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Czogała, Wojciech, Wojciech Strojny, Przemysław Tomasik, Mirosław Bik Multanowski, Małgorzata Wójcik, Klaudia Miklusiak, Emil Krzysztofik, Albert Wróbel, Karol Miklusiak, and Szymon Skoczeń. "The Insight into Insulin-Like Growth Factors and Insulin-Like Growth-Factor-Binding Proteins and Metabolic Profile in Pediatric Obesity." Nutrients 13, no. 7 (July 15, 2021): 2432. http://dx.doi.org/10.3390/nu13072432.
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Insulin-like growth factors (IGFs) and insulin-like growth-factor-binding proteins (IGFBPs) regulate cell proliferation and differentiation and may be of importance in obesity development. The aim of the study was to analyze the expression of chosen IGF-axis genes and the concentration of their protein products in 28 obese children (OB) and 34 healthy control (HC), and their correlation with essential parameters associated with childhood obesity. The gene expression of IGFBP7 was higher, and the expression of IGF2 and IGFBP1 genes was lower in the OB. The expression of IGFBP6 tended to be lower in OB. IGFBP4 concentration was significantly higher, and IGFBP3 tended to be higher in the OB compared to the HC, while IGFBP1, IGFBP2, and IGFBP6 were significantly lower, and IGFBP7 tended to be lower in OB. We found numerous correlations between IGFs and IGFBP concentration and obesity metabolic parameters. IGFBP6 correlated positively with apelin, cholecystokinin, glucagone-like peptide-1, and leptin receptor. These peptides were also significantly lower in obese children in our study. The biological role of decreased levels of IGFBP6 in obese children needs further investigation.
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Zhong, Zhenglan, Xiaoping Xu, Shiguo Han, Yongxiang Shao, and Yong Yi. "Comprehensive Analysis of Prognostic Value and Immune Infiltration of IGFBP Family Members in Glioblastoma." Journal of Healthcare Engineering 2022 (July 4, 2022): 1–13. http://dx.doi.org/10.1155/2022/2929695.
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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The insulin-like growth factor-binding protein (IGFBP) family is involved in tumorigenesis and the development of multiple cancers. However, little is known about the prognostic value and regulatory mechanisms of IGFBPs in GBM. Oncomine, Gene Expression Profiling Interactive Analysis, PrognoScan, cBioPortal, LinkedOmics, TIMER, and TISIDB were used to analyze the differential expression, prognostic value, genetic alteration, biological function, and immune cell infiltration of IGFBPs in GBM. We observed that IGFBP1, IGFBP2, IGFBP3, IGFBP4, and IGFBP5 mRNA expression was significantly upregulated in patients with GBM, whereas IGFBP6 was downregulated; this difference in mRNA expression was statistically insignificant. Subsequent investigations showed that IGFBP4 and IGFBP6 mRNA levels were significantly associated with overall survival in patients with GBM. Functional Gene Ontology Annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that genes coexpressed with IGFBP4 and IGFBP6 were mainly enriched in immune-related pathways. These results were validated using the TIMER and TSMIDB databases. This study demonstrated that the IGFBP family has prognostic value in patients with GBM. IGFBP4 and IGFBP6 are two members of the IGFBP family that had the highest prognostic value; thus, they have the potential to serve as survival predictors and immunotherapeutic targets in GBM.
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Zheng, Ruoyi, Wenming Chen, Weiting Xia, Jingyu Zheng, and Qing Zhou. "The Prognostic Values of the Insulin-Like Growth Factor Binding Protein Family in Ovarian Cancer." BioMed Research International 2020 (November 16, 2020): 1–15. http://dx.doi.org/10.1155/2020/7658782.
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Purpose. To assess the expression of insulin-like growth factor binding protein (IGFBP) family and its prognostic impact in ovarian cancer (OC) patients. Materials and Methods. The mRNA expression and protein expression of individual IGFBPs in healthy ovarian samples and OC tissues were explored through Oncomine, Gene Expression Profiling Interactive Analysis, and Human Protein Atlas database. Additionally, the prognostic values of the six IGFBP members in patients with OC were evaluated by Kaplan-Meier plotter. Results. IGFBP2 and IGFBP4 mRNA expression were remarkably upregulated in patients with OC. To be specific, the mRNA expression of IGFBP2 was upregulated in patients with serous ovarian cancer (SOC), while IGFBP1/3/4/5/6 mRNA levels were downregulated. In addition, the IGFBP4 protein expression was upregulated in SOC, and the IGFBP6 protein expression was upregulated in both of SOC and endometrioid ovarian cancer (EOC) tissues. High IGFBP1 mRNA levels showed favorable overall survival (OS) and progression-free survival (PFS) in all OC. Meanwhile, increased IGFBP5/6 mRNA levels revealed worsen OS and PFS in all OC patients. IGFBP4/6 mRNA levels predicted unfavorable OS and PFS only in SOC patients. Moreover, the aberrant mRNA expression of IGFBP1/2/4/5/6 was correlated with significantly prognosis in patients receiving different chemotherapeutic regimens. Conclusion. This study indicates that the IGFBP family reveals distinct prognosis in patients with OC. IGFBP1/2/4/5/6 are useful prognostic predictors for chemotherapeutic effect in OC patients, and IGFBP2/4 are potential tumor markers for the diagnosis of OC.
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Minchenko, Dmytro O., D. O. Tsymbal, O. P. Yavorovsky, N. V. Solokha, and O. H. Minchenko. "Expression of genes encoding IGFBPs, SNARK, CD36, and PECAM1 in the liver of mice treated with chromium disilicide and titanium nitride nanoparticles." Endocrine Regulations 51, no. 2 (April 25, 2017): 84–95. http://dx.doi.org/10.1515/enr-2017-0008.
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AbstractObjective. The aim of the present study was to examine the effect of chromium disilicide and titanium nitride nanoparticles on the expression level of genes encoding important regulatory factors (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, SNARK/NUAK2, CD36, and PECAM1/CD31) in mouse liver for evaluation of possible toxic effects of these nanoparticles.Methods. Male mice received 20 mg chromium disilicide nanoparticles (45 nm) and titanium nitride nanoparticles (20 nm) with food every working day for 2 months. The expression of IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, SNARK, CD36, and PECAM1 genes in mouse liver was studied by quantitative polymerase chain reaction.Results. Treatment of mice with chromium disilicide nanoparticles led to down-regulation of the expression of IGFBP2, IGFBP5, PECAM1, and SNARK genes in the liver in comparison with control mice, with more prominent changes for SNARK gene. At the same time, the expression of IGFBP3 and CD36 genes was increased in mouse liver upon treatment with chromium disilicide nanoparticles. We have also shown that treatment with titanium nitride nanoparticles resulted in down-regulation of the expression of IGFBP2 and SNARK genes in the liver with more prominent changes for SNARK gene. At the same time, the expression of IGFBP3, IGFBP4, and CD36 genes was increased in the liver of mice treated with titanium nitride nanoparticles. Furthermore, the effect of chromium disilicide nanoparticles on IGFBP2 and CD36 genes expression was significantly stronger as compared to titanium nitride nanoparticles.Conclusions. The results of this study demonstrate that chromium disilicide and titanium nitride nanoparticles have variable effects on the expression of IGFBP2, IGFBP3, IGFBP4, IGFBP5, SNARK, CD36, and PECAM1 genes in mouse liver, which may reflect the genotoxic activities of the studied nanoparticles.
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Rehman, Muhammad Saif-ur, Muqeet Mushtaq, Faiz-ul Hassan, Zia-ur Rehman, Muhammad Mushahid, and Borhan Shokrollahi. "Comparative Genomic Characterization of Insulin-Like Growth Factor Binding Proteins in Cattle and Buffalo." BioMed Research International 2022 (July 25, 2022): 1–15. http://dx.doi.org/10.1155/2022/5893825.
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The somatotropic axis consists of genes associated with economic traits like muscle growth and carcass traits in livestock. Insulin-like growth factor binding proteins (IGFBPs) are the major proteins that play a vital role in the somatotropic axis. The present study performed a genome-wide characterization of IGFBP genes in cattle. Genomic sequences of the IGFBP gene family for different mammals (cattle, buffalo, goat, and sheep) were recovered from the NCBI database. Sequence analyses were performed to investigate cattle’s genomic variations in the IGFBP gene family. Phylogenetic analysis, gene structure, motif patterns, and conserved domain analysis (CDA) of the IGFBP family revealed the evolutionarily conserved nature of the IGFBP genes in cattle and other studied species. Physicochemical properties of IGFBP proteins in cattle revealed that most of these proteins are unstable, hydrophilic, thermostable, and acidic. Comparative amino acid analysis revealed variations in all protein sequences with single indels in IGFBP3 and IGFBP6. Mutation analysis revealed only one nonsynonymous mutation D212 > E in the IGFBP6 protein of cattle. A total of 245 nuclear hormone receptor (NHRs) sites were detected, including 139 direct repeats (DR), 65 everted repeats (ER), and 41 inverted repeats (IR). Out of 133 transcription factors (TFs), 10 TFs (AHR, AHRARNT, AP4, CMYB, E47, EGR2, GATA, SP1, and SRF) had differential distribution ( P value < 0.05) of putative transcriptional binding sites (TFBS) in cattle compared to buffalo. Synteny analysis revealed the conserved nature of genes between cattle and buffalo. Two gene pairs (IGFBP1/IGFBP3 and IGFBP2/IGFBP5) showed tandem duplication events in cattle and buffalo. This study highlights the functional importance of genomic variation in IGFBP genes and necessitates further investigations better to understand the role and mechanisms of IGFBPs in bovines.
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Simmons, Rebecca M., David W. Erikson, Jinyoung Kim, Robert C. Burghardt, Fuller W. Bazer, Greg A. Johnson, and Thomas E. Spencer. "Insulin-Like Growth Factor Binding Protein-1 in the Ruminant Uterus: Potential Endometrial Marker and Regulator of Conceptus Elongation." Endocrinology 150, no. 9 (June 4, 2009): 4295–305. http://dx.doi.org/10.1210/en.2009-0060.
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Abstract Establishment of pregnancy in ruminants requires conceptus elongation and production of interferon-τ (IFNT), the pregnancy recognition signal that maintains ovarian progesterone (P4) production. These studies determined temporal and spatial alterations in IGF binding protein (IGFBP)-1 and IGFBP3 in the ovine and bovine uterus; effects of P4 and IFNT on their expression in the ovine uterus; and effects of IGFBP1 on ovine trophectoderm cell proliferation, migration, and attachment. IGFBP1 and IGFBP3 were studied because they are the only IGFBPs specifically expressed by the endometrial luminal epithelia in sheep. In sheep, IGFBP1 and IGFBP3 expression was coordinate with the period of conceptus elongation, whereas only IGFBP1 expression was coordinate with conceptus elongation in cattle. IGFBP1 mRNA in the ovine endometria was between 5- and 29-fold more abundant between d 12 and 16 of pregnancy compared with the estrous cycle and greater on d 16 of pregnancy than nonpregnancy in the bovine uterus. In sheep, P4 induced and IFNT stimulated expression of IGFBP1 but not IGFBP3; however, the effect of IFNT did not mimic the abundant increase observed in pregnant ewes. Therefore, IGFBP1 expression in the endometrium is regulated by another factor from the conceptus. IGFBP1 did not affect the proliferation of ovine trophectoderm cells in vitro but did stimulate their migration and mediate their attachment. These studies reveal that IGFBP1 is a common endometrial marker of conceptus elongation in sheep and cattle and most likely regulates conceptus elongation by stimulating migration and attachment of the trophectoderm.
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Fouque, D., Y. Le Bouc, M. Laville, F. Combarnous, M. O. Joly, P. Raton, and P. Zech. "Insulin-like growth factor-1 and its binding proteins during a low-protein diet in chronic renal failure." Journal of the American Society of Nephrology 6, no. 5 (November 1995): 1427–33. http://dx.doi.org/10.1681/asn.v651427.
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The effects of a low-protein diet on the serum insulin-like growth factor (IGF)-1 and IGF binding proteins (IGFBP) were investigated during a 3-month controlled study in 12 adult chronic renal failure patients. Six patients were randomly supplemented with keto acids (Cetolog, Clintec, Velizy, France). Protein intake was prescribed so that both groups were isonitrogenous. Dietary survey included a monthly 3-day food record and a 24-h urinary urea measurement. After a 4- to 6-wk equilibrium period (1.11 g of protein, 32 kcal/kg body wt per day), patients reduced their protein intake to 0.71 g protein/kg body wt per day. Energy intake was kept constant (31 kcal/kg body wt per day) during the 3-month period. Serum IGF-1 levels were in normal range and, for 11 of the 12 patients, were correlated with the GFR (P = 0.01). These serum IGF-1 values did not decrease after reducing the protein intake. By Western ligand blotting, serum IGFBP1, IGFBP2, and IGFBP4 levels were significantly higher than normal adults, whereas the IGFBP3 level was not increased. IGFBP were not modified when protein intake was reduced. The IGFBP1 level was elevated despite a normal insulin level. IGFBP4 changes were inversely correlated with IGF-1 variations. There was no difference between groups receiving or not receiving the keto acids. Thus, in adult chronic renal failure, reducing protein intake by 40% did not modify the growth hormone/IGF-1/IGFBP axis.
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Alterki, Abdulmohsen, Eman Al Shawaf, Irina Al-Khairi, Preethi Cherian, Devarajan Sriraman, Maha Hammad, Thangavel A. Thanaraj, et al. "The Rise of IGFBP4 in People with Obstructive Sleep Apnea and Multilevel Sleep Surgery Recovers Its Basal Levels." Disease Markers 2021 (October 4, 2021): 1–9. http://dx.doi.org/10.1155/2021/1219593.
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IGFBP4 is the smallest member of the insulin-like growth factor binding protein family (IGFBP). It is a hepatic protein that plays a role in modulating the activity and bioavailability of IGF-I. The expression of IGFBP4 was found to increase under conditions of hypoxia. Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic episodes of intermittent hypoxia and fragmented sleep. Our aim was to quantify levels of circulating IGFBP1, IGFBP2, IGFBP3, IGFBP4, and IGFBP7 in fasting plasma samples of 69 Kuwaiti participants and explore its correlation with indices of OSA. The quantification was performed using multiplexing assay. The study involved 28 controls and 41 patients with OSA. Levels of circulating IGFBP4 were significantly higher in people with OSA ( 289.74 ± 23.30 ng/ml) compared to the control group ( 217.60 ± 21.74 ng/ml, p = 0.028 ). The increase in IGFBP4 correlated significantly and positively with AHI ( r = .574 , p = .01 ) and AI ( r = .794 , p = .001 ) in people with moderate and severe OSA. There was a significant decline in circulating IGFBP4 after 3 months of surgery ( 225.89 ± 18.16 ng/ml, p = 0.012 ). This was accompanied by a prominent improvement in OSA (AHI 8.97 ± 2.37 events/h, p = 0.001 ). In this study, our data showed a significant increase in circulating IGFBP4 in people with OSA. We also report a significant positive correlation between IGFBP4 and indices of OSA at baseline, which suggests IGFBP4 as a potential diagnostic biomarker for OSA. There was a significant improvement in OSA after 3 months of surgical intervention, which concurred with a significant decline in IGFBP4 levels. Altogether, the detected change suggests a potential link between IGFBP4 and OSA or an OSA-related factor, whereby OSA might play a role in triggering the induction of IGFBP4 expression.
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Alterki, Abdulmohsen, Eman Al Shawaf, Irina Al-Khairi, Preethi Cherian, Devarajan Sriraman, Maha Hammad, Thangavel A. Thanaraj, et al. "The Rise of IGFBP4 in People with Obstructive Sleep Apnea and Multilevel Sleep Surgery Recovers Its Basal Levels." Disease Markers 2021 (October 4, 2021): 1–9. http://dx.doi.org/10.1155/2021/1219593.
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IGFBP4 is the smallest member of the insulin-like growth factor binding protein family (IGFBP). It is a hepatic protein that plays a role in modulating the activity and bioavailability of IGF-I. The expression of IGFBP4 was found to increase under conditions of hypoxia. Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic episodes of intermittent hypoxia and fragmented sleep. Our aim was to quantify levels of circulating IGFBP1, IGFBP2, IGFBP3, IGFBP4, and IGFBP7 in fasting plasma samples of 69 Kuwaiti participants and explore its correlation with indices of OSA. The quantification was performed using multiplexing assay. The study involved 28 controls and 41 patients with OSA. Levels of circulating IGFBP4 were significantly higher in people with OSA ( 289.74 ± 23.30 ng/ml) compared to the control group ( 217.60 ± 21.74 ng/ml, p = 0.028 ). The increase in IGFBP4 correlated significantly and positively with AHI ( r = .574 , p = .01 ) and AI ( r = .794 , p = .001 ) in people with moderate and severe OSA. There was a significant decline in circulating IGFBP4 after 3 months of surgery ( 225.89 ± 18.16 ng/ml, p = 0.012 ). This was accompanied by a prominent improvement in OSA (AHI 8.97 ± 2.37 events/h, p = 0.001 ). In this study, our data showed a significant increase in circulating IGFBP4 in people with OSA. We also report a significant positive correlation between IGFBP4 and indices of OSA at baseline, which suggests IGFBP4 as a potential diagnostic biomarker for OSA. There was a significant improvement in OSA after 3 months of surgical intervention, which concurred with a significant decline in IGFBP4 levels. Altogether, the detected change suggests a potential link between IGFBP4 and OSA or an OSA-related factor, whereby OSA might play a role in triggering the induction of IGFBP4 expression.
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Kharkova, A., D. Minchenko, D. Tsymbal, and O. Minchenko. "Expression of IGFBP1, IGFBP2 and IGF2BP3 genes in U87 glioma cells with suppressed ERN1 signaling enzyme function in glutamine and glucose deprivation conditions." Bulletin of Taras Shevchenko National University of Kyiv. Series: Biology 68, no. 3 (2014): 24–29. http://dx.doi.org/10.17721/1728_2748.2014.68.24-29.
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Insulin-like growth factor binding proteins play an important role in the regulation of cell proliferation and malignant tumor growth. It was shown that blockade of both enzymatic functions of sensor and signaling enzyme ERN1 (from endoplasmic reticulum to nuclei-1), the major component of endoplasmic reticulum stress signaling, decreases the expression level of IGFBP1, IGFBP2 and IGF2BP3 genes in U87 glioma cell. The decreased level of these gene expressions in glioma cells with ERN1 signaling enzyme loss of function correlates with suppression of cell proliferation. It was shown that glutamine deprivation condition leads to enhance the expression of IGFBP1 gene, but did not change significantly the expression of IGFBP2 and IGF2BP3 genes in both types of glioma cells. Moreover, this effect of glutamine deprivation did not depend from suppression of ERN1 enzyme function. At the same time, the expression of IGFBP2 and IGF2BP3 genes is decreased in glucose deprivation condition in both types of glioma cells and blockade of ERN1 signaling enzyme enhanced this effect. Thus, results of this investigation demonstrated that the expression of IGFBP1, IGFBP2 and IGF2BP3 genes in U87 glioma cells is dependent from signaling enzyme ERN1 and is changed in glutamine and glucose deprivation conditions, but only effect of glucose deprivation was depended of ERN1 signaling enzyme function. Moreover, the decreasing of IGFBP1, IGFBP2 and IGF2BP3 gene expressions in glioma cells with blockade of both enzymatic activities of ERN1 is possibly related to suppression of these cells proliferation.
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Al Shawaf, Eman, Mohamed Abu-Farha, Sriraman Devarajan, Zahra Alsairafi, Irina Al-Khairi, Preethi Cherian, Hamad Ali, et al. "ANGPTL4: A Predictive Marker for Diabetic Nephropathy." Journal of Diabetes Research 2019 (October 27, 2019): 1–8. http://dx.doi.org/10.1155/2019/4943191.
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Background. ANGPTL4 is a glycoprotein that is involved in regulating triglyceride metabolism by inhibiting LPL activity under fasting conditions. Additionally, ANGPTL4 has been suggested as a link between hypertriglyceridemia and albuminuria in the nephrotic syndrome. In this study, we examined levels of circulating ANGPTL4 in people with diabetic nephropathy (DN) and its association with established DN-associated proteins such as IGFBP1 and IGFBP4. Methods. We quantified circulating ANGPTL4, IGFBP1, IGFBP3, and IGFBP4 in fasting plasma samples of 122 Kuwaiti participants using a multiplexing assay. The study involved 36 controls, as well as 86 people with type 2 diabetes (T2D) including 37 people with normal kidney function and 49 people with DN. Results. ANGPTL4 level was increased in people with DN (241.56±14.1 μg/ml) compared to the control group (178.43±24.09 μg/ml). The increase in ANGPTL4 correlated with clinical parameters of DN including albumin-to-creatinine ratio (r=0.271, P=0.002), serum creatinine (r=0.381, P=0.0001), and eGFR (r=−0.349, P<0.0001). Furthermore, ANGPTL4 correlated positively with both IGFBP1 (r=0.202, P=0.026) and IGFBP4 (r=0.364, P<0.0001). Multiple regression analysis showed increased IGFBP1 and TG as predictors of higher ANGPTL4 in people with DN. In people with T2D, only IGFBP1 acted as a positive predictor of a rise in ANGPTL4. Conclusion. In this study, our data showed a significant increase in circulating ANGPTL4, IGFBP1, and IGFBP4 in patients with DN. The elevation in ANGPTL4 correlated significantly with clinical markers of DN such as ACR, serum creatinine, and eGFR, as well as IGFBP1 and IGFBP4. Altogether, this suggests a potential role for ANGPTL4 in DN perhaps through its role in inhibiting LPL activity and promotes ANGPTL4 as a biochemical marker for the detection of a diabetic kidney disease in patients with T2D.
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Narayanan, Ram P., Bo Fu, Adrian H. Heald, Kirk W. Siddals, Robert L. Oliver, Julie E. Hudson, Antony Payton, et al. "IGFBP2 is a biomarker for predicting longitudinal deterioration in renal function in type 2 diabetes." Endocrine Connections 1, no. 2 (November 2012): 95–102. http://dx.doi.org/10.1530/ec-12-0053.
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ObjectiveInsulin-like growth factors are implicated in the development of diabetic nephropathy. IGF-binding protein 2 (IGFBP2) and IGF2 are expressed in the kidney, but their associations with diabetic nephropathy are unclear. We therefore tested the hypothesis that circulating levels of IGF2 and IGFBP2 predict longitudinal renal function in individuals with type 2 diabetes.Design and methodsIGFBP2 and IGF2 measurements were performed in 436 individuals (263 males) with type 2 diabetes. Linear mixed-effect regression analysis was used to model the relationship between plasma IGFBP2 concentration and longitudinal changes in estimated glomerular filtration rate (eGFR) over an 8-year period. Analyses were also performed for IGF1, IGF2, IGFBP1 and IGFBP3 concentrations as predictors of longitudinal renal outcomes.ResultsHigh IGFBP2 concentration at baseline was associated with a decreased eGFR over an 8-year period (β=−0.02, (95% confidence interval −0.03 to −0.01), P<0.001). High IGFBP1, IGFBP2 and IGFBP3 were also associated with low baseline eGFR concentration.ConclusionThis study demonstrates that IGFBP2 is a predictor of longitudinal deterioration of renal function in type 2 diabetes.
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Yeap, Bu B., S. A. Paul Chubb, Ken K. Y. Ho, Johnson W. S. Setoh, Kieran A. McCaul, Paul E. Norman, Konrad Jamrozik, and Leon Flicker. "IGF1 and its binding proteins 3 and 1 are differentially associated with metabolic syndrome in older men." European Journal of Endocrinology 162, no. 2 (February 2010): 249–57. http://dx.doi.org/10.1530/eje-09-0852.
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ObjectiveCirculating IGF1 declines with age, and reduced circulating IGF1 is associated with increased cardiovascular mortality in some but not all studies. The relationship between IGF-binding proteins 3 and 1 (IGFBP3 and IGFBP1) with risk of cardiovascular disease remains unclear. We sought to examine associations between IGF1, IGFBP3 and IGFBP1 with metabolic syndrome in older men.DesignCross-sectional analysis of 3980 community-dwelling men aged ≥70 years.MethodsMorning plasma levels of IGF1, IGFBP3 and IGFBP1 were assayed. Metabolic syndrome was defined according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria.ResultsFor IGF1 and IGFBP3, there was a U-shaped relationship, with middle quintiles possessing the lowest odds ratios (OR) for metabolic syndrome (reference Q1, Q3 IGF1: OR 0.74, 95% confidence intervals 0.57–0.96, Q3 IGFBP3: OR 0.67, 0.51–0.87). Increasing IGFBP1 was associated with reduced risk of metabolic syndrome with a dose–response gradient (reference Q1, OR for Q2 to Q5 IGFBP1: 0.56, 0.33, 0.22 and 0.12 respectively, P<0.001). IGF1 was associated with two, IGFBP1 with four and IGFBP3 with all five components of the metabolic syndrome. The ratio of IGF1/IGFBP3 was not associated with metabolic syndrome.ConclusionsIn older men, both lower and higher IGF1 and IGFBP3 levels may be metabolically unfavourable. IGFBP1, as a marker of insulin sensitivity, is relevant in the assessment of metabolic syndrome, while the IGF1/IGFBP3 ratio is less informative. Longitudinal follow-up of this cohort would be needed to determine whether these distributions of IGF1, IGFBP3 and IGFBP1 predict incidence of cardiovascular events during male ageing.
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Yeap, Bu B., Jennie Hui, Matthew W. Knuiman, Chubb S A Paul, Ho Ken K Y, Leon Flicker, Mark L. Divitini, et al. "Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men." European Journal of Endocrinology 182, no. 1 (January 2020): 23–33. http://dx.doi.org/10.1530/eje-19-0638.
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Objective Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70–84 years. Methods Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardio-metabolic risk factors, median splits defined low/high groups. Results Mean age was 76.7 ± 3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, P = 0.001 and 0.45, P = 0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1 s.d. increase in IGF1, P = 0.007, and 0.011 per 1 s.d. IGFBP3, P = 0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1 s.d. increase in estradiol, P = 0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 µg/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, P = 0.018). Conclusions Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological aging.
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Narayanan, Ram P., Matthew Gittins, Kirk W. Siddals, Robert L. Oliver, Julie E. Hudson, Anne White, Paul Durrington, Robert R. Davies, Martin K. Rutter, and J. Martin Gibson. "Atorvastatin administration is associated with dose-related changes in IGF bioavailability." European Journal of Endocrinology 168, no. 4 (April 2013): 543–48. http://dx.doi.org/10.1530/eje-12-0844.
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ObjectiveIGF levels, their binding proteins (IGFBPs) and high-dose statin therapy have been linked to the development of diabetes. We aimed to identify whether atorvastatin caused dose-related changes in IGF proteins.Design and methodsWe measured IGF1, IGF2, IGFBP1 and IGFBP3 concentrations at baseline, 6 and 12 months in Protection Against Nephropathy in Diabetes with Atorvastatin trial participants with type 2 diabetes randomised to 10 mg (n=59) vs 80 mg (n=60) of atorvastatin (n=119; mean (s.d.): age 64 (10) years; 83% male; HbA1c 61 (10) mmol/mol; blood pressure 131/73 mmHg).ResultsAtorvastatin was associated with overall reductions in circulating IGF1, IGF2 and IGFBP3 concentrations (P<0.05 for all changes). The adjusted mean (95% CI) between-group differences that indicate dose-related changes in IGF proteins were not significant for IGF1: −3 (−21 to 14) ng/ml; IGF2: −23 (−65 to 18) ng/ml and IGFBP3: −0.34 (−0.71 to 0.03) μg/ml, negative values indicating numerically greater lowering with high dose. The IGFBP1 concentration did not change with atorvastatin therapy overall but the adjusted mean (95% CI) between-group difference indicating a dose-related change in log IGFBP1 was highly significant −0.41 (−0.69 to 0.13, P=0.004).ConclusionIGF1, IGF2 and IGFBP3 concentrations decreased following atorvastatin therapy. A differential effect of low- vs high-dose atorvastatin on IGFBP1 concentrations was observed with likely implications for IGF bioavailability. The dose-related differential impact of atorvastatin treatment on concentration of IGF proteins merits investigation as a mechanism to explain the worsening of glucose tolerance with statin therapy.
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Frystyk, Jan, Anders J. Schou, Carsten Heuck, Henrik Vorum, Mikkel Lyngholm, Allan Flyvbjerg, and Ole D. Wolthers. "Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total or free IGF1." European Journal of Endocrinology 168, no. 1 (January 2013): 1–8. http://dx.doi.org/10.1530/eje-12-0518.
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ObjectiveEnd-point bioassays based on thymidine or sulfate incorporation have demonstrated that glucocorticoid (GC) treatment inhibits serum IGF1 action, but the mechanism is unknown as serum IGF1 concentrations have been reported to either increase or remain unchanged.AimTo investigate whether GC treatment affects the ability of serum to activate the IGF1 receptor (IGF1R) in vitro (i.e. bioactive IGF1), using a specific cell-based IGF1 kinase receptor activation assay.Subjects and methodsTwenty children with stable asthma (age 7.7–13.8 years) treated for 1 week with 5 mg prednisolone in a randomized, double-blind, placebo-controlled crossover study. Non-fasting serum samples were collected in the afternoon after each 7-day period and assayed for bioactive IGF1, free IGF1, total IGFs, IGF-binding proteins (IGFBPs), and insulin.ResultsPrednisolone treatment reduced IGF1 bioactivity by 12.6% from 2.22±0.18 to 1.94±0.15 μg/l (P=0.01) compared with placebo. In contrast, no changes were observed for (μg/l; placebo vs prednisolone) total IGF1 (215±27 vs 212±24), free IGF1 (1.50±0.16 vs 1.43±0.17), total IGF2 (815±26 vs 800±31), IGFBP3 (3140±101 vs 3107±95), IGFBP2 (238±21 vs 220±19), IGFBP1 (32±6 vs 42±10), or IGFBP1-bound IGF1 (24±5 vs 26±7). Insulin remained unchanged as did IGFBP levels as estimated by western ligand blotting. Prednisolone had no direct effects on IGF1R phosphorylation.ConclusionsOur study gives evidence that GC treatment induces a circulating substance that is able to inhibit IGF1R activation in vitro without affecting circulating free or total IGF1. This may be one of the mechanisms by which GC inhibits IGF1 action in vivo. However, the nature of this circulating substance remains to be identified.
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Yeap, Bu B., S. A. Paul Chubb, Kieran A. McCaul, Leon Flicker, Ken K. Y. Ho, Jonathan Golledge, Graeme J. Hankey, and Paul E. Norman. "Associations of IGF1 and its binding proteins with abdominal aortic aneurysm and aortic diameter in older men." European Journal of Endocrinology 166, no. 2 (February 2012): 191–97. http://dx.doi.org/10.1530/eje-11-0725.
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ObjectiveAbdominal aortic aneurysm (AAA) is most prevalent in older men. GH secretion declines with age resulting in reduced IGF1 levels. IGF1 and its binding proteins (IGFBPs) are expressed in vasculature, and lower IGF1 levels have been associated with cardiovascular risk factors and disease. However, the relationship of the IGF1 system with aortic dilation and AAA is unclear. We tested the hypothesis that circulating IGF1 and IGFBPs are associated with AAA and aortic diameter in older men.DesignA cross-sectional analysis involving 3981 community-dwelling men aged 70–89 years was performed.MethodsAbdominal aortic diameter was measured by ultrasound. Plasma total IGF1, IGFBP1 and IGFBP3 were measured by immunoassays.ResultsAfter adjustment for age, body mass index, waist:hip ratio, smoking, hypertension, dyslipidemia, diabetes, coronary heart disease and serum creatinine, a higher IGF1 level was associated with AAA (odds ratio (OR)/1 s.d. increase 1.18, 95% confidence interval (CI) 1.05–1.33, P=0.006), as was the ratio of IGF1/IGFBP3 (OR=1.22, 95% CI 1.10–1.35, P<0.001). Highest IGF1 concentrations compared with lowest quintile were significantly associated with AAA (quintile (Q) 5 vs Q1: OR=1.80, 95% CI 1.20–2.70, P=0.004) as were IGF1/IGFBP3 ratios (Q5 vs Q1: OR=2.52, 95% CI 1.59–4.02, P<0.001). IGF1 and IGFBP1 were independently associated with aortic diameter (β=0.200, 95% CI 0.043–0.357, P=0.012 and β=0.274, 95% CI 0.098–0.449, P=0.002 respectively).ConclusionsIn older men, higher IGF1 and an increased ratio of IGF1/IGFBP3 are associated with AAA, while IGFBP1 is independently associated with increased aortic diameter. Components of the IGF1 system may contribute to, or be a marker for, aortic dilation in ageing men.
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Yeap, Bu B., S. A. Paul Chubb, Kieran A. McCaul, Ken K. Y. Ho, Graeme J. Hankey, Paul E. Norman, and Leon Flicker. "Associations of IGF1 and IGFBPs 1 and 3 with all-cause and cardiovascular mortality in older men: the Health In Men Study." European Journal of Endocrinology 164, no. 5 (May 2011): 715–23. http://dx.doi.org/10.1530/eje-11-0059.
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ObjectiveCirculating IGF1 declines with age while ill-health increases. Controversy remains whether differences in the levels of IGF1 and its binding proteins 1 and 3 (IGFBP1 and IGFBP3) determine health outcomes during ageing. We examined associations of IGF1, IGFBP1 and IGFBP3 with all-cause and cardiovascular mortality in older men.DesignWe conducted a prospective cohort study of community-dwelling men aged ≥70 years.MethodsPlasma collected at baseline (2001–2004) was assayed for total IGF1, IGFBP1 and IGFBP3. Incidence and causes of death from time of recruitment to 31 December 2008 were ascertained using the Western Australian Data Linkage System. Cox regression analyses were performed, adjusting for conventional cardiovascular risk factors.ResultsAmong 3983 men followed for 5.2 years (median), 694 deaths occurred, 243 from cardiovascular disease (CVD). There was no difference in survival according to quintiles of IGF1. Increased IGFBP1 predicted increased all-cause mortality (highest versus lowest quintile: adjusted hazard ratio (HR)=1.98, 95% confidence interval (CI)=1.52–2.57, P<0.001 for trend) and increased cardiovascular mortality (HR=3.42 (2.03–5.77), P<0.001 for trend). Decreased IGFBP3 predicted increased all-cause mortality (lowest versus highest quintile: HR=1.57, 95% CI=1.23–2.01, P=0.007 for trend). Associations of IGFBP1 and IGFBP3 with all-cause mortality were not attenuated by adjustment for IGF1 levels.ConclusionsIn older men, higher IGFBP1 and lower IGFBP3 levels predict overall and CVD-related mortality, while IGF1 levels are not associated with mortality. Further studies are needed to clarify the underlying mechanisms by which IGFBP1 and IGFBP3 levels are associated with mortality risk, and whether this occurs independently of IGF1.
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Riedl, Stefan, Michael Kluge, Katharina Schweitzer, Thomas Waldhör, and Herwig Frisch. "Adaptation of ghrelin and the GH/IGF axis to high altitude." European Journal of Endocrinology 166, no. 6 (June 2012): 969–76. http://dx.doi.org/10.1530/eje-12-0007.
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ObjectiveHigh altitude (HA) provokes a variety of endocrine adaptive processes. We investigated the impact of HA on ghrelin levels and the GH/IGF axis.DesignObservational study as part of a medical multidisciplinary project in a mountainous environment.MethodsThirty-three probands (12 females) were investigated at three timepoints during ascent to HA (A: d −42, 120 m; B: d +4, 3440 m; C: d +14, 5050 m). The following parameters were obtained: ghrelin; GH; GH-binding protein (GHBP); IGF1; IGF2; IGF-binding proteins (IGFBPs) -1, -2, and -3; acid-labile subunit (ALS); and insulin. Weight was monitored and general well being assessed using the Lake Louise acute mountain sickness (AMS) score.ResultsGhrelin (150 vs 111 pg/ml;P<0.01) and GH (3.4 vs 1.7 μg/l;P<0.01) were significantly higher at timepoint C compared with A whereas GHBP, IGF1, IGF2, IGFBP3, ALS, and insulin levels did not change. IGFBP1 (58 vs 47 μg/l;P<0.05) and, even more pronounced, IGFBP2 (1141 vs 615 μg/l;P<0.001) increased significantly. No correlation, neither sex-specific nor in the total group, between individual weight loss (females: −2.1 kg; males: −5.1 kg) and rise in ghrelin was found. Five of the subjects did not reach investigation point C due to AMS.ConclusionsAfter 14 days of exposure to HA, we observed a significant ghrelin and GH increase without changes in GHBP, IGF1, IGF2, IGFBP3, ALS, and insulin. Higher GH seems to be needed for acute metabolic effects rather than IGF/IGFBP3 generation. Increased IGFBP1 and -2 may reflect effects from HA on IGF bioavailability.
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Fan, Xiubo, Pak Yan Chu, Florence Gay, Sudipto Bari, Justina Ang, SaiKiang Lim, and William Hwang. "Low Dose IGFBP1, IGFBP2 and ANGPTL3 Coordinately Stimulate Ex Vivo Expansion of Human Umbilical Cord Blood (UCB) Hematopoietic Stem Cells (HSCs)." Blood 116, no. 21 (November 19, 2010): 1546. http://dx.doi.org/10.1182/blood.v116.21.1546.1546.
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Abstract Abstract 1546 Ex vivo expansion of umbilical cord blood (UCB) hematopoietic stem cells (HSCs) may overcome the obstacle of low cell dose for UCB transplantation in adults. Insulin like growth factors (IGFs), IGF binding proteins (IGFBPs) and angiopoietin like proteins (ANGPTLs) can further enhance the ex vivo expansion of HSCs when used with a standard cytokine cocktail of stem cell factor (SCF), thrombopoietin (TPO) and FLT3-ligand (FL). Current doses of IGFBPs and ANGPTLs are in the range of 100∼500ng/ml, but these concentrations may not be optimal and high concentrations could be costly for clinical use. In order to determine the optimal dosage of IGFs, IGFBPs and ANGPTLs, 4×105cells/mL of cryopreserved clinical UCB was inoculated in serum-free Stemspan® medium supplied with standard basal cytokine combination of 100ng/ml SCF, 50ng/ml FL and 100ng/ml TPO on an MSCs stromal layer and with individually varied doses of IGFBP1, IGFBP2, IGF2 and ANGPTL3 in the range of 0∼200ng/ml. In order to determine optimal cytokine combination, complete permutation was carried out after establishing the optimal dosage of each cytokine. On day 7, the same amount of Stemspan® medium with the indicated cytokine combination was replenished to the culture system. Cord blood cells were harvested after 12 days ex vivo culture and assayed for total cell count, cell surface phenotype (viability determined by CD45/AnnV/7AAD staining, primitive progenitor determined by CD45/CD34/CD38/CD90 staining) and functional studies (Colony-forming unit-granulocyte and macrophage (CFU-GM) was determined by methylcellulose colony culture). Paradoxically, the highest expansion of CD34+CD38-CD90+ primitive progenitor was at a low dose of 20ng/ml for IGFBP1, IGFBP2, IGF2 and ANGPTL3 when concentrations of 0, 20, 50, 100 and 200 ng/ml were studied (Fig. 1A). Based on this results the cytokine dosage range was narrowed down to 0∼50ng/ml and experiments (Fig. 1B) showed that the optimal cytokines dosages were 20ng/ml of IGFBP2 and ANGPTL3, 15ng/ml IGFBP1 and 10ng/ml IGF2, which could stimulate 13.0±1.1 fold, 13.3±2.4 fold, 11.0±0.8 fold and 14.3±2.1 fold expansion of CD34+CD38-CD90+ primitive progenitor compared to 6.8±0.2 fold with standard cytokine control (p =0.01). Studying multiple permutations, combination “ABD” comprising 15ng/ml IGFBP1, 20ng/ml IGFBP2 and 20ng/ml ANGPTL3 had the highest expansion of CD34+CD38-CD90+ primitive progenitor (27.7±2.2 fold compared to 8.5±1.1 fold with standard cytokines, p =0.01), was found to be superior to all other combinations, including combinations “A”, “B”, “BC”, “BD”, “CD” and “ABCD”, which could stimulate over 2 fold expansion of primitive progenitor compare to control (Figure 1C). Interestingly, despite expansion of primitive CD34+CD38-CD90+ cells, there was no further enhancement of the expansion of total cells and general progenitors compare to control (data not shown), suggesting that the cyokine cocktail enhanced only the earliest progenitors. In conclusion, IGFBP1, IGFBP2, IGF2 and ANGPTL3 can stimulate the expansion of CD34+CD38-CD90+ primitive progenitor at low dosage, and the optimal combination comprises IGFBP1, IGFBP2 and ANGPTL3. Further in vivo experimentation is in progress to verify the effect of our optimized cytokine combination culture system on ex vivo expansion of cryopreserved unselected clinical UCB HSCs. Disclosures: No relevant conflicts of interest to declare.
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Minchenko, Dmytro O., Dariia O. Tsymbal, Vadim V. Davydov, and Oleksandr H. Minchenko. "Expression of genes encoding IGF1, IGF2, and IGFBPs in blood of obese adolescents with insulin resistance." Endocrine Regulations 53, no. 1 (January 1, 2019): 34–45. http://dx.doi.org/10.2478/enr-2019-0005.
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AbstractObjective. The development of obesity and its metabolic complications is associated with dys-regulation of various intrinsic mechanisms, which control basic metabolic processes via changes in the expression of numerous regulatory genes. The main goal of this work was to study the association between the expression of insulin-like growth factors (IGF1 and IGF2) and IGF-binding proteins and insulin resistance in obese adolescents for evaluation of possible contribution of these genes in development of insulin resistance.Methods. The expression of IGF1, IGF2, and IGFBPs mRNA was measured in blood of obese adolescents with normal insulin sensitivity and insulin resistance in comparison with the normal (control) individuals.Results. In the blood of obese adolescents with normal insulin sensitivity the expression of IGFBP4, IGFBP5 and HTRA1 genes was down-regulated, but IGFBP2 and IGFBP7 genes up-regulated as compared to control (normal) group. At the same time, no significant changes in IGF1 and IGF2 gene expressions in this group of obese adolescents were found. Insulin resistance in obese adolescents led to up-regulation of IGF2, IGFBP2, and IGFBP7 gene expressions as well as to down-regulation of the expression of IGF1, IGFBP5 and HTRA1 genes in the blood in comparison with the obese patients, which have normal insulin sensitivity. Furthermore, the level of IGFBP4 gene expression was similar in both groups of obese adolescents.Conclusions. Results of this investigation provide evidence that insulin resistance in obese adolescents is associated with gene specific changes in the expression of IGF1, IGF2, IGFBP2, IGFBP5, IGFBP7, and HTRA1 genes and these changes possibly contribute to the development of glucose intolerance and insulin resistance.
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Espelund, Ulrick, Søren Cold, Jan Frystyk, Hans Ørskov, and Allan Flyvbjerg. "Elevated free IGF2 levels in localized, early-stage breast cancer in women." European Journal of Endocrinology 159, no. 5 (November 2008): 595–601. http://dx.doi.org/10.1530/eje-08-0154.
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ObjectiveEpidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease.DesignThe participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured.ResultsIn patients, mean free IGF2 was increased (+57%, P<0.001), in spite of reduced total IGF2 levels (−12%, P=0.003) when compared with controls. Similar changes were seen in free IGF1 (+28%, P=0.004) and total IGF1 (−16% P=NS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (P=0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged.ConclusionWomen with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women.
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Alonso-Gómez, Aitana, Diego Madera, Ángel Luis Alonso-Gómez, Ana Isabel Valenciano, and María Jesús Delgado. "Daily Rhythms in the IGF-1 System in the Liver of Goldfish and Their Synchronization to Light/Dark Cycle and Feeding Time." Animals 12, no. 23 (November 30, 2022): 3371. http://dx.doi.org/10.3390/ani12233371.
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The relevance of the insulin-like growth factor-1 (IGF-1) system in several physiological processes is well-known in vertebrates, although little information about their temporal organization is available. This work aims to investigate the possible rhythmicity of the different components of the IGF-1 system (igf-1, the igf1ra and igf1rb receptors and the paralogs of its binding proteins IGFBP1 and IGFBP2) in the liver of goldfish. In addition, we also study the influence of two environmental cues, the light/dark cycle and feeding time, as zeitgebers. The hepatic igf-1 expression showed a significant daily rhythm with the acrophase prior to feeding time, which seems to be strongly dependent on both zeitgebers. Only igfbp1a-b and igfbp1b-b paralogs exhibited a robust daily rhythm of expression in the liver that persists in fish held under constant darkness or randomly fed. The hepatic expression of the two receptor subtypes did not show daily rhythms in any of the experimental conditions. Altogether these results point to the igf-1, igfbp1a-b, and igfbp1b-b as clock-controlled genes, supporting their role as putative rhythmic outputs of the hepatic oscillator, and highlight the relevance of mealtime as an external cue for the 24-h rhythmic expression of the IGF-1 system in fish.
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Højlund, Kurt, Henning Beck-Nielsen, Allan Flyvbjerg, and Jan Frystyk. "Characterisation of adiponectin multimers and the IGF axis in humans with a heterozygote mutation in the tyrosine kinase domain of the insulin receptor gene." European Journal of Endocrinology 166, no. 3 (March 2012): 511–19. http://dx.doi.org/10.1530/eje-11-0790.
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ObjectiveLow levels of adiponectin, IGF-binding protein 1 (IGFBP1) and IGFBP2 and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies, plasma adiponectin is paradoxically increased despite severe insulin resistance, whereas the IGF axis is sparsely described. Here, we aimed to characterise the multimeric distribution of adiponectin and the IGF axis in humans with a heterozygous INSR mutation (Arg1174Gln).MethodsBlood samples obtained from six Arg1174Gln carriers and ten lean, healthy controls before and after a euglycaemic–hyperinsulinaemic clamp were examined for plasma adiponectin multimers, leptin, total IGF1, IGF2, free IGF1, IGFBP1 and IGFBP2.ResultsDespite tenfold elevated fasting insulin and marked insulin resistance in Arg1174Gln carriers, the levels of total adiponectin, leptin, IGFBP1 and IGFBP2 were similar to those observed in controls, while total IGF1, IGF2 and free IGF1 levels were increased. The relative fraction of high-molecular weight adiponectin was increased, whereas both the absolute concentration and the fraction of low-molecular weight adiponectin were decreased in Arg1174Gln carriers. Interestingly, exogenous insulin failed to suppress total adiponectin in Arg1174Gln carriers, but reduced IGFBP1 and increased IGFBP2 as in controls.ConclusionThe normal levels of adiponectin, IGFBP1 and IGFBP2 in the face of highly elevated insulin levels suggest an impaired ability of insulin to suppress markers of common insulin resistance in carriers of a dominant-negative INSR mutation. However, together with the adaptive increases in IGF1 and IGF2 and a potentially improved distribution of adiponectin multimers, these changes may contribute to rescue insulin action in insulin receptor-deficient individuals.
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Mashayekhi, Farhad, Somayeh Shabani, and Zivar Salehi. "Comparison of serum IGF1, IGF2 and IGFBP1-6 concentration in the children with different stages of autism spectrum disorders." Archives of Psychiatry and Psychotherapy 24, no. 3 (October 15, 2022): 20–24. http://dx.doi.org/10.12740/app/144882.
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Aim of the studyAutism spectrum disorder (ASD) is a neurodevelopmental condition considered by early-onset difficulties in social communication. Insulin-like growth factors (IGFs) play crucial roles in synapse formation. Most of circulating IGFs are bound to IGF-binding proteins (IGFBPs) that modify IGF action. IGFBPs prolong the plasma half-life of IGFs. In this project we studied the association of IGF1/2 and IGFBP1-6 serum concentration with the severity of ASD (Levels 1-3; Mild, Moderate and severe, respectively).Subject or material and methodsA hundred and eighty patients with ASD (Mild; n=69, Moderate; n=58 and Severe; n=53) and 118 controls age matched were used in this project and IGF1/2 and IGFBP1-6 serum concentration were measured by ELISA.ResultsThe results demonstrated that IGF1, IGF2 and IGFBP1-6 were present in all serum samples. The results showed that the concentration of IGF1 and IGF2 was significantly higher in ASD patients when compared to controls, starting from stages I to III ASD, a significant increase of IGF1 and IGF2 serum concentration was observed. Results obtained also showed that IGFBP1-6 concentration in the ASD group were lower when compared to controls and low serum IGFBP1-6 concentration is associated with advanced stages of ASD.DiscussionIGFs plays important role in synapse formation and changes in IGFs expression may be important in the pathogenesis of ASD.ConclusionsIt is suggested that IGFs and IGFBPs may be involved in the pathogenesis of ASD. Therefore, the detection of serum soluble IGFs and IGFBPs may be useful in classifying ASD.
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Lund, Jacob, Mads T. Søndergaard, Cheryl A. Conover, and Michael T. Overgaard. "Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex." Journal of Molecular Endocrinology 52, no. 3 (March 6, 2014): 345–55. http://dx.doi.org/10.1530/jme-13-0184.
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IGF1 and IGF2 are potent stimulators of diverse cellular activities such as differentiation and mitosis. Six IGF-binding proteins (IGFBP1–IGFBP6) are primary regulators of IGF half-life and receptor availability. Generally, the binding of IGFBPs inhibits IGF receptor activation. However, it has been shown that IGFBP2 in complex with IGF2 (IGF2/IGFBP2) stimulates osteoblast function in vitro and increases skeletal mass in vivo. IGF2 binding to IGFBP2 greatly increases the affinity for 2- or 3-carbon O-sulfated glycosaminoglycans (GAGs), e.g. heparin and heparan sulfate, which is hypothesized to preferentially and specifically target the IGF2/IGFBP2 complex to the bone matrix. In order to obtain a more detailed understanding of the interactions between the IGF2/IGFBP2 complex and GAGs, we investigated heparin-binding properties of IGFBP2 and the IGF2/IGFBP2 complex in a quantitative manner. For this study, we mutated key positively charged residues within the two heparin-binding domains (HBDs) in IGFBP2 and in one potential HBD in IGF2. Using heparin affinity chromatography, we demonstrate that the two IGFBP2 HBDs contribute differentially to GAG binding in free IGFBP2 and the IGF2/IGFBP2 protein complex. Moreover, we identify a significant contribution from the HBD in IGF2 to the increased IGF2/IGFBP2 heparin affinity. Using molecular modeling, we present a novel model for the IGF2/IGFBP2 interaction with heparin where all three proposed HBDs constitute a positively charged and surface-exposed area that would serve to promote the increased heparin affinity of the complex compared with free intact IGFBP2.
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Wang, Yan, Xuefeng Han, Zhiliang Tan, Jinhe Kang, and Zheng Wang. "Rumen-Protected Glucose Stimulates the Insulin-Like Growth Factor System and mTOR/AKT Pathway in the Endometrium of Early Postpartum Dairy Cows." Animals 10, no. 2 (February 23, 2020): 357. http://dx.doi.org/10.3390/ani10020357.
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This study aimed to elucidate the effects of a dietary rumen-protected glucose (RPG) addition on uterine involution through the analysis of an insulin-like growth factor (IGF) system and associated pathways in the post-natal endometrium. Twelve Holstein cows were assigned equally to two groups: a control group (CT) and an RPG group (200 g of RPG per cow per day). The plasma content of insulin-like growth factor 1 (IGF1) was determined by using the ELISA method. Expressions of IGF members, the matrix metalloproteinase, protein kinase B (AKT)/mechanistic target of rapamycin complex1 (mTOR) signaling pathway, and cell proliferation factors (proliferating cell nuclear antigen (PCNA) and Ki67) were detected using real-time polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence, respectively. The results showed that the positive cells of PCNA and Ki67 were increased in the endometrium of RPG versus CT cows. The RPG addition significantly increased the plasma IGF1 level 14 d after delivery. The mRNA expressions of the IGF family members (IGF1, IGF2, type 1 IGF receptor (IGF1R) and IGF-binding proteins (IGFBP1, IGFBP2, IGFBP4 and IGFBP5)) were upregulated, and mRNA expressions of matrix metalloproteinase MMP3 and MMP9 were downregulated in cows from the RPG group compared with the CT group. Meanwhile, the protein expressions of IGF1, IGF2, IGF1R, IGFBP1 and IGFBP4 were upregulated in cows from the RPG group compared with the CT group. Immunohistochemical analysis identified a positive response for IGF1R and IGF2R in the endometrium of RPG versus CT cows. Furthermore, the RPG supplementation increased the protein expressions of phosphorylated (p)-AKT to total AKT and p-mTOR to total mTOR ratio in the endometrium. The current results indicated that the RPG supplementation promoted the proliferation of endometrial cells by stimulating the IGFs and mTOR/AKT pathway in the early post-natal endometrium of dairy cows.
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van Adrichem, R. C. S., L. J. Hofland, R. A. Feelders, M. C. De Martino, P. M. van Koetsveld, C. H. J. van Eijck, R. R. de Krijger, D. M. Sprij-Mooij, J. A. M. J. L. Janssen, and W. W. de Herder. "Chromogranin A, Ki-67 index and IGF-related genes in patients with neuroendocrine tumors." Endocrine Connections 2, no. 4 (December 2013): 172–77. http://dx.doi.org/10.1530/ec-13-0052.
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Chromogranin A (CgA) and the Ki-67 proliferation index are considered as important biochemical and pathological markers for clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP NETs), respectively. The IGF system has been suggested as an important regulator of GEP NET proliferation and differentiation. A possible relationship between serum CgA (sCgA), Ki-67 proliferation index, and expression of IGF-related genes in patients with GEP NETs has not been demonstrated yet. This study investigates the relationship between sCgA, the Ki-67 proliferation index, and the expression of IGF-related genes in GEP NET tissues and their relation with 5-year survival. Tumor and blood samples from 22 GEP NET patients were studied. Tumoral mRNA expression of IGF-related genes (IGFs: IGF1, IGF2; IGF receptors: IGF1R, IGF2R; insulin receptors: subtype A (IR-A) and B (IR-B); IGF-binding proteins (IGFBPs): IGFBP1, IGFBP2, IGFBP3, and IGFBP6) was measured using quantitative RT-PCR. Ki-67 proliferation index was determined using immunohistochemistry. sCgA was measured with ELISA. Five-year survival in patients with nonelevated sCgA (n=11) was 91 vs 46% in patients with elevated sCgA (n=11) (P=0.006). IR-A mRNA expression was significantly higher in tumors obtained from patients with elevated sCgA than in those from patients with nonelevated sCgA (6.42±2.08 vs 2.60±0.40; P=0.04). This data suggests that sCgA correlates well with 5-year survival of GEP NET patients, and that IR-A mRNA expression correlates well with tumor mass in GEP NET patients.
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Kit, O. I., E. M. Frantsiyants, D. A. Kharagezov, V. A. Bandovkina, N. D. Cheryarina, Yu A. Pogorelova, Yu N. Lazutin, A. G. Milakin, I. A. Leyman, and O. N. Stateshny. "Varying severity COVID-19 effects on the blood indicators of insulin-like growth factors family in patients with nonsmall cell lung cancer." South Russian Journal of Cancer 4, no. 2 (May 11, 2023): 6–15. http://dx.doi.org/10.37748/2686-9039-2023-4-2-1.
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Purpose of the study. An analysis of IGF and their carrying proteins levels in blood serum of patients with non‑small cell lung cancer (NSCLC), depending on the severity of the previous COVID-19 infection.Materials and methods. 60 patients with histologically verified NSCLC T2–3NхM0 receiving treatment at the Thoracic Department (National Medical Research Centre for Oncology, 2020–2021), were included in the study. The control group included 30 NSCLC patients after asymptomatic or mild COVID-19 disease (15 men and 15 women); the main group included 30 (15 men and 15 women) patients after severe or moderate to severe COVID-19. The mean age of patients was 59.11 ± 2.89 years. Blood counts of donors of the same age were used as the norm.Results. The levels of IGF-I, IGF-II, IGFBP2 and IGFBP3 in the blood serum of patients with NSCLC of the main and control groups were higher than those of donors by an average of 2.5, 2.1, 1.7 and 2.7 times, respectively (p < 0.05). The concentration of IGFBP1 was higher in the control group compared to the main group, and decreased in relation to donors: in the control in men and women by 1.4 and 1.9 times, and in the main group by 3.0 and 6.4 times, respectively (p < 0.05). The ratios of IGF and IGFBP1 increased in both groups: IGF-I/IGFBP1 – in the control group from 3.8 to 4.2 times, and in the main group from 7.9 to 14.4 times; IGF-II/IGFBP1 – in the control from 2.4 to 4.5 times, and in the main group from 6.6 to 12.7 times in men and women, respectively (p < 0.05).Conclusions. The level of ligands and almost all of the studied carrier proteins, except for IGFBP1, increases in the blood of patients with NSCLC of both sexes, regardless of the severity of COVID-19. The ratio of IGF-I/IGFBP1 and IGF-II/IGFBP1 in the blood increases in both groups, most significantly in the group with severe and moderate COVID-19, which indicates excessive accumulation of IGF levels and may contribute to a more aggressive course of the malignant process.
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Ma, Zhulin, Jens Sandahl Christiansen, Torben Laursen, Torsten Lauritzen, and Jan Frystyk. "Short-term effects of NPH insulin, insulin detemir, and insulin glargine on the GH–IGF1–IGFBP axis in patients with type 1 diabetes." European Journal of Endocrinology 171, no. 4 (October 2014): 471–79. http://dx.doi.org/10.1530/eje-14-0258.
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ObjectiveInsulin regulates the GH–IGF1 axis. Insulin analogs differ from human insulin in receptor affinity and possibly liver accessibility. Therefore, we compared the GH–IGF1 axis response with human NPH insulin, insulin detemir, and insulin glargine in patients with type 1 diabetes (T1D).MethodsA total of 17 patients (seven were women) with T1D (age of 42 (24–63) years (mean and range), BMI of 24.7 (19.5–28.3) kg/m2, HbA1c of 7.2 (6.3–8.0) % (55 (45–64) mmol/mol), T1D duration of 26 (8–45) years) were studied using a randomized, three-period crossover design. Patients received s.c. injections of equal, individual doses of NPH, detemir, and glargine at 1800 h. Plasma glucose, serum total IGF1, bioactive IGF, IGF-binding protein (IGFBPs), and GH were measured hourly for 14 h post-injection.ResultsWhen compared with the area under the curve (AUC) following NPH and glargine, detemir resulted in the lowest 6–14 h AUC (mean and range) of IGFBP1 (1518 (1280–1800)) vs 1621 (1367–1922) vs 1020 (860–1210) μg/l×h) and GH (17.1 (14.1–20.6) vs 15.4 (12.7–18.6) vs 10.2 (8.5–12.3) μg/l×h), but in the highest AUC of bioactive IGF (3.8 (3.5–4.2) vs 3.7 (3.4–4.0) vs 4.4 (4.1–4.8) μg/l×h) (allP<0.01). These differences were unrelated to plasma glucose. By contrast, profiles of total IGF1, IGFBP2, and IGFBP3 were comparable.ConclusionsIndependent of plasma glucose, a single dose of detemir caused larger suppression in serum IGFBP1 than NPH and glargine, whereas bioactive IGF was higher, thereby explaining the lower GH levels. Thus, detemir appears to be more liver specific than NPH insulin and glargine.
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Verheus, Martijn, Gertraud Maskarinec, Christy G. Woolcott, Christopher A. Haiman, Loïc Le Marchand, Brian E. Henderson, Iona Cheng, and Laurence N. Kolonel. "IGF1, IGFBP1, and IGFBP3 genes and mammographic density: The Multiethnic Cohort." International Journal of Cancer 127, no. 5 (December 28, 2009): 1115–23. http://dx.doi.org/10.1002/ijc.25142.
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Terry, Kathryn L., Shelley S. Tworoger, Margaret A. Gates, Daniel W. Cramer, and Susan E. Hankinson. "Common genetic variation in IGF1 , IGFBP1 and IGFBP3 and ovarian cancer risk." Carcinogenesis 30, no. 12 (October 25, 2009): 2042–46. http://dx.doi.org/10.1093/carcin/bgp257.
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Garfinkel, Benjamin P., Shiri Arad, Phuong T. Le, Michael Bustin, Clifford J. Rosen, Yankel Gabet, and Joseph Orly. "Proportionate Dwarfism in Mice Lacking Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) Is Associated With Alterations in the Endocrine IGF-1 Pathway." Endocrinology 156, no. 12 (September 24, 2015): 4558–70. http://dx.doi.org/10.1210/en.2015-1668.
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Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3, we have previously described an Hp1bp3−/− mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length, and organ weight. In addition to their small size, microcomputed tomography analysis showed that Hp1bp3−/− mice present a dramatic impairment of their bone development and structure. By 3 weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3−/− bone marrow and splenocytes, respectively, showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to noncell autonomous systemic cues in vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of IGF-1, the IGF receptors, and the IGF-binding proteins (IGFBPs). At 3 weeks of age, Hp1bp3−/− mice exhibited a 60% reduction in circulating IGF-1 and a 4-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1, and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components.
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Zheng, Wei, Yayu Lai, Peng Jin, Wenzhu Gu, Qi Zhou, and Xiaojing Wu. "Association of Circulating IGFBP1 Level with the Severity of Coronary Artery Lesions in Patients with Unstable Angina." Disease Markers 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/1917291.
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Aims.Local IGFBP1 level was reported to affect the development of coronary artery plaque. This study investigated the association of circulating IGFBP1 level with the severity of coronary artery lesions in patients with unstable angina.Materials and Methods.In 112 consecutive patients with clinically diagnosed unstable angina, admitted from July 2014 to July 2015, we studied the correlations of circulating IGFBP1 and the severity of coronary artery disease (CAD).Results.All patients underwent scheduled coronary angiography, and 67 cases were diagnosed with critical and 45 with noncritical CAD. Of the 67 critical CAD patients, 41 (61.19%) presented with multivessel and 26 (38.81%) with single-vessel lesions. IGFBP1 levels were higher in patients with multivessel than those with single-vessel lesions. Moreover, the IGFBP1 level was positively correlated with the GRACE score. Among clinical variables, the IGFBP1 level was correlated with HDL-C. IGFBP1 alone (cutoff 20.86 ng/ml) demonstrated a sensitivity of 0.448 and specificity of 0.933 in predicting CAD. Combination of IGFBP1 and HDL-C had a sensitivity of 0.821 and specificity of 0.800 in predicting CAD.Conclusions.Circulating IGFBP1 level positively correlated with the severity of CAD. IGFBP1, when combined with HDL-C, might be useful in screening for high risk CAD patients.
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Wathes, D. Claire, Zhangrui Cheng, Mark A. Fenwick, Richard Fitzpatrick, and Joe Patton. "Influence of energy balance on the somatotrophic axis and matrix metalloproteinase expression in the endometrium of the postpartum dairy cow." REPRODUCTION 141, no. 2 (February 2011): 269–81. http://dx.doi.org/10.1530/rep-10-0177.
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Postpartum dairy cows enter a period of negative energy balance (NEB) associated with low circulating IGF1, during which the uterus must undergo extensive repair following calving. This study investigated the effects of NEB on expression of IGF family members and related genes in the involuting uterus. Cows were allocated to two treatments using differential feeding and milking regimes to produce mild NEB or severe NEB (SNEB). Uterine endometrial samples collected 2 weeks post partum were analysed by quantitative PCR. The expression of IGF-binding protein 4 (IGFBP4) mRNA increased in the endometrium of SNEB cows, with trends towards increased IGFBP1 and reduced IGFBP6 expression. There were no significant differences between treatments in mRNA expression of IGF1, IGF2 or of any hormone receptor studied, but significant correlations across all cows in the expression levels of groups of receptors suggested common regulatory mechanisms: type 1 IGF receptor (IGF1R), IGF2R and insulin receptor (INSR); GHR with ESR1; and ESR2 with NR3C1. The expression of IGF1R and INSR also positively correlated with the circulating urea concentration. Matrix metalloproteinases (MMPs) are important in tissue remodelling and can affect IGF signalling via interaction with IGFBPs. The expression levels of MMP1, MMP3, MMP9 and MMP13 mRNAs all showed major upregulation in the endometrium of cows in SNEB and all except MMP9 were highly correlated with expression of IGFBP4. Alpha(2)-HS-glycoprotein (AHSG) and PDK4, two genes implicated in insulin resistance, were also highly expressed in SNEB. These results suggest that cows in SNEB experience alterations to the IGF and insulin signalling pathways in the postpartum endometrium. This may affect the rate of tissue repair with a possible negative impact on subsequent fertility.
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Ye, Haobin, Nabilah Khan, Mohammad Minhajuddin, Biniam Adane, and Craig T. Jordan. "Adipose Tissue-Derived IGFBP1 Facilitates Progression of Leukemia." Blood 128, no. 22 (December 2, 2016): 3058. http://dx.doi.org/10.1182/blood.v128.22.3058.3058.
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Abstract We recently reported that adipose tissue functions as a reservoir for leukemia stem cells (LSCs) using a murine model of leukemia (Ye et al., Cell Stem Cell, 2016). Intriguingly, the presence of leukemic cells in adipose tissue induces increased lipolysis and the release of free fatty acids (FFA) which in turn fuels the growth of LSCs. Further, adipose tissue protects resident LSCs from chemotherapy. These findings indicate that the unique characteristics of adipose tissue may provide key insights on the growth and survival of leukemic cells. Thus, in the present study we focus on the endocrine function of adipose tissue and explore its role in leukemia development. First, to evaluate secreted factors, we applied adipokine arrays which detect 38 adipokines to leukemia serum collected at different stages of leukemia pathogenesis. Interestingly, we observed a significantly elevated level of serum IGFBP1 as soon as leukemic disease became evident at low levels (~0.5%) in marrow. IGFBP1 increased to levels approximate 200X normal at peak stages of disease burden. ELISA analyses further confirmed these observations. IGFBP1 is normally considered as a liver-derived protein. However, we did not find any changes of IGFBP1 expression in leukemic liver. Rather, we observed a significant increase in the expression of IGFBP1 in adipose tissue. IGFBP1 in conditioned medium (CM) from leukemic gonadal adipose tissue (GAT) is approximate 100X higher than naive GAT. Together, these findings suggest adipose tissue-derived IGFBP1 contributes to the increased serum IGFBP1 we detected in leukemic animals. We next examined the role of IGFBP1 in leukemia development using a neutralizing antibody. Treatment of experimental animals with anti-IGFBP1 antibody significantly decreased leukemic burden in GAT (~40% IgG treated VS. 20% Anti-IGFBP1 treated) while bone marrow (BM) and spleen leukemic engraftment remained unchanged (~40%). Further, less atrophy of adipose tissue as well as less body weight loss was seen in the IGFBP1 neutralizing antibody treated group. Consistent with this observation, serum FFA level was also reduced, suggesting less lipolysis in the IGFBP1 antagonized group. Together, these results indicate that IGFBP1 is involved in the regulation of leukemic cells homing to adipose tissue and consequently leukemia-induced lipolysis. Next we explored the mechanisms for the increased expression of IGFBP1 in adipose tissue. Studies have shown that both FGF21 and hypoxia induce IGFBP1 expression. We did not find any changes of FGF21 expression in adipose tissue or in liver, suggesting FGF21 was not involved in IGFBP1 regulation in our system. In contrast, we observed a five-fold elevation in IGFBP1 mRNA in primary adipose tissue cultured under hypoxic conditions. Studies have shown that both BM and spleen in leukemia mice are already hypoxic in early stages of leukemic development (Benito et al., Plos One, 2011). Thus, we hypothesize that tissue hypoxia may at least partially regulate IGFBP1 in leukemia. Ongoing experiments are testing this hypothesis. Additionally, inflammatory cytokines have been reported to increase IGFBP1 expression. We previously reported significantly increased levels of inflammatory cytokines in the adipose tissue of leukemic mice including TNF-α, IL1 and CSF2 (1.5X normal adipose tissue). Therefore, we hypothesize the local inflammatory cytokine production may also contribute to increased expression of IGFBP1, a theory that is also currently under investigation. IGFBP1 has recently been reported to activate osteoclasts and thus promotes bone metabolism (Wang et al., Cell Metabolism, 2015). Studies have found an increased number of osteoclasts and thus bone loss in our leukemic model (Frisch et al., Blood, 2012). We hypothesize that adipose tissue-derived IGFBP1 contributes to bone loss in leukemic mice. Ongoing experiments are testing whether antagonization of IGFBP1 in leukemic mice will rescue bone loss. Collectively, these findings suggest that adipose tissue-derived IGFBP1 facilitates progression of leukemia through regulation of adipose tissue lipolysis and may promote bone marrow colonization by leukemia cells through activation of osteoclasts. Disclosures No relevant conflicts of interest to declare.
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DeMambro, V. E., D. R. Clemmons, L. G. Horton, M. L. Bouxsein, T. L. Wood, W. G. Beamer, E. Canalis, and C. J. Rosen. "Gender-Specific Changes in Bone Turnover and Skeletal Architecture in Igfbp-2-Null Mice." Endocrinology 149, no. 5 (February 14, 2008): 2051–61. http://dx.doi.org/10.1210/en.2007-1068.
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IGF-binding protein-2 (IGFBP-2) is a 36-kDa protein that binds to the IGFs with high affinity. To determine its role in bone turnover, we compared Igfbp2−/− mice with Igfbp2+/+ colony controls. Igfbp2−/− males had shorter femurs and were heavier than controls but were not insulin resistant. Serum IGF-I levels in Igfbp2−/− mice were 10% higher than Igfbp2+/+ controls at 8 wk of age; in males, this was accompanied by a 3-fold increase in hepatic Igfbp3 and Igfbp5 mRNA transcripts compared with Igfbp2+/+ controls. The skeletal phenotype of the Igfbp2−/− mice was gender and compartment specific; Igfbp2−/− females had increased cortical thickness with a greater periosteal circumference compared with controls, whereas male Igfbp2−/− males had reduced cortical bone area and a 20% reduction in the trabecular bone volume fraction due to thinner trabeculae than Igfbp2+/+ controls. Serum osteocalcin levels were reduced by nearly 40% in Igfbp2−/− males, and in vitro, both CFU-ALP+ preosteoblasts, and tartrate-resistant acid phosphatase-positive osteoclasts were significantly less abundant than in Igfbp2+/+ male mice. Histomorphometry confirmed fewer osteoblasts and osteoclasts per bone perimeter and reduced bone formation in the Igfbp2−/− males. Lysates from both osteoblasts and osteoclasts in the Igfbp2−/− males had phosphatase and tensin homolog (PTEN) levels that were significantly higher than Igfbp2+/+ controls and were suppressed by addition of exogenous IGFBP-2. In summary, there are gender- and compartment-specific changes in Igfbp2−/− mice. IGFBP-2 may regulate bone turnover in both an IGF-I-dependent and -independent manner.
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Rosendahl, Ann H., Maria Hietala, Maria Henningson, Håkan Olsson, and Helena Jernström. "IGFBP1 and IGFBP3 polymorphisms predict circulating IGFBP-3 levels among women from high-risk breast cancer families." Breast Cancer Research and Treatment 127, no. 3 (December 8, 2010): 785–94. http://dx.doi.org/10.1007/s10549-010-1277-1.
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Goodyer, Cynthia G., Rilene M. O. Figueiredo, Stephanie Krackovitch, Lilia De Souza Li, Jennifer A. Manalo, and George Zogopoulos. "Characterization of the growth hormone receptor in human dermal fibroblasts and liver during development." American Journal of Physiology-Endocrinology and Metabolism 281, no. 6 (December 1, 2001): E1213—E1220. http://dx.doi.org/10.1152/ajpendo.2001.281.6.e1213.
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Human tissues express growth hormone receptors (hGHR) by the 3rd mo of gestation. We assessed developmental changes in hGHR function in fibroblasts and liver, testing binding and hormonal response. Fetal cells showed low but reproducible hGH binding. No age-related changes occurred in fibroblasts (9 wk–34 yr). In contrast, there was a fourfold increase in hGH binding in postnatal liver, with a sixfold increase in hGHR mRNA. Both full-length and truncated hGHR mRNAs were detected in all livers. Cross-linking revealed a larger hGH/receptor complex in fetal liver. Fetal hepatocytes produced 10 times more insulin-like growth factor (IGF)-II than IGF-I, and responded to hGH (150 ng/ml) with a significant increase in IGF-II. Fetal hepatocytes secreted three IGF-binding proteins (IGFBPs), including IGFBP1, but not IGFBP3. hGH did not alter fetal hepatocyte IGFBPs but stimulated glucose uptake. Exposure of fibroblasts to hGH decreased hGH binding only in >1-yr postnatal fibroblasts, whereas treatment with dexamethasone (100–400 nM) increased binding only in postnatal cells. Thus, although fetal hepatocytes and fibroblasts possess functional hGHR, these receptors (and/or their signaling pathways) are immature or have adapted to the in utero environment.
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Huot, Joshua R., Fabrizio Pin, and Andrea Bonetto. "Abstract 3490: IGFBP1 mediates musculoskeletal defects in colorectal cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3490. http://dx.doi.org/10.1158/1538-7445.am2023-3490.
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Abstract Colorectal cancer (CRC) is frequently accompanied by cachexia, an uncured multi-systemic wasting syndrome that affects the majority of patients, especially when the disease recurs with liver metastases (LMs). Muscle and bone loss are amongst the most detrimental symptoms of cachexia and directly cause increased morbidity and mortality. We and others have shown that CRC also promotes metabolic and genomic perturbations of the liver, and further, that formation of LMs exacerbates muscle and bone wasting. These observations, along with evidence that liver-derived factors (i.e., hepatokines) may poorly influence musculoskeletal health, suggest an endocrine role of the liver in mediating cancer-induced cachexia. In the present study, we identified the hepatokine insulin-like growth factor binding protein 1 (IGFBP1) as a novel mediator of musculoskeletal wasting in CRC. Plasma from CRC patients and preclinical mouse models of CRC (C26, MC38, HCT116, ApcMin/+) were assessed for circulating IGFBP1 levels. AML12 hepatocytes were cultured with CRC cells (C26, MC38, HCT116) to assess tumor induced hepatic IGFBP1 production, while C2C12 myotubes and osteoclast precursor cells were cultured to examine the in vitro effects of IGFBP1 on myotube atrophy and osteoclastogenesis. 8-week-old male wild-type (WT) C57BL/6J and IGFBP1-KO mice were intrasplenically injected with MC38 tumor cells (mMC38) to mimic hepatic dissemination of cancer cells, while sham-operated animals received saline. Animals were assessed for muscle force 24-hours prior to euthanasia, and skeletal muscles and bone were collected for molecular and morphological analyses. CRC patients and CRC tumor-bearing mice demonstrated markedly elevated circulating plasma IGFBP1, also supported by increased liver IGFBP1 mRNA expression in C26, MC38 and HCT116 hosts. Follow-up in vitro studies demonstrated that co-culturing CRC cells (lacking IGFBP1 expression) with AML12 hepatocytes promotes IGFBP1 production, thereby suggesting that IGFBP1 is purely host-derived. Further, treatment with recombinant IGFBP1 was sufficient to stimulate osteoclastogenesis, while also promoting atrophy of C2C12 myotubes. Conversely, use of anti-IGFBP1 neutralizing antibodies prevented osteoclastogenesis and preserved C2C12 myotube size when exposed to plasma from mice bearing CRCs. Notably, WT mMC38 bearers displayed reductions in muscle mass and strength, as well as in trabecular bone volume fraction (BV/TV) and trabecular number (Tb.N). Conversely, IGFBP1-KO tumor hosts exhibited preserved skeletal muscle and bone mass. Altogether, our data implicate IGFBP1, an exquisitely liver-derived factor, as a novel mediator of musculoskeletal deficits in CRC cachexia, and supports novel strategies to counteract host-derived factors in the treatment of cancer-associated multi-organ complications. Citation Format: Joshua R. Huot, Fabrizio Pin, Andrea Bonetto. IGFBP1 mediates musculoskeletal defects in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3490.
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Trepitaki, Lidia K., Irina V. Kaplieva, Elena M. Frantsiyants, Viktoriya L. Volkova, Dmitry A. Kharagezov, Igor A. Leyman, Oleg N. Stateshny, and Anton G. Milakin. "Levels of the IGF system components in malignant lesions of the lungs with preventive effect of 1,3-diethylbenzimidazolium triiodide in the experiment." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15095-e15095. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15095.
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e15095 Background: The system of insulin-like growth factors (IGF) is involved in carcinogenesis, since it promotes proliferation and survival of tumor cells. The purpose of the study was an analysis of the dynamics of the IGF system components in the lungs of rats with antitumor effect of 1,3-diethylbenzimidazolium triiodide. Methods: The main group included male (n=27) and female (n=27) white outbred rats with sarcoma 45 inoculated into the subclavian vein (2×106 cells in 0.5 mL saline) but not developed in the lungs due to administration of 1,3-diethylbenzimidazolium triiodide (intragastrically, 0.4 mg/kg once a day according to the regimen: administration for 5 days with a 2-day interval). Control group included males (n=14) and females (n=14) with sarcoma 45 growing in the lungs without treatment. Intact groups included 5 males and 5 females. After 4, 5 and 8 weeks of the experiment animals were decapitated, and levels of IGFI, IGFII, IGFBP1, IGFBP2 and IGFBP3 were measured by ELISA in 10% lung homogenates (CUSABIO BIOTECH Co., Ltd., China). Results: The sarcoma development in the lung was accompanied by the IGFI increase by 2.4-3.0 times in males and by 4.3 times in females, and the opposite IGFII dynamics: an increase in males (by 4.6 times) and decrease in females (by 4.3 times), together with the IGFBP decline. 1,3-diethylbenzimidazolium triiodide upregulated IGFI levels in the lungs of all rats on average by 1.3 times (p<0.05) and normalized IGFII in males, while increasing it in females by 1.6 times (p<0.05), together with higher (compared to controls) IGFBP levels. Conclusions: Preventive antitumor effect of 1.3-diethylbenzimidazolium triiodide is based on the stabilization of the IGF system grossly altered during the malignant process development in the lung.
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Tang, Qing, JingJing Wu, Fang Zheng, Swei Sunny Hann, and YuQing Chen. "Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer." Cellular Physiology and Biochemistry 41, no. 1 (2017): 339–57. http://dx.doi.org/10.1159/000456281.
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Background: Emodin has anti-neoplastic activities on multiple tumors. However, the molecular mechanisms underlying this effect still remain to be fully understood. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays and flow cytometry, respectively. Cell invasion and migration were examined by transwell invasion and wound healing assays. Western blot analysis was performed to examine the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα), extracellular signaling-regulated kinase 1/2 (ERK1/2), peroxisome proliferators-activated receptor gamma (PPARγ), insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and the transcription factor Sp1. QRT-PCR was used to examine the mRNA levels of the IGFBP1 gene. Small interfering RNAs (siRNAs) were used to knockdown PPARγ and IGFBP1 genes. Exogenously expression of IGFBP1 and Sp1 was determined by transient transfection assays. IGFBP1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. In vivo nude mice xenograft model and bioluminescent imaging system were used to confirm the findings. Results: We showed that emodin induced cell cycle arrest of NSCLC cells. Emodin increased PPARγ protein and luciferase reporter activity, which were abolished by inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK)/ERK and AMPK. Silencing of PPARγ abrogated emodin-inhibited cell growth and cell cycle arrest. Furthermore, emodin elevated IGFBP1 mRNA, protein, and promoter activity through activation of PPARγ. Intriguingly, overexpressed Sp1 attenuated emodin-induced IGFBP1 expression, which was not observed in cells with silenced PPARγ gene. Moreover, silencing of IGFBP1 gene blunted emodin-induced inhibition of cell growth and cell cycle arrest. On the contrary, overexpressed IGFBP1 enhanced emodin-induced phosphorylation of AMPKα and ERK1/2, and restored emodin-inhibited growth in cells with silenced endogenous IGFBP1 gene. Emodin also inhibited growth of lung xenograft tumors and Sp1, and increased IGFBP1 and PPARγ protein expressions In vivo. Conclusion: Collectively, our results show that emodin inhibits growth of non-small-cell lung cancer (NSCLC) cells through ERK and AMPKα-mediated induction of PPARγ, followed by reduction of Sp1. This in turn induces IGFBP1 gene expression. Thus, the signaling cascades, positive feedback loop and cooperative interplay between transcription factors-induced the expression of IGFBP1 gene contribute to the overall responses of emodin. This study provides a novel mechanism by which emodin inhibits growth of human lung cancer cells.
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Lewitt, Moira S., Agneta Hilding, Kerstin Brismar, Suad Efendic, Claes-Göran Östenson, and Kerstin Hall. "IGF-binding protein 1 and abdominal obesity in the development of type 2 diabetes in women." European Journal of Endocrinology 163, no. 2 (August 2010): 233–42. http://dx.doi.org/10.1530/eje-10-0301.
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ObjectiveLow levels of IGF-binding protein 1 (IGFBP1) are associated with metabolic syndrome and predict diabetes development in men. The aim of this study was to determine the levels of IGFBP1 in women who later develop diabetes, in relation to abdominal obesity, and to compare these levels with those of men.MethodsIGFBP1 levels were determined at baseline and after 8 years in a case–control, prospective study of Swedish women aged 35–56 years. Individuals with normal oral glucose tolerance test (OGTT) who developed abnormal glucose regulation (n=240) were pair matched to controls for age and family history of diabetes and also compared to men of the same age (n=355).ResultsLow fasting IGFBP1 and increased waist measurement predicted development of diabetes in women (n=60; odds ratio (OR) 70, 95% confidence interval (CI) 8–661, lowest tertile and OR 27, 95% CI 5–141, highest tertile). In women developing diabetes, baseline IGFBP1 levels were lower than expected for fasting insulin values, were associated with impaired suppression after OGTT and increased during 8 years despite an increase in fasting insulin. All individuals in the highest tertile for waist and with ≤40% suppression of IGFBP1 developed diabetes within 8 years. Circulating IGFBP1 concentrations were higher in women compared to men. Women and men who developed diabetes had a similar degree of abdominal obesity, corrected for height.ConclusionsWe conclude that low IGFBP1 and elevated waist measurement predict diabetes development and that IGFBP1 production is suppressed by a novel factor(s) in women developing diabetes. Increasing levels of IGFBP1 during the emergence of diabetes in men and women suggest the emergence of hepatic insulin resistance.
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Shi, L., D. Banerjee, A. Dobierzewska, S. Sathishkumar, A. A. Karakashian, N. V. Giltiay, and M. N. Nikolova-Karakashian. "Direct regulation of IGF-binding protein 1 promoter by interleukin-1β via an insulin- and FoxO-1-independent mechanism." American Journal of Physiology-Endocrinology and Metabolism 310, no. 8 (April 15, 2016): E612—E623. http://dx.doi.org/10.1152/ajpendo.00289.2015.
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The level of insulin-like growth factor-binding protein 1 (IGFBP1), a liver-produced serum protein that regulates insulin-like growth factor-I bioactivity, glucose homeostasis, and tissue regeneration, increases during inflammation. This manuscript describes a novel pathway for the regulation of hepatic IGFBP1 mRNA and protein levels by interleukin (IL)-1β. Experiments with the luciferase reporter system show that IL-1β stimulates transcriptional activity from the 1-kb promoter region of IGFBP1. Although IL-1β stimulation suppresses the insulin activation of protein kinase B, the major upstream regulator of IGFBP1 mRNA transcription, the induction of IGFBP1 by IL-1β did not require an intact insulin response element. Furthermore, neither overexpression nor silencing of FoxO-1 had any effect on the IL-1β-induced increase in IGFBP1 mRNA levels and promoter activity. However, inhibition of the ERK MAP kinases effectively prevented the IL-1β effects. Inhibition of neutral sphingomyelinase, a key player in the IL-1β signaling cascade that acts upstream of ERK, also suppressed the IL-1β effects, while increasing the ceramide, through the addition of C2-ceramide or via treatment with exogenous sphingomyelinase, was sufficient to induce IGFBP1 promoter-driven luciferase activity. Studies in primary rat hepatocytes where the levels of neutral sphingomyelinase were either elevated or suppressed using adenoviral constructs affirmed the key role of neutral sphingomyelinase and ceramide (exerted likely through ERK activation) in the IL-1β-induced IGFBP1 production. Finally, the IL-1β effects on IGFBP1 mRNA production and protein secretion could be abolished by the addition of insulin, either at very late time points or at very high doses.
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Forsberg, Elisabete A., Ileana R. Botusan, Jing Wang, Verena Peters, Ishrath Ansurudeen, Kerstin Brismar, and Sergiu Bogdan Catrina. "Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1." Journal of Endocrinology 225, no. 3 (April 13, 2015): 159–67. http://dx.doi.org/10.1530/joe-14-0571.
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IGF binding protein 1 (IGFBP1) is a member of the binding proteins for the IGF with an important role in glucose homeostasis. Circulating IGFBP1 is derived essentially from the liver where it is mainly regulated negatively by insulin. Carnosine, a natural antioxidant, has been shown to improve metabolic control in different animal models of diabetes but its mechanisms of action are still not completely unraveled. We therefore investigate the effect of carnosine treatment on the IGFBP1 regulation in db/db mice. Db/db mice and heterozygous non-diabetic mice received for 4 weeks regular water or water supplemented with carnosine.Igfbp1mRNA expression in the liver was evaluated using qPCR and the protein levels in plasma by western blot. Plasma IGF1 and insulin were analyzed using immunoassays. HepG2 cells were used to study thein vitroeffect of carnosine on IGFBP1. The modulation of hypoxia inducible factor-1 alpha (HIF-1α) which is the central mediator of hypoxia-induction of IGFBP1 was analyzed using: WB, reporter gene assay and qPCR. Carnosine decreased the circulating IGFBP1 levels and the liver expressionIgfbp1, through a complex mechanism acting both directly by suppressing the HIF-1α-mediated IGFBP1 induction and indirectly through increasing circulating insulin level followed by a decrease in the blood glucose levels and increased the plasma levels or IGF1. Reduction of IGFBP1 in diabetes through insulin-dependent and insulin-independent pathways is a novel mechanism by which carnosine contributes to the improvement of the metabolic control in diabetes.
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Zheng, Fang, Jingjing Wu, Xiong Li, Qing Tang, LiJun Yang, Xiaobing Yang, WanYin Wu, and Swei Sunny Hann. "Chinese Herbal Medicine Fuzheng Kang-Ai Decoction Inhibited Lung Cancer Cell Growth through AMPKα-Mediated Induction and Interplay of IGFBP1 and FOXO3a." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/5060757.
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The aim of this study is to investigate the actions of Chinese herbal medicine, called “Fuzheng Kang-Ai” (FZKA for short) decoction, against non-small cell lung cancer (NSCLC) and its mechanismsin vitroandin vivo. We showed that the effect of FZKA decoction significantly inhibited growth of A549 and PC9 cells. Furthermore, FZKA increased phosphorylation of AMP-activated protein kinase alpha (AMPKα) and induced protein expression of insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and forkhead homeobox type O3a (FOXO3a). The specific inhibitor of AMPKα(Compound C) blocked FZKA-induced protein expression of IGFBP1 and FOXO3a. Interestingly, silencing of IGFBP1 and FOXO3a overcame the inhibitory effect of FZKA on cell growth. Moreover, silencing of IGFBP1 attenuated the effect of FZKA decoction on FOXO3a expression, and exogenous expression of FOXO3a enhanced the FZKA-stimulated phosphorylation of AMPKα. Accordingly, FZKA inhibited the tumor growth in xenograft nude mice model. Collectively, our results show that FZKA decoction inhibits proliferation of NSCLC cells through activation of AMPKα, followed by induction of IGFBP1 and FOXO3a proteins. Exogenous expression of FOXO3a feedback enhances FZKA decoction-stimulated IGFBP1 expression and phosphorylation of AMPKα. The reciprocal interplay of IGFBP1 and FOXO3a contribute to the overall responses of FAKA decoction.
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Wächter, Kristin, Marcel Köhn, Nadine Stöhr, and Stefan Hüttelmaier. "Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains." Biological Chemistry 394, no. 8 (August 1, 2013): 1077–90. http://dx.doi.org/10.1515/hsz-2013-0111.
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Abstract The IGF2 mRNA-binding protein family (IGF2BPs) directs the cytoplasmic fate of various target mRNAs and controls essential cellular functions. The three IGF2BP paralogues expressed in mammals comprise two RNA-recognition motifs (RRM) as well as four KH domains. How these domains direct IGF2BP paralogue-dependent protein function remains largely elusive. In this study, we analyze the role of KH domains in IGF2BPs by the mutational GXXG-GEEG conversion of single KH domain loops in the context of full-length polypeptides. These analyses reveal that all four KH domains of IGF2BP1 and IGF2BP2 are essentially involved in RNA-binding in vitro and the cellular association with RNA-binding proteins (RBPs). Moreover the KH domains prevent the nuclear accumulation of these two paralogues and facilitate their recruitment to stress granules. The role of KH domains appears less pronounced in IGF2BP3, because GxxG-GEEG conversion in all four KH domains only modestly affects RNA-binding, subcellular localization and RNA-dependent protein association of this paralogue. These findings indicate paralogue-dependent RNA-binding properties of IGF2BPs which likely direct distinct cellular functions. Our findings suggest that IGF2BPs contact target RNAs via all four KH domains. This implies significant structural constraints, which presumably allow the formation of exceedingly stable protein-RNA complexes.
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Kistner, Anna, Mireille Vanpée, and Kerstin Hall. "Leptin may enhance hepatic insulin sensitivity in children and women born small for gestational age." Endocrine Connections 2, no. 1 (March 2013): 38–49. http://dx.doi.org/10.1530/ec-12-0071.
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Objective Children born small for gestational age (SGA) are at risk for developing type 2 diabetes. Lipodystrophy leads to early type 2 diabetes and leptin reverses the metabolic consequences of the disease. Low IGF-binding protein 1 (IGFBP1) can predict the development of type 2 diabetes. The aim of this study was to determine leptin, insulin, and IGFBP1 in children and adult women born preterm or SGA to evaluate the role of leptin as a compensatory mechanism in insulin resistance development. Methods Seventy-six children (8.5–10 years, 41 girls and 35 boys) and 45 women (23–30 years) were studied. The children comprised subjects born appropriate for gestational age (<30 gestational weeks) (n=22), born SGA at term (n=23), and full-term normal-weight controls (n=31). Among the women, the corresponding figures were, n=10, n=18, and n=17 respectively. Fasting levels of IGFBP1, leptin, insulin, and IGF1 were determined and total adiponectin only in women. Results In girls and women, term SGA subjects had higher leptin levels in relation to BMI SDS (P=0.042 and P=0.03 respectively). More than half of IGFBP1 variability was explained by leptin and insulin in children. In term SGA women, IGFBP1 level was lower compared with controls (P=0.012) and the regression line of IGFBP1 on insulin was suppressed below −1 s.d. of a reference material. Conclusion Leptin levels were elevated in term SGA girls and women, in particular in adult women, but not found in preterm girls and women. IGFBP1 was lower in term SGA women. In children, leptin and insulin were strong suppressors of IGFBP1. We speculate that higher leptin levels could be a protective event to enhance hepatic insulin sensitivity.
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Van Dyck, Lisa, Inge Derese, Sarah Vander Perre, Pieter J. Wouters, Michaël P. Casaer, Greet Hermans, Greet Van den Berghe, and Ilse Vanhorebeek. "The GH Axis in Relation to Accepting an Early Macronutrient Deficit and Outcome of Critically Ill Patients." Journal of Clinical Endocrinology & Metabolism 104, no. 11 (July 30, 2019): 5507–18. http://dx.doi.org/10.1210/jc.2019-00842.
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Abstract Context Changes in the GH axis during critical illness resemble fasting in healthy adults and contribute to hypercatabolism, which potentially affects outcome. Accepting macronutrient deficits by withholding parenteral nutrition (PN) during the first week in the intensive care unit (ICU; late PN) reduced complications and accelerated recovery as compared with early use of PN (early PN). Objective To investigate how late PN affects the GH axis in relation to its clinical outcome benefits. Design Preplanned subanalysis of the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients randomized controlled trial. Participants A total of 1128 patients for time-course study, 20 patients investigated for nocturnal GH pulsatility, and 600 patients investigated for muscle weakness, with early PN and late PN patients having comparable baseline characteristics. Intervention Withholding PN during the first ICU week (late PN) vs early PN. Main Outcome Measures Changes in serum GH, IGF-I, IGF-binding protein (IGFBP) 3, and IGFBP1 concentrations from ICU admission to day 4 or last ICU day for patients with a shorter ICU stay (d4/LD) and association in multivariable analyses with likelihood of earlier live ICU discharge, risk of new infection, and muscle weakness. Results Late PN attenuated a rise in serum GH and IGF-I (P < 0.0001), did not affect IGFBP3, and attenuated a decrease in IGFBP1 concentrations from admission to d4/LD (P < 0.0001) as compared with early PN. Late PN decreased nonpulsatile (P = 0.005), but not pulsatile, GH secretion. Adjusting the multivariable models for the observed GH axis alterations increased the independent benefit of late PN for all outcomes. GH axis alterations induced by late PN were independently associated with adverse outcomes (P ≤ 0.03). Conclusion Accepting macronutrient deficits early during critical illness further suppressed the GH axis, which statistically attenuated its clinical outcome benefits.
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Ashraf Soliman, Noor Hamed, Fawzia Alyafei, Nada Alaaraj, Shayma Ahmad, Maya Itani, and Nada Soliman. "Insulin like growth factor 1 (IGF-1) and IGF binding proteins in obese pregnant women and their babies: Potential effects on placental function and fetal growth." World Journal of Advanced Research and Reviews 17, no. 2 (February 28, 2023): 093–100. http://dx.doi.org/10.30574/wjarr.2023.17.2.0222.
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Introduction: The placenta expresses significant amounts of insulin and IGF1 receptors at distinct locations on both fetal and maternal surfaces. This makes the IGF1 and the insulin receptor accessible to fetal and/or maternal insulin, IGF1 and IGF2. IGFs are involved in the receptor-mediated regulation of placental growth and transport, and placental angiogenesis. Maternal obesity during gestation mediates significant changes in the metabolism of mothers, placentas as well as fetal growth. Objectives: In obese women. the role of the insulin like growth factor system IGFs, IGF receptors, IGF-binding proteins (IGFBPs) and IGFBP proteases during gestation, and their effect on placental growth and fetal anthropometric changes need further clarification. In this update we reviewed the literature on the detected changes in the maternal and fetal IGFs in relation to placental growth and function and to fetal growth and newborn size in pregnant obese mothers. Eighteen research articles fitted the criteria of this update. Results: Twenty-three research papers were including 2817 pregnant obese and non-obese women (controls) and their babies were selected and reviewed. Results showed that obesity and excessive nutrient intake during gestation increase maternal IGF1and decreases IGBP1. Increased maternal IGF1 and/or its availability due to decreased IGFBP1 can increase the size (weight) and development of the placenta, stimulate mTOR signaling which stimulates protein synthesis, mitochondrial function, and upregulate specific placental amino acid transporter isoforms (amino acids transport), GLUT-1, (glucose transport) and possibly lipid transport to the fetus which can induce fetal IGF1 secretion and lead to overgrowth. Conclusions: In obese women during pregnancy, increased level of IGF1 and/or its availability due to decreased IGFBP1 can increase the size (weight) and development of the placenta, stimulate mTOR signaling which stimulates protein synthesis, mitochondrial function, and upregulate placental transport of amino acids, glucose and possibly fatty acids.