfish (Seriola aureovittata) of the Carangidae family has high economic value and nutrition value. It is a warm and temperate oceanic fish with long distance migration characteristics that is distributed in the middle and upper oceans globally. This species is large with a fast growth rate, and is a promising candidate for aquaculture in land-based industrial circulating water system, deep-water cages, net pen systems, and aquaculture craft, etc. Our laboratory studied the regulatory mechanism of the rapid growth of yellowtail kingfish and cloned gh, igf-1, igf-2, ghr, and other growth-related functional genes to reveal their molecular regulation in early growth and development. igfbp genes regulate the growth, development, and nutrient metabolism of fish through their interaction with growth axis. The mechanism of IGFBP and how it influences the regulation of yellowtail kingfish growth is unreported. This paper further studied the growth of yellowtail kingfish by analyzing the key growth axis factors.RNAiso Plus reagent (TaKaRa) was used to extract total RNA from tissues. RNA integrity was detected by agarose gel electrophoresis, and RNA quality was determined by a NanoDrop 2000C spectrophotometer (Thermo Fisher Scientific, USA). First, cDNA strand was synthesized using a PrimeScript™ RT reagent kit with a gDNA Eraser (Perfect Real-Time) reverse transcription kit (TaKaRa). Primers were designed to clone the predicted sequence of yellowtail kingfish igfbp gene according to the NCBI GenBank database. The product was amplified by polymerase chain reaction, purified from agarose gel electrophoresis, linked with T4 Ligases, transformed into Trans1-T1 Phage Resistant Chemically Competent Cell, and positive clones were selected and tested. Quantitative real time polymerase chain reaction (qRT-PCR) was used to analyze the distribution of yellowtail kingfish tissues and the expression patterns of liver tissues under different densities of industrial culture.The lengths of igfbp-1, igfbp-2a, igfbp-2b open reading frame (ORF) domains were 741 bp, 882 bp, and 801 bp, and encoded 246 amino acids, 293 amino acids, and 269 amino acids, respectively. The conserved domain of insulin growth factor-binding protein homologues (IB) was present in the N-terminus of the three igfbps, and the conserved domain of thyroglobulin type-1 repeat (Ty-1) was present in the C-terminus. They had a wide range of tissue expression characteristics and were highly expressed in the liver. There were differences between the expression of the same gene in the same tissues of male and female fish. For example, the expression of igfbp-1 and igfbp-2b genes was significantly higher in the liver of male fish compared with female fish, while igfbp-2a expression was significantly higher in the liver of female fish compared with male fish. The tissue differential expression of genes between sexes indicates that igfbp may have sex dimorphism when it plays a physiological role. However, the specific characteristics of this difference between males and females and the possible signaling pathway are unclear. The fish in the low-density group showed the greatest growth rate and the highest expression levels of igfbp-1, igfbp-2a, igfbp-2b, igf-1, and igf-2 under industrial culture conditions. These expression levels were significantly different from those of the medium and high-density groups (P < 0.05). However, there were no significant differences in the expression levels of growth and liver genes between the middle and high-density groups.igfbp-1, igfbp-2a, and igfbp-2b participated in the growth regulation of yellowtail kingfish. The expression regulation of igf-1 and igf-2 had a positive synergistic effect with growth regulation of yellowtail kingfish. The ORF regions of igfbp-1, igfbp-2a, and igfbp-2b genes of yellowtail kingfish were cloned, and the structural characteristics, tissue expression characteristics, and relationships with growth performance were analyzed under different culture densities. The content of serum IGF-1, GH, cortisol, and glucose concentration was detected in the early stage. The expression trend of igfbp-1, igfbp-2, igf-1, and igf-2 was the same as that of serum IGF-1 and GH in the liver of yellowtail kingfish rapidly growing at the low-density group, but contrary to the expression trend of cortisol content and glucose concentration. This indicated that the key factors of growth axis, cortisol, and glucose participated in the growth regulation of yellowtail kingfish at different densities. However, the specific regulatory mechanism requires further study. The results provide a theoretical basis for interpreting the molecular mechanism of the growth of yellowtail kingfish and the regulation of suitable culture densities under industrial conditions.

We conducted a prospective double-blind study to compare two vaginal diagnostic methods in singleton pregnancies with threatened preterm labor (TPL) at the University Hospital of Clermont-Ferrand (France) from August 2018 to December 2020. Our main objective was to compare the diagnostic capacity at admission, in terms of positive predictive value (PPV) and negative predictive value (NPV), of Premaquick® (combined detection of IL-6/total IGFBP-1/native IGFBP-1) and QuikCheck fFN™ (fetal fibronectin) for delivery within 7 days in cases of TPL. We included 193 patients. Premaquick® had a sensitivity close to 89%, equivalent to QuikCheck fFN™, but a higher statistical specificity of 49.5% against 38.6% for QuikCheck fFN™. We found no superiority of Premaquick® over QuickCheck fFN™ in terms of PPV (6.6% vs. 7.9%), with NPV being equivalent in predicting childbirth within 7 days in cases of TPL (98.6% vs. 98.9%). Nevertheless, the combination of positive native and total IGFBP-1 and the combination of all three positive markers were associated with a higher PPV. Our results, though non-significant, support this combined multiple-biomarker approach to improve testing in terms of predictive values. [ABSTRACT FROM AUTHOR]

Abstract Background Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC. Methods We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin‐like growth factor‐binding protein‐1 (IGFBP‐1) levels of 31 lenvatinib‐treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain‐ and loss‐of‐function experiments were performed. Results In the patient cohort, IGFBP‐1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP‐1 levels via the hypoxia‐hypoxia inducible factor signaling. IGFBP‐1 stimulated angiogenesis through activation of the integrin α5β1‐focal adhesion kinase pathway. Consequently, loss of IGFBP‐1 and integrin α5β1 by genetic and pharmacological approaches re‐sensitized HCC to lenvatinib treatment. Conclusions Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP‐1, which promoted angiogenesis through activating the IGFBP‐1‐integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP‐1 inhibitors.

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. [ABSTRACT FROM AUTHOR]

The metabolic syndrome is a cluster of overlapping conditions resulting in an increased incidence of type 2 diabetes, cardiovascular disease, and cancer. In the last few decades, prevalence of the metabolic syndrome in the Western world has reached epidemic proportions and this is likely due to alterations in diet and the environment as well as decreased physical activity. This review discusses how the Western diet and lifestyle (Westernization) has played an important etiological role in the pathogenesis of the metabolic syndrome and its consequences by exerting negative effects on activity of the insulin–insulin-like growth factor-I (insulin–IGF-I) system. It is further proposed that interventions that normalize/reduce activity of the insulin–IGF-I system may play a key role in the prevention and treatment of the metabolic syndrome. For successful prevention, limitation, and treatment of the metabolic syndrome, the focus should be primarily on changing our diets and lifestyle in accordance with our genetic make-up, formed in adaptation to Paleolithic diets and lifestyles during a period of several million years of human evolution. Translating this insight into clinical practice, however, requires not only individual changes in our food and lifestyle, starting in pediatric populations at a very young age, but also requires fundamental changes in our current health systems and food industry. Change is needed: primary prevention of the metabolic syndrome should be made a political priority. New strategies and policies should be developed to stimulate and implement behaviors encouraging the sustainable use of healthy diets and lifestyles to prevent the metabolic syndrome before it develops. [ABSTRACT FROM AUTHOR]

Objective: Adiponectin and insulin-like growth factor (IGF) binding proteins IGFBP-1 and IGFBP-2 are biomarkers of insulin sensitivity. IGFBP-1 reflects insulin sensitivity in the liver, adiponectin in adipose tissue and IGFBP-2 in both tissues. Here, we study the power of the biomarkers adiponectin, IGFBP-1, IGFBP-2, and also included IGF-I and IGF-II, in predicting prediabetes and type 2 diabetes (T2D) in men and women with normal oral glucose tolerance (NGT). Design: Subjects with NGT (35-56 years) recruited during 1992-1998 were reinvestigated 8-10 years later. In a nested case control study, subjects progressing to prediabetes (133 women, 164 men) or to T2D (55 women, 98 men) were compared with age and sex matched NGT controls (200 women and 277 men). Methods: The evaluation included questionnaires, health status, anthropometry, biochemistry and oral glucose tolerance test. Results: After adjustment, the lowest quartile of adiponectin, IGFBP-1 and IGFBP-2 associated independently with future abnormal glucose tolerance (AGT) in both genders in multivariate analyses. High IGFs predicted weakly AGT in women. In women, low IGFBP-2 was the strongest predictor for prediabetes (OR:7.5), and low adiponectin for T2D (OR:29.4). In men, low IGFBP-1 was the strongest predictor for both prediabetes (OR:13.4) and T2D (OR:14.9). When adiponectin, IGFBP-1 and IGFBP-2 were combined, the ROC-AUC reached 0.87 for women and 0.79 for men, higher than for BMI alone. Conclusion: Differences were observed comparing adipocyte- and hepatocyte-derived biomarkers in forecasting AGT in NGT subjects. In women the strongest predictor for T2D was adiponectin and in men IGFBP- 1, and for prediabetes IGFBP-2 in women and IGFBP-1 in men. [ABSTRACT FROM AUTHOR]

ObjectiveAdiponectin and insulin-like growth factor (IGF) binding proteins IGFBP-1 and IGFBP-2 are biomarkers of insulin sensitivity. IGFBP-1 reflects insulin sensitivity in the liver, adiponectin in adipose tissue and IGFBP-2 in both tissues. Here, we study the power of the biomarkers adiponectin, IGFBP-1, IGFBP-2, and also included IGF-I and IGF-II, in predicting prediabetes and type 2 diabetes (T2D) in men and women with normal oral glucose tolerance (NGT).DesignSubjects with NGT (35-56 years) recruited during 1992-1998 were re-investigated 8-10 years later. In a nested case control study, subjects progressing to prediabetes (133 women, 164 men) or to T2D (55 women, 98 men) were compared with age and sex matched NGT controls (200 women and 277 men).MethodsThe evaluation included questionnaires, health status, anthropometry, biochemistry and oral glucose tolerance test.ResultsAfter adjustment, the lowest quartile of adiponectin, IGFBP-1 and IGFBP-2 associated independently with future abnormal glucose tolerance (AGT) in both genders in multivariate analyses. High IGFs predicted weakly AGT in women. In women, low IGFBP-2 was the strongest predictor for prediabetes (OR:7.5), and low adiponectin for T2D (OR:29.4). In men, low IGFBP-1 was the strongest predictor for both prediabetes (OR:13.4) and T2D (OR:14.9). When adiponectin, IGFBP-1 and IGFBP-2 were combined, the ROC-AUC reached 0.87 for women and 0.79 for men, higher than for BMI alone.ConclusionDifferences were observed comparing adipocyte- and hepatocyte-derived biomarkers in forecasting AGT in NGT subjects. In women the strongest predictor for T2D was adiponectin and in men IGFBP-1, and for prediabetes IGFBP-2 in women and IGFBP-1 in men.

Introduction: The known markers of insulin resistance in obese children are well studied. However, they require serial measurements and complicated calculations. The objective is to study IGFBP-1 and its relation with other known risk measures. Materials and Methods: The study included 98 New York City school students of diverse ethnic/racial backgrounds (57 males and 41 females), 11–15 years of age. Subjects were enrolled in a cross-sectional study, and anthropometric measures were collected. They underwent fasting intravenous glucose tolerance tests (IVGTT), and glucose, insulin, lipids, IGFBP-1, adiponectin and inflammatory markers were collected. Results: The subjects were stratified into 3 groups based upon the BMI Z-score. Out of all the subjects, 65.3% were in the group with a BMI Z-score <1 SDS, 16.3% subjects were in the group with a BMI Z-score of 1 to 2 SDS, and 18.4% of the subjects were in the group with a BMI Z-score of more than 2 SDS. The group with a BMI Z-score of more than 2 SDS had increased waist circumference (WC), body fat, increased fasting insulin, and triglycerides (TG). This group had decreased levels of adiponectin and HDL and low IGFBP-1 as compared to the group with BMI <1 SDS. The group with a BMI Z-score of 1 to 2 SDS had a decreased level of IGFBP-1 as compared to the group with a BMI Z-score less than 1 SDS. IGFBP-1 inversely correlated with age, WC, BMI, body fat, TG, and insulin levels. IGFBP-1 positively correlated with adiponectin and HDL levels. Conclusion: IGFBP-1 in children can identify the presence of insulin resistance in the group with BMI 1 to 2 SDS, even before the known markers of insulin resistance such as elevated triglycerides and even before decreased HDL and adiponectin levels are identified. [ABSTRACT FROM AUTHOR]

IntroductionThe known markers of insulin resistance in obese children are well studied. However, they require serial measurements and complicated calculations. The objective is to study IGFBP-1 and its relation with other known risk measures.Materials and MethodsThe study included 98 New York City school students of diverse ethnic/racial backgrounds (57 males and 41 females), 11–15 years of age. Subjects were enrolled in a cross-sectional study, and anthropometric measures were collected. They underwent fasting intravenous glucose tolerance tests (IVGTT), and glucose, insulin, lipids, IGFBP-1, adiponectin and inflammatory markers were collected.ResultsThe subjects were stratified into 3 groups based upon the BMI Z-score. Out of all the subjects, 65.3% were in the group with a BMI Z-score

The metabolic syndrome is a cluster of overlapping conditions resulting in an increased incidence of type 2 diabetes, cardiovascular disease, and cancer. In the last few decades, prevalence of the metabolic syndrome in the Western world has reached epidemic proportions and this is likely due to alterations in diet and the environment as well as decreased physical activity. This review discusses how the Western diet and lifestyle (Westernization) has played an important etiological role in the pathogenesis of the metabolic syndrome and its consequences by exerting negative effects on activity of the insulin–insulin-like growth factor-I (insulin–IGF-I) system. It is further proposed that interventions that normalize/reduce activity of the insulin–IGF-I system may play a key role in the prevention and treatment of the metabolic syndrome. For successful prevention, limitation, and treatment of the metabolic syndrome, the focus should be primarily on changing our diets and lifestyle in accordance with our genetic make-up, formed in adaptation to Paleolithic diets and lifestyles during a period of several million years of human evolution. Translating this insight into clinical practice, however, requires not only individual changes in our food and lifestyle, starting in pediatric populations at a very young age, but also requires fundamental changes in our current health systems and food industry. Change is needed: primary prevention of the metabolic syndrome should be made a political priority. New strategies and policies should be developed to stimulate and implement behaviors encouraging the sustainable use of healthy diets and lifestyles to prevent the metabolic syndrome before it develops.

Abstract Background Gestational 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. Methods This 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. Results In the metformin and insulin groups combined, hsCRP decreased (p = 0.01), whereas IL-6 (p = 0.002), GlycA (p

Aims/hypothesis: Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes. Methods: IGFBP expression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging. Results: Data from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerular IGFBP-1 in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)–forkhead box O1 (FoxO1) activity. In vitro, IGFBP-1 signalled to podocytes via β1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability. Conclusions/interpretation: This work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression of IGFBP-1 is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor (IGF) system plays a significant role in many cellular processes, including proliferation, and survival. In estrogen receptor positive breast cancer, the level of circulating IGF-1 is positively associated with the incidence and at least 50% of cases have elevated IGF-1R signaling. Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα-positive breast cancer. Unfortunately, tamoxifen resistance is a frequent occurrence in patients receiving treatment and the molecular mechanisms that underlie tamoxifen resistance not adequately defined. It has recently been reported that the inhibition of IGF-1R activation and the proliferation of breast cancer cells upon tamoxifen treatment is mediated by the accumulation of extracellular insulin-like growth factor binding protein 1 (IGFBP-1). Elevated IGFBP-1 expression was observed in tamoxifen-resistant (TamR) MCF-7 and T-47D cells lines suggesting that the tamoxifen-resistant state is associated with IGFBP-1 accumulation. MCF-7 and T-47D breast cancer cells stably transfected with and IGFBP-1 expression vector were generated (MCF7-BP1 and T47D-BP1) to determine the impact of breast cancer cell culture in the presence of increased IGFBP-1 expression. In these cells, the expression of IGF-1R was significantly reduced compared to controls and was similar to our observations in tamoxifen-resistant MCF-7 and T-47D cells. Also similar to TamR breast cancer cells, MCF7-BP1 and T47D-BP1 were resistant to tamoxifen treatment, had elevated epidermal growth factor receptor (EGFR) expression, increased phospho-EGFR (pEGFR), and phospho-Erk (pErk). Furthermore, tamoxifen sensitivity was restored in the MCF7-BP1 and T47D-BP1 upon inhibition of Erk phosphorylation. Lastly, the transient knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 inhibited pErk accumulation and increased tamoxifen sensitivity. Taken together, these data support the conclusion that IGFBP-1 is a key component of the development of tamoxifen resistance in breast cancer cells.

Physical activity is accompanied by the changes in Insulin-like Growth Factor I (IGF-I)/IGF-Binding Protein 1 (IGFBP-1) axis. Inconsistent results concerning IGF-I and IGFBP-1 levels were reported. In this study we have raised some questions on the events that occur at the molecular level of the exercise-related IGFBP-1 changes. We have examined the fragmentation pattern of IGFBP-1, IGFBP-1 protease activity, interaction between IGFBP-1 and alpha2-macroglobulin (α2M), and possible existence of minor structural changes of IGFBP-1 in professional soccer players. Athletes had significantly greater amounts of fragmented IGFBP-1, whereas no difference was found in the amount of intact IGFBP-1 compared with controls. An increased activity of matrix metalloprotease-9 (MMP-9) was detected in athletes, causing IGFBP-1 degradation down to the fragment of 9 kDa as the major one. The amount of α2M, which protects IGFBP-1 from proteolysis, or the amount of IGFBP-1/α2M complexes was unaltered. Finally, we have examined whether IGFBP-1 isolated from soccer players exhibited altered reactivity with several chemical surfaces used in surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS). Different reactivity was detected with anion and cation exchangers, suggesting existence of at least one sequence within IGFBP-1, whose ionization pattern was not equal in athletes and controls. Differences in spectra obtained with ion exchanges may reflect differences in IGFBP-1 phosphorylation. Physiological implications of the events described in this study on the IGF-I availability are, at this time, unknown. It can be hypothesized that IGFBP-1 proteolysis leads to altered distribution of IGF-I among IGFBPs, which may affect the final IGF-associated response. [ABSTRACT FROM AUTHOR]

Abstract Purpose High‐mobility group N (HMGN) proteins are the only non‐histone proteins that specifically bind within the nucleosome between core histones and DNA. Among them, HMGN5 is one of the candidates that could participate in mouse endometrial decidualization; however, the specific role of HMGN5 remains to be clarified in human endometrial stromal cells (HESCs). Methods Primary HESCs were isolated from hysterectomy specimens and incubated with or without 8‐bromo‐cyclic adenosine monophosphate (8‐br‐cAMP) and medroxyprogesterone acetate (MPA). Results We demonstrated that HMGN5 expression in decidualized HESCs stimulated by 8‐br‐cAMP and MPA decreased significantly. The inhibition of HMGN5 expression by small interfering RNA (siRNA) induced the major decidual marker genes expression, including IGFBP1 (insulin‐like growth factor binding protein 1) and PRL (prolactin). In addition, microRNA‐542‐3p (miR‐542‐3p), which was identified as a regulatory miRNA of IGFBP1 during decidualization, was significantly suppressed by HMGN5 siRNA. However, the expression of HMGN5 was not alternated by miR‐542‐3p overexpression. Conclusions These findings suggest that the down‐regulation of HMGN5 plays a role in the promotion of human endometrial stromal decidualization and acts upstream of miR‐542‐3p.

Background: Bishop Score is still the usual method to expect the results of labor induction. Transvaginal ultrasonographic measurement of cervical length (TVUS-CL) is more objective and insulin like growth factor binding protein-1(IGFBP-1) has been recently used for this aim. Objective: This study was conducted to compare between TVUS-CL and detection of cervical (IGFBP-1) for prediction of results of induction of labor after 37 week of pregnancy. Patients and Methods: A prospective cohort study on 140 pregnant women underwent induction of labor. All patients were subjected to TVUS-CL and detection of cervical (IGFBP-1) and Bishop Score. The primary outcome measure was induction success. The secondary outcome measure was induction to delivery interval. Results: In our study (97) females delivered by simple vaginal delivery (SVD), (79) females delivered within 24 hour of induction, (18) females delivered after 24 hour, and (43) females delivered by caesarian section. The mean cervical length measured by TVUS in females who delivered by SVD was 24.89 ±5.48 mm and was 26.79±3.06 mm in those who delivered by CS. IGFBP-1 was positive in 71 females who delivered by SVD and in 17 females who delivered by CS and it was negative in 26 females who delivered by SVD and 26 females who delivered by CS. Conclusion: Success of labor induction correlated significantly with detection of cervical IGFBP-1 and measurement of cervical length by TVUS. [ABSTRACT FROM AUTHOR]

Background: Gestational 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.Methods: This 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.Results: In 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.Conclusions: Metformin 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 Registration: The trial comparing metformin and insulin treatment was registered in ClinicalTrials.gov ( NCT01240785 ) November 3, 2010. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor (IGF) system plays a significant role in many cellular processes, including proliferation, and survival. In estrogen receptor positive breast cancer, the level of circulating IGF-1 is positively associated with the incidence and at least 50% of cases have elevated IGF-1R signaling. Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα-positive breast cancer. Unfortunately, tamoxifen resistance is a frequent occurrence in patients receiving treatment and the molecular mechanisms that underlie tamoxifen resistance not adequately defined. It has recently been reported that the inhibition of IGF-1R activation and the proliferation of breast cancer cells upon tamoxifen treatment is mediated by the accumulation of extracellular insulin-like growth factor binding protein 1 (IGFBP-1). Elevated IGFBP-1 expression was observed in tamoxifen-resistant (TamR) MCF-7 and T-47D cells lines suggesting that the tamoxifen-resistant state is associated with IGFBP-1 accumulation. MCF-7 and T-47D breast cancer cells stably transfected with and IGFBP-1 expression vector were generated (MCF7-BP1 and T47D-BP1) to determine the impact of breast cancer cell culture in the presence of increased IGFBP-1 expression. In these cells, the expression of IGF-1R was significantly reduced compared to controls and was similar to our observations in tamoxifen-resistant MCF-7 and T-47D cells. Also similar to TamR breast cancer cells, MCF7-BP1 and T47D-BP1 were resistant to tamoxifen treatment, had elevated epidermal growth factor receptor (EGFR) expression, increased phospho-EGFR (pEGFR), and phospho-Erk (pErk). Furthermore, tamoxifen sensitivity was restored in the MCF7-BP1 and T47D-BP1 upon inhibition of Erk phosphorylation. Lastly, the transient knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 inhibited pErk accumulation and increased tamoxifen sensitivity. Taken together, these data support the conclusion that IGFBP-1 is a key component of the development of tamoxifen resistance in breast cancer cells. [ABSTRACT FROM AUTHOR]

Steady state insulin-like growth factor-1 (IGF-1) levels vary significantly during continuous intravenous infusion of recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3) in the first weeks of life in extremely preterm infants. We evaluated interleukin-6 (IL-6) and insulin-like growth factor binding protein-1 (IGFBP-1) levels as predictors of low IGF-1 levels. Nineteen extremely preterm infants were enrolled in a trial, 9 received rhIGF-1/rhIGFBP-3 and 10 received standard neonatal care. Blood samples were analyzed daily for IGF-1, IL-6 and IGFBP-1 during intervention with rhIGF-1/rhIGFBP-3. Thirty seven percent of IGF-1 values during active treatment were <20 μg/L. Among treated infants, higher levels of IL-6, one and two days before sampled IGF-1, were associated with IGF-1 < 20 μg/L, gestational age adjusted OR 1.30 (95% CI 1.03–1.63), p =.026, and 1.57 (95% CI 1.26–1.97), p <.001 respectively. Higher levels of IGFBP-1 one day before sampled IGF-1 was also associated with IGF-1 < 20 μg/L, gestational age adjusted OR 1.74 (95% CI 1.19–2.53), p =.004. In preterm infants receiving continuous infusion of rhIGF-1/rhIGFBP-3, higher levels of IL-6 and IGFBP-1 preceded lower levels of circulating IGF-1. These findings demonstrate a need to further evaluate if inflammation and/or infection suppress serum IGF-1 levels. The trial is registered at ClinicalTrials.gov (NCT01096784). • IGF-1 levels vary during rhIGF-1/rhIGFBP-3 treatment in preterm infants. • High IL-6 and IGFBP-1 levels predicted low serum IGF-1 < 20 μg/L. • The results suggest that inflammation and/or infection may suppress serum IGF-1. • This finding increases the understanding of the feasibility of rhIGF-1/rhIGFBP-3 treatment. [ABSTRACT FROM AUTHOR]

There is conflicting literature on whether the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena®) induces decidualisation in the tamoxifen-treated endometrium. The expression of the decidualisation marker IGFBP-1 was measured using immunohistochemistry in endometrial biopsies and in serum (using ELISA) of 20 postmenopausal women at the start of tamoxifen-treatment for breast cancer. Ten women were then fitted with LNG-IUS and the other ten received tamoxifen-treatment only and acted as controls. Samples were taken at baseline and after 12 months. At baseline, all endometrial samples were negative for IGFBP-1 and at 12 months, IGFBP-1 was only expressed in the endometria of women fitted with the LNG-IUS, confirming the observed histological features of decidualisation. By contrast, serum IGFBP-1 concentrations were increased by tamoxifen, but not in the group receiving LNG-IUS. In conclusion, tamoxifen induces a rise in serum IGFBP-1 suggesting a systemic, possibly hepatic effect, whilst LNG abrogates this in both the liver and endometrium. Impact statement What is already known on this subject? Previous reports of the use of LNG-IUS in women on tamoxifen have provided conflicting evidence as to whether the endometrium exhibited decidualisation or not. These reports were however based solely on histological examination and lacked supporting biochemical data. What do the results of this study add? After 12 months of treatment with LNG-IUS, the endometria of women on tamoxifen show histological features of decidualisation and the presence of the decidualisation marker IGFBP-1, suggesting that levonorgestrel protects the tamoxifen-treated uterus from additional pathology by causing decidualisation. Serum levels of IGFBP-1 were expected to be a reflection of uterine production, but contrary to expectations, higher levels were identified in women on tamoxifen alone. These data suggest that an inhibition of tamoxifen-induced serum IGFBP-1 production (possibly from a hepatic source) by LNG-IUS occurred and indicates independent systemic effects of both drugs in post menopausal breast cancer patients. What are the implications of these findings for clinical practice and/or further research? This research demonstrated a mechanism for endometrial protection in women on tamoxifen. It also alerts clinicians to the fact that both tamoxifen and LNG-IUS exert systemic effects in this patient group. [ABSTRACT FROM AUTHOR]

To determine the molecular differences between iMCD-thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, organomegaly (TAFRO), and iMCD-not otherwise specified (NOS). CD4-positive T cells were isolated from two iMCD-TAFRO and two iMCD-NOS patients for RNA sequencing comparison. Serum proteins of two iMCD-TAFRO and four iMCD-NOS patients were comprehensively analyzed to identify pathogenesis-associated proteins. IGFBP-1 protein, extracted from serum analysis, was compared to healthy controls, iMCD, systemic lupus erythematosus, and rheumatoid arthritis patients. RNA sequencing of CD4-positive T cells revealed enhanced mTOR-related signaling in iMCD-TAFRO compared to iMCD-NOS. Comprehensive serum analysis found IGFBP-1 linked to iMCD pathogenesis, significantly higher in iMCD-TAFRO. This protein may be elevated in patients with iMCD caused by an enhanced mTOR pathway. The mTOR pathway is suggested to be activated in iMCD-TAFRO compared to iMCD-NOS, which may elevate the protein IGFBP-1. This protein may be a biomarker to distinguish iMCD-TAFRO from iMCD-NOS. • The mTOR pathway is suggested to be activated in iMCD-TAFRO compared to iMCD-NOS. • Elevated serum IGFBP-1 may be associated with activation of the mTOR pathway. • Serum IGFBP-1 may be a biomarker to distinguish between iMCD-TAFRO and iMCD-NOS. [ABSTRACT FROM AUTHOR]

Inflammation plays a role in development of diabetic complications. The postprandial state has been linked to chronic low grade inflammation. We therefore aimed to investigate the acute effects of fructose loading, with and without a pizza, on metabolic and inflammatory markers in patients with type 2 diabetes (T2D) (n = 7) and in healthy subjects (HS) (n = 6), age 47–76 years. Drinks consumed were blueberry drink (18 g fructose), Coca-Cola (17.5 g fructose), and fructose drink (35 g fructose). The levels of glucose, insulin, insulin-like growth factor binding protein-1 (IGFBP-1) and inflammatory markers: Interleukin-6 (IL-6), Monocyte chemoattractant protein-1 (MCP-1), Interleukin-18 (IL-18), Intercellular Adhesion Molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and bacterial lipopolysaccharides (LPS) were analyzed in blood. The postprandial responses were assessed using Wilcoxon’s matched-pairs test, Friedman’s ANOVA and Mann–Whitney U test. There was no difference in baseline levels of inflammatory markers between the groups. In T2D, MCP-1 decreased following blueberry drink and Coca-Cola (p = 0.02), Coca-Cola + pizza and fructose + pizza (p = 0.03). In HS, IL-6 increased following blueberry + pizza and fructose + pizza (p = 0.03), there was a decrease in MCP-1 following blueberry drink and Coca-Cola (p = 0.03), and in ICAM-1 following blueberry + pizza (p = 0.03). These results may indicate a role for MCP-1 as a link between postprandial state and diabetes complications, however further mechanistic studies on larger population of patients with T2D are needed for confirmation of these results.

Introduction: Growing evidence indicates that circulating concentrations of insulin-like growth factor 1 (IGF-I), along with IGF-I relative to IGF-binding proteins (IGFBP), are associated with an increased risk of cancer. In accord, regular exercise is linked with a lower risk of cancer. Purpose: To assess the effects of a 16-week home-based strength training (HBST) program on serum IGF-I, IGFBP-1 and IGFBP-3. Methods: A total of 32 obese Latino adolescent males (aged 14–18 years) were randomized into a twice-weekly HBST (n = 16) or a control group (C, n = 16) for 16 weeks. The following were measured at pre- and post-intervention: IGF-I, IGFBP-1 and IGFBP-3, glucose/insulin indices by oral and/or intravenous (IV) glucose tolerance tests, strength by one-repetition maximum (1RM), dietary intake by 3-d records, body composition by DEXA and physical activity using the Actigraph GT1X. The generalized linear model (GLM) was used to assess differences in changes among outcome measures between the HBST and C groups. Results: Exercise adherence in the HBST group was 89%. IGF-1 showed a trend for significant within-subject improvements (p = 0.078) but no significant within-subject or between-subject differences for IGFBP-1, IGFBP-3 two-glucose, fasting glucose or 2-h glucose (p > 0.05). There was a significant decrease (p > 0.05) in fasting glucose in the C group (p = 0.02) and also in the intervention group (p = 0.03) between baseline and follow-up testing. A significant difference was also found in the C group for 2-h glucose with an increase at follow-up testing (p = 0.04). Conclusions: Though not statistically significant (p < 0.05), the results indicated that a 16-week HBST program decreased IGF-I and increased IGFBP-1, along with IGFBP-3, concentrations among overweight/obese Latino boys. However, further studies should consider increasing either the dose or the duration of the intervention to elicit greater improvements in this at-risk pediatric population. [ABSTRACT FROM AUTHOR]

G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMP-activated protein kinase (AMPK)-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased GPER1-mediated and tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] may increase breast cancer cell sensitivity to tamoxifen. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that modifies one aspect tamoxifen action in breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: We investigated the impact of fish oil and/or probiotics on serum and vaginal inflammatory and metabolic proteins and their relation to the onset of gestational diabetes mellitus (GDM). Methods: Overweight/obese pregnant women received fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo from early pregnancy until six months postpartum (fish oil: 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid; probiotics: Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each). Serum high sensitivity C-reactive protein (hsCRP) and serum/vaginal (s/v) phosphorylated insulin-like growth factor binding-protein-1 (phIGFBP-1), IGFBP-1 and matrix metalloproteinase 8 (MMP-8) were analyzed. GDM was diagnosed according to 2 h 75 g OGTT. Results: The intervention had no impact on the change in proteins during pregnancy. Nevertheless, s-MMP-8 decreased and s-IGFBP-1 increased more in obese than in overweight women in the fish oil + probiotics group, while a decrease in s-MMP-8 was seen in obese women and an increase was seen in overweight women in the probiotics + placebo group. The late pregnancy s-phIGFBP-1 was higher in women who developed GDM in fish oil + probiotics-group compared to fish oil + placebo-group. The concentrations of s-phIGFBP-1 (635.9 ± 315.3 ng/mL vs. 753.2 ± 335.1 ng/mL, p = 0.005) and s-IGFBP-1 (3.78 ± 0.72 ng/mL vs. 3.96 ± 0.69 ng/mL, p = 0.042) were lower in early pregnancy in women who developed GDM than in women remaining healthy. Conclusions: The intervention per se had no impact on the proteins, but obesity and GDM may modify the effect. IGFBPs may affect the development of GDM.

Background: The insulin-like growth factor (IGF) signaling system plays a major role in development and progression of various malignancies including ovarian cancer, and its components are considered as potential diagnostic and prognostic markers and the objects of molecular targeted therapy.Aim: Comparative evaluation of IGF-I and IGF-II, and IGF-binding proteins (IGFBP)-1, 2 and 3 content in blood serum and tumors of ovarian tumor patients, analysis of their associations with key clinical pathologic characteristics of ovarian cancer and evaluation of clinical value of these markers for disease diagnostics and prognosis.Materials and methods: IGF-I, II, IGFBP-1, 2 and 3 levels were measured with standard ELISA kits (Mediagnost, Germany) in blood serum and tumor extracts of 74 patients with ovarian cancer, 16 patients with benign and 14 with borderline ovarian tumors. The control group comprised 77 healthy women. Results: Three potential serological markers of ovarian cancer, namely IGF-I, IGFBP-1, and IGFBP-2 were revealed. The best sensitivity to specificity ratio was demonstrated for IGFBP-2: at a 370 ng/ml cut-off level, these indices were 87 and 79%, respectively. The diagnostic markers found in our study were also associated with the prognosis of overall survival in ovarian cancer. In the multivariate analysis, low IGF-I serum levels retained its independent unfavorable prognostic value. The disease prognosis is influenced also by IGF-II and IGFBP-1 content in the tumor tissue.Conclusion: In ovarian cancer patients, there is a disbalance of IGFs/IGFBPs. Some components of this system could be potentially used as diagnostic and prognostic markers of the disease.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

Insulin-like growth factors (IGF) 1 and 2 and IGF binding proteins (IGFBP) 1 and 3 levels were measured by ELISA techniques in blood serum of 74 primary colorectal cancer (СRC) patients and 30 control practically healthy persons. Significant increase of IGF-1 level and decrease of IGFBP-3 level were demonstrated in patients’ serum as compared to control group. Sensitivity of IGF-1 as a prospective diagnostic СRС marker comprised 80 % with 75 % specificity using 140 ng/ml as cut-off level. Significant negative association was found be-tween both patients and donors’ age and serum IGF-1 levels, but in CRC patients it was much weaker than in control group. No associations were found between serum IGF 1 and 2 levels and main criteria of colorectal cancer progression.

Purpose: High‐mobility group N (HMGN) proteins are the only non‐histone proteins that specifically bind within the nucleosome between core histones and DNA. Among them, HMGN5 is one of the candidates that could participate in mouse endometrial decidualization; however, the specific role of HMGN5 remains to be clarified in human endometrial stromal cells (HESCs). Methods: Primary HESCs were isolated from hysterectomy specimens and incubated with or without 8‐bromo‐cyclic adenosine monophosphate (8‐br‐cAMP) and medroxyprogesterone acetate (MPA). Results: We demonstrated that HMGN5 expression in decidualized HESCs stimulated by 8‐br‐cAMP and MPA decreased significantly. The inhibition of HMGN5 expression by small interfering RNA (siRNA) induced the major decidual marker genes expression, including IGFBP1 (insulin‐like growth factor binding protein 1) and PRL (prolactin). In addition, microRNA‐542‐3p (miR‐542‐3p), which was identified as a regulatory miRNA of IGFBP1 during decidualization, was significantly suppressed by HMGN5 siRNA. However, the expression of HMGN5 was not alternated by miR‐542‐3p overexpression. Conclusions: These findings suggest that the down‐regulation of HMGN5 plays a role in the promotion of human endometrial stromal decidualization and acts upstream of miR‐542‐3p. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to measure changes of insulin-like growth factor binding protein-1 (IGFBP-1) in patients with type 2 diabetes mellitus (T2D) following gastric bypass surgery.Methods: A total of 10 patients with T2D underwent laparoscopic Roux-en-Y gastric bypass (RYGB) surgery. Patient height, weight, waist circumference, and hip circumference were measured pre- and post-operatively at 6 months after surgery. Serum samples were collected at 6 months after surgery to determine fasting blood glucose, glycosylated Hb, fasting insulin, C-peptide, and 2-h postprandial blood glucose, insulin, and C-peptide. Serum was collected at 3 days and 6 months after surgery and IGFBP-1 level determined using ELISA. Serum samples were also collected from 30 healthy weight subjects and 27 overweight control subjects.Results: Body weight, BMI, and waist circumference were significantly improved following RYGB surgery. Blood glucose, fasting blood glucose, 2-h postprandial blood glucose, and HbA1c were also significantly improved. Fasting C-peptide and 2-h postprandial C-peptide were non-significantly reduced. Serum IGFBP-1 significantly increased at 3 days and 6 months after RYGB surgery. Pre-operative serum IGFBP-1 was not significantly different from healthy weight subjects or overweight subjects.Conclusion: Increased serum level of IGF-binding proteins after RYGB in 6 months is increased post-surgery compared with overweight and healthy weight controls. IGFBP-1 may serve as part of new supplementary criteria for surgical selection and for defining the success of RYGB. [ABSTRACT FROM AUTHOR]

Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) are used in tissue repair and regeneration; however, the mechanisms involved are not well understood. We investigated the hair growth-promoting effects of hUCB-MSCs treatment to determine whether hUCB-MSCs enhance the promotion of hair growth. Furthermore, we attempted to identify the factors responsible for hair growth. The effects of hUCB-MSCs on hair growth were investigated in vivo, and hUCB-MSCs advanced anagen onset and hair follicle neogeneration. We found that hUCB-MSCs coculture increased the viability and up-regulated hair induction-related proteins of human dermal papilla cells (hDPCs) in vitro. A growth factor antibody array revealed that secretory factors from hUCB-MSCs are related to hair growth. Insulin-like growth factor binding protein-1 (IGFBP-1) and vascular endothelial growth factor (VEGF) were increased in co-culture medium. Finally, we found that IGFBP-1, through the colocalization of an IGF-1 and IGFBP-1, had positive effects on cell viability; VEGF secretion; expression of alkaline phosphatase (ALP), CD133, and ß-catenin; and formation of hDPCs 3D spheroids. Taken together, these data suggest that hUCB-MSCs promote hair growth via a paracrine mechanism. [ABSTRACT FROM AUTHOR]

Background: A major pathway through which obesity increases the risk of cardiometabolic diseases and cancer is by inducing hormonal and metabolic abnormalities, including hyperinsulinemia and altered insulin-like growth factor (IGF) signaling. However, little is known about the influence of lifetime adiposity on the relevant biomarkers. Objective: The aim of this study was to examine associations of trajectories of body fatness with plasma biomarker concentrations of the insulin-IGF system in 2 large prospective cohorts of US men and women. Design: Associations between trajectories of body fatness and concentrations of plasma C-peptide, IGF-I, IGF-binding protein (IGFBP) 1, IGFBP-3, and the IGF-I-to-IGFBP-3 molar ratio was examined in 9386 women of the Nurses' Health Study and 3941 men of the Health Professionals Follow-Up Study.Group-based trajectory modeling was used to create trajectory groups on the basis of self-reported somatotype data at ages 5, 10, 20, 30, and 40 y and body mass index (BMI) at ages 45, 50, 55, and 60 y. We used multivariate linear regression models to examine the associations of trajectories with biomarker concentrations. Results: Five trajectories of body fatness were identified: "leanstable," "lean-moderate increase," "lean-marked increase," "medium-stable/increase," and "medium-marked increase." Compared with the lean-stable group, the lean-marked increase and medium-marked increase groups had significantly higher concentrations of C-peptide (percentage difference-women: 44% and 73%; men: 27% and 51%) and lower concentrations of IGFBP-1 (women: -61% and -78%; men: -47% and -65%). Adjustment for current BMI attenuated the association to null for the medium- marked increase group, but the lean-marked increase group still had modestly higher concentrations of C-peptide (women: 10%; men: 6%) and lower concentrations of IGFBP-1 (women: -18%; men: -21%) than the lean-stable group. Conclusions: Adiposity across the life span was associated with higher C-peptide and lower IGFBP-1 concentrations in adulthood. The associations were largely driven by attained adiposity and, to a lesser extent, weight gain in early-middle adulthood. [ABSTRACT FROM AUTHOR]

Objectives Obese children are often taller than age-matched subjects. Reports on GH and IGF-I levels in obese individuals are controversial, with normal and reduced GH-IGF-I levels having been reported in this group of patients. Thus, the aim of this study was to analyse insulin-like growth factor type 1 receptor (IGF-IR) mRNA expression in obese children. Methods Forty-seven pre-pubertal children were included in this study: 29 were obese and taller than their target height, and 18 were normal eutrophic controls. Fasting blood samples were collected for IGF-IR mRNA expression in isolated lymphocytes and serum IGF-I, ALS, IGFBP-3, and IGFBP-1 concentration analysis. Results Relative IGF-IR gene expression (2 − ΔΔ C T ) was significantly ( P = 0.025) higher in obese children (median 1.87) than in controls (1.15). Fourteen of the 29 obese subjects showed 2 − ΔΔ C T values greater than or equal to 2, while only 2 individuals in the control group showed values above 2 ( P = 0.01). Obese children showed significantly ( P = 0.01) higher IGF-I concentrations than the control group (237 ng/ml and 144 ng/ml, respectively). Among obese patients, 65.5% had IGF-I values above the 75 percentile of the control group ( P = 0.02). ALS concentration was significantly ( P = 0.04) higher in the obese group, while IGFBP-3 levels were similar in obese and control children. IGFBP-1 concentration was lower in obese children, while insulin levels and HOMA-IR index were higher than in controls. Conclusions The higher IGF-IR mRNA expression observed in obese children, associated with the higher IGF-I and ALS and the lower IGFBP-1 levels, suggest that the higher stature observed in these children may be due to increased IGF-I bioactivity. [ABSTRACT FROM AUTHOR]

The Chinese alligator Alligator sinensis (Fauvel, 1879) is an endangered species endemic to China. Up to this date, very little is known about the regulation of its growth and development. Insulin-like growth factor binding protein-1 (IGFBP-1) plays essential roles in regulating vertebrate growth and development by modulating IGFs action. In this study, we cloned the full-length cDNA of Chinese alligator IGFBP-1 (caIGFBP-1) for the first time, which has an open reading frame (ORF) of 885-bp nucleotides encoding a peptide of 294 amino acid residues. The caIGFBP-1 contains all features of IGFBP-1 peptide with the conserved cysteine-rich N- and C-terminal domains and variable central L-domain. Multiple alignment analysis showed that caIGFBP-1 shares high identity in amino acid sequence with the IGFBP-1 s of American alligator Alligator mississippiensis (Daudin, 1802) (99.32%) and birds (66.32-74.53%). Phylogenetic tree analysis of IGFBP-1 amino acid sequences indicated that alligators cluster into bird branch. The caIGFBP-1 is widely expressed in all the examined tissues, the expression level is highest in liver, higher in kidney, moderate in pancreas, stomach, small intestine, and lower in ovary, muscle, lung, heart. During the hibernating period, the expression level of caIGFBP-1 was significantly reduced in liver, kidney, stomach, pancreas and small intestine, while did not significantly change in heart, lung, ovary and muscle. The caIGFBP-1 mRNA expression changes during the active and hibernating periods, which coincides with that of Chinese alligator IGF, implicating that it might play important roles in the IGF-mediated growth and development of Chinese alligator. [ABSTRACT FROM AUTHOR]

The possibility of using the endometrial cell line as a model for studying the pharmacological activity of progesterone analogues is considered. Conditions for obtaining and culturing of endometrial cell lines are described, the morphological characteristic is given, and the immunophenotypic profile, karyotype, and expression of progesterone and estrogen receptors are presented. Not all studied endometrial lines showed the ability to decidualize cells under the action of hormonal inducers (combinations of estradiol with progesterone and its analogues). It appeared that lines sensitive to hormones are able to increase the secretion of specific markers of decidualization under the action of highly active gestagenes (progesterone analogues) to a greater extent than under action of progesterone. These data are a basis for further development of the cellular model for studying the pharmacological activity of gestagenic compounds. [ABSTRACT FROM AUTHOR]

Background and aims:Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3–4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD. Methods:Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3–4). Results:Patients with advanced fibrosis (stage 3–4 vs. 0–2) had lower IGF-SD (−1.17 vs. 0.11,p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l,p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0–1.07,p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44–0.92,p = .02). Conclusions:This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed. [ABSTRACT FROM PUBLISHER]

Purpose: To determine values of combinations of interleukin-6 (IL-6)/cervical native insulin-like growth factor-binding protein-1 (IGFBP-1)/total IGFBP-1 (Premaquick©) in predicting spontaneous deliveries and spontaneous exclusive preterm deliveries in women with threatened preterm labor. Methods: Women with singleton pregnancies between gestation age (GA) of 24 weeks and 36 weeks and 6 days with preterm labor were recruited during a prospective multicenter study. Premaquick© was positive when at least two of three biomarkers were positive. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were estimated for both prediction of spontaneous deliveries and spontaneous exclusive preterm deliveries. Results: Ninety-seven (99.0%) out of 98 women enrolled were analyzed. Based on delivery status 7/14 days postenrollment of general study population, Premaquick© had a sensitivity of 87.1/85.7%, a specificity of 92.4/96.8%, a PPV of 84.4/93.8% and a NPV of 93.9/92.3% for prediction of spontaneous delivery. Predictive accuracy of Premaquick © test in relation to days of enrollment were: 90.7% (≤ 7 days) and 92.8% (≤ 14 days). For women enrolled at GA < 35 weeks, Premaquick© had a sensitivity of 100.0/87.5%, a specificity of 94.1/96.9%, a PPV of 70.5/87.5%, a NPV of 100.0/96.9% and an accuracy of 95.0/95.0% for prediction of preterm delivery within 7/14 days of enrollment, respectively. PPV was most significantly different in both groups when outcomes were compared between 2 days and 14 days post-enrollment (P < 0.001). Conclusion: This novel triple biomarker model of native and total IGFBP-1 and IL-6 appears to be an accurate test in predicting spontaneous deliveries and spontaneous exclusive preterm deliveries in threatened preterm labor in singleton pregnancies. [ABSTRACT FROM AUTHOR]

Diabetes is one of the global health threat. Type 2 Diabetes mellitus (T2DM) is associated with life-threatening complications. This work, aimed to study the association between T2DM and IGFBP-1 gene methylation, gene polymorphism and serum levels of IGFBP-1. We included 100 subjects with T2DM and 100 control. DNA methylation of IGFBP-1 was analyzed using pyrosequencing, IGFBP-1 gene polymorphism was analyzed using real time polymerase chain reaction and serum level of IGFBP-1 was measured by ELISA. There was DNA hyper methylation levels of IGFBP1 gene at each of the six CpG sites in T2DM patients than control (P < 0.001). IGFBP-1 gene polymorphism (rs 2854843) CC pattern was significantly associated with DM, P = 0.002. Also, there was decrease in serum IGFBP-1 in patients with T2DM than control group (P < 0.001). We concluded that DNA hyper methylation of IGFBP-1 gene and CC polymorphism (rs 2854843) of IGFBP-1 gene are associated with T2DM in Egyptian patients, also, decrease serum level of IGFBP-1. Further cohort study is recommended with large sample size to detect which one, epigenetic changes or polymorphism of IGFBP-1 gene, is the cause of T2DM or even both. [ABSTRACT FROM AUTHOR]

Ultra-endurance competitions are becoming increasingly popular but there is limited research on female participants. The purpose of this study was to examine changes in estrogen and the IGF-I system in women after an ultra-marathon. Six pairs of pre- and post- menopausal women were matched for race finish times;mean finish time was 20 hours. Blood samples were drawn 24 hours before the race, at the finish, and 24 hours into recovery. Samples were analysed for estradiol, total IGF-I, IGFBP-1, and intact IGFBP-3. There was a significant increase in estradiol following the race in both groups (P

Variable individual growth rate is a phenomenon observed in fish cohorts that influences the aquaculture performance and fish cohort ecological viability. Our aim was to compare gene expression patterns of key growth genes in zebrafish larvae with different growth rate. The body length of sibling zebrafish larvae at 6 days post hatching (dph) was measured. The larvae were reared to 20 dph and measured again. Two body-length groups were clearly observed: 4 mm (small larvae) and 5-6 mm (large larvae). Total RNA was isolated from both groups. Growth hormone (gh), growth hormone receptor (ghr), insulin-like growth factor 1 (igf-1), insulin-like growth factor receptor (igf-1r a/b), insulin-like growth factor binding protein 1 (igfbp-1), thyroglobulin (tg), cholecystokinin (cck), and ghrelin were evaluated by quantitative polymerase chain reaction (qPCR). Glucokinase (gck) and igfbp-1 were included as a gene expression marker of larvae nutritional status. Two genes showed significant differences between the body length groups, igfbp-1 (P = 0.01) and igf-1r (P = 0.02). The igfbp-1 suggests than growth rate variability was associated with the larvae nutritional status and this condition affect the gene expression pattern of igf-1r. Therefore these genes are interesting genes markers for growth rate variabilities studies. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor binding protein-1 (IGFBP-1), a secreted protein, implicated of various cells in mediating the proliferation, migration, invasion, adhesion, survival and so on. In this study, we assessed the expression and release of IGFBP-1 from gastric cancer cells with H. pylori 2669 5 infection and the biological functions of IGFBP-1 in gastric cancer cells. The results showed that the expression and release of IGFBP-1 were increased in gastric cancer cells (MGC-803, BGC-823, SGC-7901) infected with H. pylori 26695. In addition, the upregulation of IGFBP-1 was dose-dependent in BGC-823 cells infected with H. pylori 26695 but not time-dependent. The upregulation of IGFBP-1 got to peak at 12 h after H. pylori 26695 infection and then decreased over time. Subsequently, we measured its functions by silencing and overexpressing IGFBP1 which suggested that overexpression of IGFBP-1 could inhibit the migration of BGC-823 and SGC-7901 cells. However, knocking down the IGFBP-1 could increase the migration of BGC-823 and SGC-7901 cells. Functional findings illustrated that IGFBP-1 was implicated in H. pylori 26695-induced MMP-9 expression in BGC-823 cells. In addition, overexpressing IGFBP1 reduce the promoting effect of MMP-9 on the BGC-823 cells migration. In summary, we demonstrated that IGFBP-1 suppress the migration of BGC-823 cells and play a protective role in the process of H. pylori -induced gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic gastric bypass (LGB) abruptly causes remission of type 2 diabetes (T2D). Such dramatic metabolic changes have previously been found to cause worsening of diabetic retinopathy (DR) and circulating insulin-like growth factor I (IGF-I) has been suggested as a causal mediator. We aimed to evaluate baseline imbalances in the circulating IGF-system and changes after LGB in patients with T2D. Methods: Prospective ocular examinations and measurement of the IGF-axis before and 3 and 12 months after LGB. IGF-bioactivity was measured by cell-based IGF-I receptor (IGF-IR) kinase activation assay (bioactive IGF). Total IGF-I, IGF-II and IGF binding protein (IGFBP) 1 and 3 were determined by immunoassays. Results: At baseline, 18 of 36 patients presented with DR. These patients had higher levels of bioactive IGF ( p = 0.03) than patients without DR and this association was strengthened in multivariate analysis ( p = 0.006). Three patients had worsening of DR, unrelated to other markers. In univariate analysis, bioactive IGF increased at 3 months ( p = 0.05) but this change became insignificant in multivariate analysis ( p = 0.11). IGFBP-1 increased whereas IGFBP-3 and total IGF-II decreased at the two postoperative visits ( p ≤ 0.001). Total IGF-I showed no significant changes. HbA1c, glucose, HOMA-IR and lipids improved after surgery. Two patients did not complete the 12-month visit. Conclusions: In obese T2D patients, bioactive IGF is a potential biomarker for DR and levels tended to increase 3 months after bariatric surgery. IGFBP-1 increased while IGFBP-3 and total IGF-II decreased postoperatively, but these changes were unassociated with the development of DR. Markers of the metabolic syndrome improved. [ABSTRACT FROM AUTHOR]

Fibrinogen and insulin-like growth factor-binding protein-1 (IGFBP-1) are tightly connected to metabolic changes and complications in patients with diabetes mellitus (DM), and since they mutually interact to form complexes in plasma, we investigated whether and to what extent IGFBP-1/fibrinogen complexes change due to glyco-oxidative processes in DM and whether they participate in fibrin clot formation. These complexes were determined by immunoblotting in plasma samples from healthy adults and patients with DM type 2 (DM2). The influence of glyco-oxidationin vitroon the complexes was also investigated. Amounts of IGFBP-1/fibrinogen complexes in plasma from patients with DM2 were slightly but not significantly lower than in healthy persons. Such complexes in patients’ samples participated in fibrin clot formation to a significantly decreased extent.In vitroexperiments with glucose or methylglyoxal (MGO) as reactive agents demonstrated that the complexes underwent glyco-oxidative modification leading to reduced formation and/or stability. Extensively oxidized fibrinogen almost completely lost its ability to bind IGFBP-1. The reduced affinity of fibrinogen for IGFBP-1 accompanying diabetes may potentially shift the equilibrium to liberate more IGFBP-1 (and possibly insulin-like growth factor (IGF)-I) able to activate platelets during coagulation, so contributing to the hypercoagulation state together with other factors. This hypothesis, however, needs further examination. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-binding protein 1 (IGFBP-1) is a member of a family of six homologous proteins that regulate the action of the insulin-like growth factors. IGFBP-1 is a 25 kDa protein that beside its native form, may exist in several phosphoforms (30 kDa), which are predominant in the circulation of humans. Phosphorylation of IGFBP-1 is a post-translational modification that has a great influence on the IGF-I action. IGFBP-1 forms multimers and complexes with α2-macroglobulin (α2M). Polymerisation of IGFBP-1 was also reported. In order to analyse and separate these IGFBP-1 molecular species, affinity chromatography methods were used in this study. The results demonstrated that most of the IGFBP-1 circulates in complexes with α2M, which can be isolated by affinity chromatography using immobilised anti-α2M antibodies. IGFBP- 1/α2M complexes may be differentiated from IGFBP-1 dimer and multimers using lectin-affinity chromatography, since the latter do not interact with lectins. It seems that the complexes contain not only monomeric IGFBP-1, but also its multimers. Dimer and multimers are stable under reducing conditions, suggesting covalent linkage between units. Free IGFBP-1 monomer can be separated from multimers using Con A-affinity chromatography. The concentration of free IGFBP-1 is relatively low in the circulation.