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Sample records for cancer insulin-like growth

  1. Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women

    DEFF Research Database (Denmark)

    Grønbæk, Henning; Flyvbjerg, Allan; Mellemkjær, L.

    2004-01-01

    BACKGROUND: Studies have shown a positive association between serum insulin-like growth factor (IGF)-I and breast cancer risk in premenopausal but not postmenopausal women. IGF-II and estrogen receptor (ER) status has never been investigated. We examined the association between IGF-I, IGF-II, IGF...... cases with breast cancer and a matched control group including 397 cohort members. We estimated breast cancer risk using Cox regression analysis with adjustment for known breast cancer risk factors. RESULTS: We observed no association for IGF-I but a positive association between levels of IGFBP-3...

  2. Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women

    DEFF Research Database (Denmark)

    Grønbæk, Henning; Flyvbjerg, Allan; Mellemkjær, L.

    2004-01-01

    BACKGROUND: Studies have shown a positive association between serum insulin-like growth factor (IGF)-I and breast cancer risk in premenopausal but not postmenopausal women. IGF-II and estrogen receptor (ER) status has never been investigated. We examined the association between IGF-I, IGF-II, IGF...... binding protein (IGFBP)-2, IGFBP-3, and IGFBP-3 protease activity and breast cancer risk in postmenopausal women, taking ER status of the breast cancer into consideration. METHODS: We conducted this case-cohort study within a Danish follow-up study based on 24,697 postmenopausal women. We identified 411...... and breast cancer risk. Per 500 units higher levels of IGFBP-3, an incidence rate ratio [IRR; 95% confidence interval (95% CI)] of 1.14 (1.00-1.30) was estimated. For ER-positive breast cancer, the IRR (95% CI) was 1.18 (1.05-1.33). IGFBP-3 protease activity was not associated with breast cancer risk. Per...

  3. The insulin-like growth factor system in cancer prevention: potential of dietary intervention strategies.

    NARCIS (Netherlands)

    Voskuil, D.W.; Vrieling, A.; Veer, L.J. van 't; Kampman, E.; Rookus, M.A.

    2005-01-01

    The insulin-like growth factor (IGF) system is related to proliferation and tumor growth, and high levels of circulating IGF-I are thought to be a risk factor for several types of cancer. This review summarizes the epidemiologic evidence for an association between circulating IGF-I and cancer risk

  4. The Insulin-like Growth Factor System in Cancer Prevention: Potential of Dietary intervention Strategies

    NARCIS (Netherlands)

    Voskuil, D.W.; Vrieling, A.; Veer, van 't L.J.; Kampman, E.; Rookus, M.A.

    2005-01-01

    The insulin-like growth factor (IGF) system is related to proliferation and tumor growth, and high levels of circulating IGF-I are thought to be a risk factor for several types of cancer. This review summarizes the epidemiologic evidence for an association between circulating IGF-I and cancer risk

  5. Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer.

    Science.gov (United States)

    Ochnik, Aleksandra M; Baxter, Robert C

    2016-11-01

    Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity 
and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers. © 2016 Society for Endocrinology.

  6. Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer.

    Science.gov (United States)

    Hartog, H; Boezen, H M; de Jong, M M; Schaapveld, M; Wesseling, J; van der Graaf, W T A

    2013-12-01

    High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion

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    Liu Jinsong

    2005-02-01

    Full Text Available Abstract Background Insulin-like growth factor binding protein 2 (IGFBP2 is overexpressed in ovarian malignant tissues and in the serum and cystic fluid of ovarian cancer patients, suggesting an important role of IGFBP2 in the biology of ovarian cancer. The purpose of this study was to assess the role of increased IGFBP2 in ovarian cancer cells. Results Using western blotting and tissue microarray analyses, we showed that IGFBP2 was frequently overexpressed in ovarian carcinomas compared with normal ovarian tissues. Furthermore, IGFBP2 was significantly overexpressed in invasive serous ovarian carcinomas compared with borderline serous ovarian tumors. To test whether increased IGFBP2 contributes to the highly invasive nature of ovarian cancer cells, we generated IGFBP2-overexpressing cells from an SKOV3 ovarian cancer cell line, which has a very low level of endogenous IGFBP2. A Matrigel invasion assay showed that these IGFBP2-overexpressing cells were more invasive than the control cells. We then designed small interference RNA (siRNA molecules that attenuated IGFBP2 expression in PA-1 ovarian cancer cells, which have a high level of endogenous IGFBP2. The Matrigel invasion assay showed that the attenuation of IGFBP2 expression indeed decreased the invasiveness of PA-1 cells. Conclusions We therefore showed that IGFBP2 enhances the invasion capacity of ovarian cancer cells. Blockage of IGFBP2 may thus constitute a viable strategy for targeted cancer therapy.

  8. Epithelial-to-mesenchymal transition in breast cancer: a role for insulin-like growth factor I and insulin-like growth factor–binding protein 3?

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    Zielinska HA

    2015-01-01

    Full Text Available Hanna A Zielinska,1 Amit Bahl,2 Jeff MP Holly,1 Claire M Perks1 1IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol, UK; 2Department of Clinical Oncology, Bristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK Abstract: Evidence indicates that for most human cancers the problem is not that gene mutations occur but is more dependent upon how the body deals with damaged cells. It has been estimated that only about 1% of human cancers can be accounted for by unmistakable hereditary cancer syndromes, only up to 5% can be accounted for due to high-penetrance, single-gene mutations, and in total only 5%–15% of all cancers may have a major genetic component. The predominant contribution to the causation of most sporadic cancers is considered to be environmental factors contributing between 58% and 82% toward different cancers. A nutritionally poor lifestyle is associated with increased risk of many cancers, including those of the breast. As nutrition, energy balance, macronutrient composition of the diet, and physical activity levels are major determinants of insulin-like growth factor (IGF-I bioactivity, it has been proposed that, at least in part, these increases in cancer risk and progression may be mediated by alterations in the IGF axis, related to nutritional lifestyle. Localized breast cancer is a manageable disease, and death from breast cancer predominantly occurs due to the development of metastatic disease as treatment becomes more complicated with poorer outcomes. In recent years, epithelial-to-mesenchymal transition has emerged as an important contributor to breast cancer progression and malignant transformation resulting in tumor cells with increased potential for migration and invasion. Furthermore, accumulating evidence suggests a strong link between components of the IGF pathway, epithelial

  9. Targeting the insulin-like growth factor-1 receptor in human cancer

    Directory of Open Access Journals (Sweden)

    Alexandre eArcaro

    2013-03-01

    Full Text Available The insulin-like growth factor (IGF signaling system plays a crucial role in human cancer and the IGF-1 receptor (IGF-1R is an attractive drug target against which a variety of novel anti-tumor agents are being developed. Deregulation of the IGF signaling pathway frequently occurs in human cancer and involves the establishment of autocrine loops comprising IGF-1 or -2 and/or IGF-1R over-expression. Epidemiologic studies have documented a link between elevated IGF levels and the development of solid tumors, such as breast, colon and prostate cancer. Anticancer strategies targeting the IGF signaling system involve two main approaches, namely neutralizing antibodies and small molecule inhibitors of the IGF-1R kinase activity. There are numerous reports describing anti-tumor activity of these agents in pre-clinical models of major human cancers. In addition, multiple clinical trials have started to evaluate the safety and efficacy of selected IGF-1R inhibitors, in combination with standard chemotherapeutic regimens or other targeted agents in cancer patients. In this Mini Review, I will discuss the role of the IGF signaling system in human cancer and the main strategies which have been so far evaluated to target the IGF-1R.

  10. Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk

    DEFF Research Database (Denmark)

    Pearce, Celeste Leigh; Doherty, Jennifer A; Van Den Berg, David J

    2011-01-01

    The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial...

  11. Isolated isoflavones do not affect the circulating insulin-like growth factor system in men at increased colorectal cancer risk.

    NARCIS (Netherlands)

    Vrieling, A.; Rookus, M.A.; Kampman, E.; Bonfrer, J.M.G.; Korse, C.M.; Doorn, J. van; Lampe, J.W.; Cats, A.; Witteman, B.J.M.; Leeuwen, F.E. van; Veer, L.J. van 't; Voskuil, D.W.

    2007-01-01

    Epidemiological studies show that increased insulin-like growth factor (IGF)-I concentrations are related to increased colorectal cancer risk. A reduced colorectal cancer risk has been associated with isoflavones, which might affect the IGF-system because of their weak estrogenic activity. We

  12. Isolated Isoflavones do not affect the circulating insulin-like growth factor system in men at increased colorectal cancer risk

    NARCIS (Netherlands)

    Vrieling, A.; Rookus, M.A.; Kampman, E.; Bonfrer, J.M.G.; Korse, C.M.; Doorn, van J.; Lampe, J.W.; Cats, A.; Witteman, B.J.M.; Leeuwen, van F.E.; van't Veer, L.J.; Voskuil, D.W.

    2007-01-01

    Epidemiological studies show that increased insulin-like growth factor (IGF)-I concentrations are related to increased colorectal cancer risk. A reduced colorectal cancer risk has been associated with isoflavones, which might affect the IGF-system because of their weak estrogenic activity. We

  13. Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer.

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    Dong, Xiaoqun; Li, Yanan; Tang, Hongwei; Chang, Ping; Hess, Kenneth R; Abbruzzese, James L; Li, Donghui

    2012-04-01

    Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer. We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes (IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS4) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level. We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2-70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60-0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons (P≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively (PC and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes (P(interaction)=.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption (P(interaction)=.03 and .019, respectively) on increased pancreatic cancer risk. These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. The insulin-like growth factor 1 receptor in cancer : Old focus, new future

    NARCIS (Netherlands)

    Hartog, Hermien; Wesseling, Jelle; Boezen, H. Marike; van der Graaf, Winette T. A.

    The importance of insulin-like growth factor 1 receptor (IGF-1R) signalling in malignant behaviour of tumour cells is well established. Currently, development of drugs targeting the IGF-1R as anticancer treatment is emerging. Several IGF-1R targeting strategies are being investigated in phases I and

  15. Insulin-like growth factor 1 gene polymorphism in women with breast cancer.

    Science.gov (United States)

    Costa-Silva, Danylo Rafhael; da Conceição Barros-Oliveira, Maria; Borges, Rafael Soares; Campos-Verdes, Larysse Maira; da Silva-Sampaio, João Paulo; Escorcio-Dourado, Carla Solange; Martins, Luana Mota; Alencar, Airlane Pereira; Baracat, Edmund Chada; Silva, Vladimir Costa; da Silva, Benedito Borges

    2017-04-01

    Breast cancer is a disease of unknown etiology; however, the major risk factors are genetic alterations. Studies have demonstrated an association between insulin-like growth factor 1 (IGF-1) gene polymorphism and cell proliferation and reduced apoptosis, in addition to its role in breast cancer growth and aggressiveness. Two polymorphic variants of the IGF-1 gene are highlighted in association with breast cancer, rs6220 and rs7136446, although controversy exists as to this relationship. The current study included 137 women (68 breast cancer cases and 69 controls without breast cancer) who had 3 ml of peripheral blood drawn for the study of genomic DNA extracted from leukocytes using the genotyping technique by real-time polymerase chain reaction. The CC genotype (rs7136446) was present in 4 women (5.9%) from the case group and in 2 (3.0%) women from the control group (p = 0.67), while the GG genotype (rs6220) occurred in 8 (11.5%) women from the case group and in 5 (7.2%) women from the control group (p = 0.75). No statistically significant difference was observed between the CC genotype of variant rs7136446 in premenopausal case and control women (p = 0.31), thus as there was also no significant difference between case and control postmenopausal women (p = 1.00). Concerning the GG genotype of rs6220, it occurred in 6 (14.2%) premenopausal case and 4 (8%) control women (p = 0.71) and no difference was found in postmenopausal women (p = 1.00). In the current study, IGF-1 gene polymorphism of SNP variants rs6220 and rs7136446 had no statistically significant association with breast cancer, both in premenopausal and postmenopausal women.

  16. Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization

    DEFF Research Database (Denmark)

    Bonilla, Carolina; Lewis, Sarah J; Rowlands, Mari-Anne

    2016-01-01

    Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotid...

  17. Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization

    DEFF Research Database (Denmark)

    Bonilla, Carolina; Lewis, Sarah J; Rowlands, Mari-Anne

    2016-01-01

    Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide...

  18. Polymorphisms in the insulin-like growth factor axis are associated with gastrointestinal cancer.

    Science.gov (United States)

    Ong, Jennie; Salomon, Jody; te Morsche, Rene H M; Roelofs, Hennie M J; Witteman, Ben J M; Dura, Polat; Lacko, Martin; Peters, Wilbert H M

    2014-01-01

    Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied. In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression. Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01) and 1.71 (95% CI, 1.10-2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC. The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.

  19. Polymorphisms in the insulin-like growth factor axis are associated with gastrointestinal cancer.

    Directory of Open Access Journals (Sweden)

    Jennie Ong

    Full Text Available INTRODUCTION: Numerous factors influence the development of gastrointestinal (GI cancer. The insulin-like growth factor (IGF axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs and over-expression of IGF receptor (IGFR-I were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs rs6214 in the IGF type I (IGF-I gene and rs6898743 in the growth hormone receptor (GHR gene in patients with GI cancer and controls was studied. MATERIALS & METHODS: In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC, 475 with esophageal cancer (EC and 544 with colorectal cancer (CRC and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC, esophageal squamous-cell carcinoma (ESCC and proximal or distal CRC was studied. Odds ratios (ORs with 95% confidence interval (95% CI were calculated via unconditional logistic regression. RESULTS: Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05, using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27 was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01 and 1.71 (95% CI, 1.10-2.68, for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86 for ESCC. CONCLUSION: The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.

  20. Insulin like growth factor 2 regulation of aryl hydrocarbon receptor in MCF-7 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tomblin, Justin K.; Salisbury, Travis B., E-mail: salisburyt@marshall.edu

    2014-01-17

    Highlights: •IGF-2 stimulates concurrent increases in AHR and CCND1 expression. •IGF-2 promotes the binding of AHR to the endogenous cyclin D1 promoter. •AHR knockdown inhibits IGF-2 stimulated increases in CCND1 mRNA and protein. •AHR knockdown inhibits IGF-2 stimulated increases in MCF-7 proliferation. -- Abstract: Insulin like growth factor (IGF)-1 and IGF-2 stimulate normal growth, development and breast cancer cell proliferation. Cyclin D1 (CCND1) promotes cell cycle by inhibiting retinoblastoma protein (RB1). The aryl hydrocarbon receptor (AHR) is a major xenobiotic receptor that also regulates cell cycle. The purpose of this study was to investigate whether IGF-2 promotes MCF-7 breast cancer proliferation by inducing AHR. Western blot and quantitative real time PCR (Q-PCR) analysis revealed that IGF-2 induced an approximately 2-fold increase (P < .001) in the expression of AHR and CCND1. Chromatin immunoprecipitation (ChIP), followed by Q-PCR indicated that IGF-2 promoted (P < .001) a 7-fold increase in AHR binding on the CCND1 promoter. AHR knockdown significantly (P < .001) inhibited IGF-2 stimulated increases in CCND1 mRNA and protein. AHR knockdown cells were less (P < .001) responsive to the proliferative effects of IGF-2 than control cells. Collectively, our findings have revealed a new regulatory mechanism by which IGF-2 induction of AHR promotes the expression of CCND1 and the proliferation of MCF-7 cells. This previously uncharacterized pathway could be important for the proliferation of IGF responsive cancer cells that also express AHR.

  1. ImmunoPET Imaging of Insulin-Like Growth Factor 1 Receptor in a Subcutaneous Mouse Model of Pancreatic Cancer

    Science.gov (United States)

    2016-06-30

    ImmunoPET Imaging of Insulin-Like Growth Factor 1 Receptor in a Subcutaneous Mouse Model of Pancreatic Cancer Christopher G. England,†,# Anyanee...and Weibo Cai*,†,‡,⊥ †Department of Medical Physics, ‡Department of Radiology, and ⊥Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin...Seoul 110-744, Korea ∥NeoClone Biotechnologies International, Madison, Wisconsin 53713, United States *S Supporting Information ABSTRACT: The role of

  2. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Sun Yunguang [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zheng Siyuan [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J. [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Carbone, David P. [Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zhao Zhongming, E-mail: zhongming.zhao@vanderbilt.edu [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Lu Bo, E-mail: bo.lu@vanderbilt.edu [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States)

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  3. Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Ludwig, Joseph A., E-mail: jaludwig@mdanderson.org; Lamhamedi-Cherradi, Salah-Eddine [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Lee, Ho-Young [Departments of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Naing, Aung [Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Benjamin, Robert [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States)

    2011-07-26

    The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

  4. Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

    Directory of Open Access Journals (Sweden)

    Aung Naing

    2011-07-01

    Full Text Available The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R, in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

  5. Effects of Lycopene on the Insulin-Like Growth Factor (IGF) System in Premenopausal Breast Cancer Survivors and Women at High Familial Breast Cancer Risk

    NARCIS (Netherlands)

    Voskuil, Dorien W.; Vrieling, Alina; Korse, Catharina M.; Beijnen, Jos H.; Bonfrer, Johannes M. G.; van Doorn, Jaap; Kaas, Reinie; Oldenburg, Hester S. A.; Russell, Nicola S.; Rutgers, Emiel J. T.; Verhoef, Senno; van Leeuwen, Flora E.; van't Veer, Laura J.; Rookus, Matti A.

    2008-01-01

    Insulin-like growth factor-I (IGF-I) is an important growth factor associated with increased risk of premenopausal breast cancer. We conducted a randomized, placebo-controlled, double-blind, crossover trial to evaluate whether tomato-derived lycopene supplementation (30 mg/day for 2 mo) decreases

  6. Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer.

    Science.gov (United States)

    Haus, E; Dumitriu, L; Nicolau, G Y; Bologa, S; Sackett-Lundeen, L

    2001-07-01

    Circadian rhythms in plasma concentrations of many hormones and cytokines determine their effects on target cells. Circadian variations were studied in cortisol, melatonin, cytokines (basic fibroblast growth factor IbFGF], EGF, insulin-like growth factor-1 [IGF-1]), and a cytokine receptor (insulin-like growth factor binding protein-3 [IGFBP-3]) in the plasma of 28 patients with metastatic breast cancer. All patients followed a diurnal activity pattern. Blood was drawn at 3h intervals during waking hours and once during the night, at 03:00. The plasma levels obtained by enzyme-linked immunoassay (ELISA) or radioimmunoassay (RIA) were evaluated by population mean cosinor (using local midnight as the phase reference) and by one-way analysis of variance (ANOVA). Cortisol and melatonin showed a high-amplitude circadian rhythm and a superimposed 12h frequency. bFGF showed a circadian rhythm with an acrophase around 13:00 with a peak-to-trough interval (double amplitude) of 18.2% and a superimposed 12h frequency. EGF showed a circadian rhythm with an acrophase around 14:20, a peak-to-trough interval of 25.8%, and a superimposed 12h frequency. IGF-1 showed a high value in the morning, which is statistically different (t test) from the low value at 10:00, but a regular circadian or ultradian rhythm was not recognizable as a group phenomenon. IGFBP-3 showed a low-amplitude (peak-to-trough difference 8.4%) circadian rhythm with the acrophase around 11:00 and low values during the night. (1) Circadian periodicity is maintained in hospitalized patients with metastatic breast cancer. (2) Ultradian (12h) variations were superimposed on the circadian rhythms of the hormones and several of the cytokines measured. (3) Studies of hormones and cytokines in cancer patients have to take their biologic rhythms into consideration. (4) The circadian periodicity of tumor growth stimulating or restraining factors raises questions about circadian and/or ultradian variations in the

  7. Lycopene supplementation elevates circulating insulin-like growth factor-binding protein-1 and-2 concentrations in persons at greater risk of colorectal cancer

    NARCIS (Netherlands)

    Vrieling, A.; Voskuil, D.W.; Bonfrer, J.M.; Korse, C.M.; Doorn, J.; Cats, A.; Depla, A.C.; Timmer, R.; Witteman, B.J.M.; Leeuwen, van F.E.; van't Veer, L.J.; Rookus, M.A.; Kampman, E.

    2007-01-01

    Background: Higher circulating insulin-like growth factor I (IGF-I) concentrations have been related to a greater risk of cancer. Lycopene intake is inversely associated with cancer risk, and experimental studies have shown that it may affect the IGF system, possibly through an effect on IGF-binding

  8. Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer.

    NARCIS (Netherlands)

    Vrieling, A.; Voskuil, D.W.; Bonfrer, J.M.G.; Korse, C.M.; Doorn, J. van; Cats, A.; Depla, A.C.; Timmer, R.; Witteman, B.J.M.; Leeuwen, F.E. van; Veer, L.J. van 't; Rookus, M.A.; Kampman, E.

    2007-01-01

    BACKGROUND: Higher circulating insulin-like growth factor I (IGF-I) concentrations have been related to a greater risk of cancer. Lycopene intake is inversely associated with cancer risk, and experimental studies have shown that it may affect the IGF system, possibly through an effect on IGF-binding

  9. No effect of red clover-derived isoflavone intervention on the insulin-like growth factor system in women at increased risk of colorectal cancer.

    NARCIS (Netherlands)

    Vrieling, A.; Rookus, M.A.; Kampman, E.; Bonfrer, J.M.G.; Bosma, A.; Cats, A.; Doorn, J. van; Korse, C.M.; Witteman, B.J.M.; Leeuwen, F.E. van; Veer, L.J. van 't; Voskuil, D.W.

    2008-01-01

    BACKGROUND: Increased insulin-like growth factor (IGF)-I and IGF-II concentrations are related to increased colorectal cancer risk. Isoflavones have been associated with reduced colorectal cancer risk, and may affect the IGF system because of their weak estrogenic activity. The aim of the study was

  10. Biologic Roles of Estrogen Receptor-β and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nalo Hamilton

    2015-01-01

    Full Text Available Triple-negative breast cancer (TNBC occurs in 10–15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2, along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

  11. Serum Insulin-Like Growth Factor Axis and the Risk of Pancreatic Cancer: Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Yuanfeng Gong

    2017-04-01

    Full Text Available Objective: To investigate the association between serum concentration of insulin-like growth factor (IGF and the risk of pancreatic cancer (PaC. Methods: We identified eligible studies in Medline and EMBASE databases (no reference trials from 2014 to 2016 in addition to the reference lists of original studies and review articles on this topic. A summary of relative risks with 95% confidence intervals (CI was calculated using a random-effects model. The heterogeneity between studies was assessed using Cochran Q and I2 statistics. Results: Ten studies (seven nested case-control studies and three retrospective case-control studies were selected as they met our inclusion criteria in this meta-analysis. All these studies were published between 1997 and 2013. The current data suggested that serum concentrations of IGF-I, IGF-II and insulin-like growth factor binding protein-3 (IGFBP-3in addition to the IGF-I/IGFBP-3 ratio were not associated with an increased risk of PaC (Summary relative risks (SRRs = 0.92, 95% CI: 0.67–1.16 for IGF-I; SRRs = 0.84, 95% CI: 0.54–1.15 for IGF-II; SRRs = 0.93, 95% CI: 0.69–1.17 for IGFBP-3; SRRs = 0.97, 95% CI: 0.71–1.23 for IGF-I/IGFBP-3 ratio. There was no publication bias in the present meta-analysis. Conclusion: Serum concentrations of IGF-I, IGF-II, IGFBP-1 and IGFBP-3 as well as the IGF-I/IGFBP-3 ratio were not associated with increased risk of PaC.

  12. Serum Insulin-Like Growth Factor Axis and the Risk of Pancreatic Cancer: Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Gong, Yuanfeng; Zhang, Bingyi; Liao, Yadi; Tang, Yunqiang; Mai, Cong; Chen, Tiejun; Tang, Hui

    2017-04-18

    To investigate the association between serum concentration of insulin-like growth factor (IGF) and the risk of pancreatic cancer (PaC). We identified eligible studies in Medline and EMBASE databases (no reference trials from 2014 to 2016) in addition to the reference lists of original studies and review articles on this topic. A summary of relative risks with 95% confidence intervals (CI) was calculated using a random-effects model. The heterogeneity between studies was assessed using Cochran Q and I² statistics. Ten studies (seven nested case-control studies and three retrospective case-control studies) were selected as they met our inclusion criteria in this meta-analysis. All these studies were published between 1997 and 2013. The current data suggested that serum concentrations of IGF-I, IGF-II and insulin-like growth factor binding protein-3 (IGFBP-3)in addition to the IGF-I/IGFBP-3 ratio were not associated with an increased risk of PaC (Summary relative risks (SRRs) = 0.92, 95% CI: 0.67-1.16 for IGF-I; SRRs = 0.84, 95% CI: 0.54-1.15 for IGF-II; SRRs = 0.93, 95% CI: 0.69-1.17 for IGFBP-3; SRRs = 0.97, 95% CI: 0.71-1.23 for IGF-I/IGFBP-3 ratio). There was no publication bias in the present meta-analysis. Serum concentrations of IGF-I, IGF-II, IGFBP-1 and IGFBP-3 as well as the IGF-I/IGFBP-3 ratio were not associated with increased risk of PaC.

  13. Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

    Science.gov (United States)

    Saldana, Sandra M; Lee, Heng-Huan; Lowery, Frank J; Khotskaya, Yekaterina B; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Steeg, Patricia S; Yu, Dihua; Hung, Mien-Chie

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

  14. Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nalo Hamilton

    2017-11-01

    Full Text Available Triple-negative breast cancer (TNBC occurs in 10–15% of all breast cancer patients, yet it accounts for about half of all breast cancer deaths. There is an urgent need to identify new antitumor targets to provide additional treatment options for patients afflicted with this aggressive disease. Preclinical evidence suggests a critical role for insulin-like growth factor-2 (IGF2 and androgen receptor (AR in regulating TNBC progression. To advance this work, a panel of TNBC cell lines was investigated with all cell lines showing significant expression of IGF2. Treatment with IGF2 stimulated cell proliferation in vitro (p < 0.05. Importantly, combination treatments with IGF1R inhibitors BMS-754807 and NVP-AEW541 elicited significant inhibition of TNBC cell proliferation (p < 0.001. Based on Annexin-V binding assays, BMS-754807, NVP-AEW541 and enzalutamide induced TNBC cell death (p < 0.005. Additionally, combination of enzalutamide with BMS-754807 or NVP-AEW541 exerted significant reductions in TNBC proliferation even in cells with low AR expression (p < 0.001. Notably, NVP-AEW541 and BMS-754807 reduced AR levels in BT549 TNBC cells. These results provide evidence that IGF2 promotes TNBC cell viability and proliferation, while inhibition of IGF1R/IR and AR pathways contribute to blockade of TNBC proliferation and promotion of apoptosis in vitro.

  15. Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells.

    Science.gov (United States)

    Lyons, Amy; Coleman, Michael; Riis, Sarah; Favre, Cedric; O'Flanagan, Ciara H; Zhdanov, Alexander V; Papkovsky, Dmitri B; Hursting, Stephen D; O'Connor, Rosemary

    2017-10-13

    Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) and PGC-1α-related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Insulin-like growth factor receptor 1 mRNA expression as a prognostic marker in advanced non-small cell lung cancer

    DEFF Research Database (Denmark)

    Vilmar, Adam; Santoni-Rugiu, Eric; Cillas, Jesus Garcia-Fon

    2014-01-01

    BACKGROUND: The insulin-like growth factor 1 receptor (IGF1R) has yet to be established as a biomarker in non-small cell lung cancer (NSCLC) but could prove useful in customized chemotherapy. We explored its prognostic value using both quantitative real-time reverse transcriptase polymerase chain...

  17. Prediagnostic circulating concentrations of plasma insulin-like growth factor-I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition

    NARCIS (Netherlands)

    Perez-Cornago, Aurora; Appleby, Paul N.; Tipper, Sarah; Key, Timothy J.; Allen, Naomi E.; Nieters, Alexandra; Vermeulen, Roel; Roulland, Sandrine; Casabonne, Delphine; Kaaks, Rudolf; Fortner, Renee T.; Boeing, Heiner; Trichopoulou, Antonia; La Vecchia, Carlo; Klinaki, Eleni; Hansen, Louise; Tjønneland, Anne; Bonnet, Fabrice; Fagherazzi, Guy; Boutron-Ruault, Marie Christine; Pala, Valeria; Masala, Giovanna; Sacerdote, Carlotta; Peeters, Petra H.; Bueno-de-Mesquita, H. Bas; Weiderpass, Elisabete; Dorronsoro, Miren; Quirós, J. Ramón; Barricarte, Aurelio; Gavrila, Diana; Agudo, Antonio; Borgquist, Signe; Rosendahl, Ann H.; Melin, Beatrice; Wareham, Nick; Khaw, Kay Tee; Gunter, Marc; Riboli, Elio; Vineis, Paolo; Travis, Ruth C.

    2017-01-01

    Insulin-like growth factor (IGF)-I has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested

  18. Impact of targeting insulin-like growth factor signaling in head and neck cancers.

    Science.gov (United States)

    Limesand, Kirsten H; Chibly, Alejandro Martinez; Fribley, Andrew

    2013-10-01

    The IGF system has been shown to have either negative or negligible impact on clinical outcomes of tumor development depending on specific tumor sites or stages. This review focuses on the clinical impact of IGF signaling in head and neck cancer, the effects of IGF targeted therapies, and the multi-dimensional role of IRS 1/2 signaling as a potential mechanism in resistance to targeted therapies. Similar to other tumor sites, both negative and positive correlations between levels of IGF-1/IGF-1-R and clinical outcomes in head and neck cancer have been reported. In addition, utilization of IGF targeted therapies has not demonstrated significant clinical benefit; therefore the prognostic impact of the IGF system on head and neck cancer remains uncertain. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Type 1 insulin-like growth factor receptor (IGF-1R targeted therapies in pediatric cancer

    Directory of Open Access Journals (Sweden)

    Michael J Wagner

    2013-02-01

    Full Text Available Data from over 20 years ago demonstrated potential use for IGF signaling modulators, specifically with IGF-1R antagonists, in a variety of pediatric and adolescent cancers, particularly in sarcomas. However, in spite of promising preclinical data, IGF-1R inhibitors have not had the success as single agents that was originally hoped for in clinical trials. Several potential mechanisms exist by which tumors are resistant to IGF-1R inhibitors. Notably, these resistance mechanisms are currently best understood in Ewing sarcoma and alveolar rhabdomyosarcoma. Various treatment schema have been proposed as a potential way to overcome this resistance. The use of IGF-1R inhibitors, mechanisms of resistance, and current ongoing clinical studies using IGF-1R inhibitors in pediatric cancers are reviewed here.

  20. Association of preoperative plasma levels of insulin-like growth factor I and insulin-like growth factor binding proteins-2 and -3 with prostate cancer invasion, progression, and metastasis.

    Science.gov (United States)

    Shariat, Shahrokh F; Lamb, Dolores J; Kattan, Michael W; Nguyen, Cuong; Kim, JaHong; Beck, Josie; Wheeler, Thomas M; Slawin, Kevin M

    2002-02-01

    We tested the hypothesis that preoperative plasma levels of insulin-like growth factor (IGF) binding protein (BP)-2 or IGFBP-3 would predict cancer stage and prognosis in patients undergoing radical prostatectomy. Plasma levels of IGF-I, IGFBP-2, and IGFBP-3 were measured preoperatively in 120 consecutive patients who underwent radical prostatectomy for clinically localized disease, postoperatively in 51 of these patients, in 44 healthy men, in 19 patients with metastases to regional lymph nodes, and in 10 patients with bone metastases. Plasma IGFBP-3 levels were lowest in patients with bone metastases (P Gleason score were independent predictors of biochemical progression (P =.043, P =.040, and P =.020, respectively). In patients with disease progression, preoperative plasma IGFBP-3 levels were lower in those with aggressive than in those with nonaggressive failure (P =.042). Elevation of plasma IGFBP-2 levels in prostate cancer patients apparently is due to increased release directly from the prostate. For patients with clinically localized prostate cancer, preoperative plasma IGFBP-2 levels are inversely associated with biologically aggressive disease and disease progression. Preoperative plasma IGFBP-3 levels were decreased in patients with prostate cancer metastases and were an independent predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy.

  1. Dietary Energy Balance Modulation of Kras– and Ink4a/Arf+/-–Driven Pancreatic Cancer: The Role of Insulin-like Growth Factor-1

    OpenAIRE

    Lashinger, Laura M.; Harrison, Lauren M.; Rasmussen, Audrey J.; Logsdon, Craig D.; Fischer, Susan M.; McArthur, Mark J.; Hursting, Stephen D.

    2013-01-01

    New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF)-1–dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arflox/+ mice, calorie restriction, versus overweight- or obesity-...

  2. Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel

    Science.gov (United States)

    Uzoh, C C; Holly, J M P; Biernacka, K M; Persad, R A; Bahl, A; Gillatt, D; Perks, C M

    2011-01-01

    Background: The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments. Aim: The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel. Methods: DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT–PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting. Results: The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel. Conclusion: The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel. PMID:21487405

  3. Insulin-like growth factor binding protein 2 is a marker for antiestrogen resistant human breast cancer cell lines but is not a major growth regulator.

    Science.gov (United States)

    Juncker-Jensen, A; Lykkesfeldt, A E; Worm, J; Ralfkiaer, U; Espelund, U; Jepsen, J S

    2006-08-01

    Antiestrogens target the estrogen receptor and counteract the growth stimulatory action of estrogen on human breast cancer. However, acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. To mimic acquired resistance, we have used a model system with the antiestrogen sensitive human breast cancer cell line MCF-7 and several antiestrogen resistant cell lines derived from the parental MCF-7 cell line. This model system was used to study the expression and possible involvement in resistant cell growth of insulin-like growth factor binding protein 2 (IGFBP-2). By an oligonucleotide based microarray, we compared the expression of mRNAs encoding insulin-like growth factor binding protein 1,2,3,4,5 and 6 (IGFBP-1 to -6) in the parental MCF-7 cell line to three human breast cancer cell lines, resistant to the antiestrogen ICI 182,780 (Faslodex/Fulvestrant). Only IGFBP-2 mRNA was overexpressed in all three resistant cell lines. Thus, we compared the IGFBP-2 protein expression in MCF-7 cells to nine antiestrogen resistant breast cancer cell lines, resistant to either ICI 182,780 or tamoxifen or RU 58,668 and found that IGFBP-2 was overexpressed in all nine resistant cell lines. Three of the resistant cell lines, resistant to different antiestrogens, were selected for further studies and IGFBP-2 overexpression was demonstrated at the mRNA level as well as the intra- and extracellular protein level. The objective of this study was to examine if IGFBP-2 is involved in growth of antiestrogen resistant human breast cancer cells. Therefore, IGFBP-2 expression was inhibited by antisense oligonucletides and siRNA. Specific inhibition of IGFBP-2 protein expression was achieved in MCF-7 and the three selected antiestrogen resistant cell lines, but no effect on resistant cell growth was observed. Thus, we were able to establish IGFBP-2 as a marker for antiestrogen resistant breast cancer cell lines, although IGFBP-2 was not a

  4. Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer.

    Science.gov (United States)

    Rosendahl, Ann H; Perks, Claire M; Zeng, Li; Markkula, Andrea; Simonsson, Maria; Rose, Carsten; Ingvar, Christian; Holly, Jeff M P; Jernström, Helena

    2015-04-15

    Epidemiologic studies indicate that dietary factors, such as coffee, may influence breast cancer and modulate hormone receptor status. The purpose of this translational study was to investigate how coffee may affect breast cancer growth in relation to estrogen receptor-α (ER) status. The influence of coffee consumption on patient and tumor characteristics and disease-free survival was assessed in a population-based cohort of 1,090 patients with invasive primary breast cancer in Sweden. Cellular and molecular effects by the coffee constituents caffeine and caffeic acid were evaluated in ER(+) (MCF-7) and ER(-) (MDA-MB-231) breast cancer cells. Moderate (2-4 cups/day) to high (≥5 cups/day) coffee intake was associated with smaller invasive primary tumors (Ptrend = 0.013) and lower proportion of ER(+) tumors (Ptrend = 0.018), compared with patients with low consumption (≤1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER(+) tumors (adjusted HR, 0.51; 95% confidence interval, 0.26-0.97). Caffeine and caffeic acid suppressed the growth of ER(+) (P ≤ 0.01) and ER(-) (P ≤ 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER(+) cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER(+) and ER(-) cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death. The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER(+) and ER(-) breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth. ©2015 American Association for Cancer Research.

  5. Insulin-like growth factor system in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Wilczak, N; de Keyser, J; Cianfarani, S; Clemmons, DR; Savage, MO

    2005-01-01

    Insulin-like growth factor-I (IGF-I) is a neurotrophic factor with insulin-like metabolic activities, and possesses potential clinical applications, particularly in neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is a chronic progressive devastating disorder of the central nervous

  6. Insulin-like Growth Factor Receptor 1 mRNA Expression as a Prognostic Marker in Advanced Non-small Cell Lung Cancer

    DEFF Research Database (Denmark)

    Vilmar, Adam; Santoni-Rugiu, Eric; Cillas, Jesus Garcia-Fon

    2014-01-01

    BACKGROUND: The insulin-like growth factor 1 receptor (IGF1R) has yet to be established as a biomarker in non-small cell lung cancer (NSCLC) but could prove useful in customized chemotherapy. We explored its prognostic value using both quantitative real-time reverse transcriptase polymerase chain...... reaction (qRT-PCR) and immunohistochemistry (IHC). MATERIALS AND METHODS: Analyses of IGF1R were performed on patients with advanced NSCLC, included in a randomized chemotherapy trial, having large, representative tissue samples. IGF1R mRNA and protein expression were correlated to clinical end...

  7. PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, S.Y. [Department of Pediatrics, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Biomedical Research Institute, School of Medicine, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Kim, M.S.; Lee, M.K. [Department of Pediatrics, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Kim, J.S.; Yi, H.K. [Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju (Korea, Republic of); Nam, S.Y. [Department of Alternative Therapy, Jeonju University, Jeonju (Korea, Republic of); Lee, D.Y.; Hwang, P.H. [Department of Pediatrics, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Biomedical Research Institute, School of Medicine, Chonbuk National University Hospital, Jeonju (Korea, Republic of)

    2015-01-13

    Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.

  8. Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2

    Directory of Open Access Journals (Sweden)

    Jeff M. P. Holly

    2017-11-01

    Full Text Available BackgroundEpidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion.MethodsFusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2 silenced or the presence of insulin-like growth factor-1 (IGF-I, insulin, or epidermal growth factor (EGF. RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs, and β-actin were analyzed by Western immunoblotting.ResultsOur data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events.ConclusionThese novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression.

  9. Pre-diagnosis insulin-like growth factor-I and risk of epithelial invasive ovarian cancer by histological subtypes : A collaborative re-analysis from the Ovarian Cancer Cohort Consortium

    NARCIS (Netherlands)

    Ose, Jennifer; Schock, Helena; Poole, Elizabeth M; Lehtinen, Matti; Visvanathan, Kala; Helzlsouer, Kathy; Buring, Julie E; Lee, I-Min; Tjønneland, Anne; Boutron-Ruault, Marie-Christine; Trichopoulou, Antonia; Mattiello, Amalia; Onland-Moret, N Charlotte; Weiderpass, Elisabete; Sánchez, María-José; Idahl, Annika; Travis, Ruth C; Rinaldi, Sabina; Merritt, Melissa A; Wentzensen, Nicolas; Tworoger, Shelley S; Kaaks, Rudolf; Fortner, Renée T

    PURPOSE: Biologic evidence suggests that the Insulin-like growth factor (IGF)-family may be involved in the etiology of epithelial invasive ovarian cancer (EOC). However, prospective studies investigating the role of IGF-I in ovarian carcinogenesis have yielded conflicting results. METHODS: We

  10. Dietary energy balance modulation of Kras- and Ink4a/Arf+/--driven pancreatic cancer: the role of insulin-like growth factor-I.

    Science.gov (United States)

    Lashinger, Laura M; Harrison, Lauren M; Rasmussen, Audrey J; Logsdon, Craig D; Fischer, Susan M; McArthur, Mark J; Hursting, Stephen D

    2013-10-01

    New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF)-I-dependent mechanism. In LSL-Kras(G12D)/Pdx-1-Cre/Ink4a/Arf(lox/+) mice, calorie restriction versus overweight- or obesity-inducing diet regimens decreased serum IGF-I, tumoral Akt/mTOR signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC), and increased pancreatic tumor-free survival. Serum IGF-I, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-I-deficient mice (vs. wild-type mice), and rescued with IGF-I infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-I and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.

  11. Insulin-like growth factors (IGFs) stimulate the release of alpha 1-antichymotrypsin and soluble IGF-II/mannose 6-phosphate receptor from MCF7 breast cancer cells.

    Science.gov (United States)

    Confort, C; Rochefort, H; Vignon, F

    1995-09-01

    The growth of hormone-responsive MCF7 human breast cancer cells is controlled by steroid hormones and growth factors. By metabolic labeling of cells grown in steroid- and growth factor-stripped serum conditions, we show that insulin-like growth factors (IGF-I and IGF-II) increase by approximately 5-fold the release of several proteins including cathepsin D, alpha 1-antichymotrypsin, and soluble forms of the multifunctional IGF-II/mannose 6-phosphate (M6P) receptor. Two soluble forms of IGF-II/M6P receptors were detected, one major (approximately 260 kilodaltons) and one minor (approximately 85 kilodaltons) that probably represents a proteolytic fragment of the larger soluble molecule. IGFs increased receptor release in a dose-dependent fashion with 50-60% of newly synthesized receptor released at 5-10 nM IGFs. The release of IGF-II/M6P receptors correlated with the levels of secreted cathepsin D in different human breast cancer cells or in rats stable transfectants that are constitutively expressing variable levels of human cathepsin D. IGFs had a stronger effect on IGF-II/M6P receptor release, whereas estradiol treatment preferentially enhanced the release of protease and antiprotease. We thus demonstrate that in human breast cancer cells, IGFs not only act as strong mitogens but also regulate release of alpha 1-antichymotrypsin, IGF-II/M6P-soluble receptor, and cathepsin D; three proteins that potentially regulate cell proliferation and/or invasion.

  12. Insulin-Like Growth Factor-1 Inscribes a Gene Expression Profile for Angiogenic Factors and Cancer Progression in Breast Epithelial Cells

    Directory of Open Access Journals (Sweden)

    J.S. Oh

    2002-01-01

    Full Text Available Activation of the insulin-like growth factor-1 receptor (IGF-11R by IGF-1 is associated with the risk and progression of many types of cancer, although despite this it remains unclear how activated IGF-1 R contributes to cancer progression. In this study, gene expression changes elicited by IGF-1 were profiled in breast epithelial cells. We noted that many genes are functionally linked to cancer progression and angiogenesis. To validate some of the changes observed, the RNA and/or protein was confirmed for c-fos, cytochrome P4501Al, cytochrome P450 1131, interleukin-1 beta, fas ligand, vascular endothelial growth factor, and urokinase plasminogen activator. Nuclear proteins were also temporally monitored to address how gene expression changes were regulated. We found that IGF-1 stimulated the nuclear translocation of phosphorylated AKT, hypoxic-inducible factor-1 alpha, and phosphorylated cAMP-responsive element-binding protein, which correlated with temporal changes in gene expression. Next, the promoter regions of IGF-1-regulated genes were searched in silico. The promoters of genes that clustered together had similar regulatory regions. In summary, IGF-1 inscribes a gene expression profile relevant to cancer progression, and this study provides insight into the mechanism(s whereby some of these changes occur.

  13. Insulin/insulin like growth factors in cancer: new roles for the aryl hydrocarbon receptor, tumor resistance mechanisms and new blocking strategies

    Directory of Open Access Journals (Sweden)

    Travis B Salisbury

    2015-02-01

    Full Text Available The insulin-like growth factor 1 receptor (IGF1R and the insulin receptor (IR are receptor tyrosine kinases (RTKs that are expressed in cancer cells. The results of different studies indicate that tumor proliferation and survival is dependent on the IGF1R and IR, and that their inhibition leads to reductions in proliferation and increases in cell death. Molecular targeting therapies that have been used in solid tumors include: anti-IGF1R antibodies, anti-IGF1/IGF2 antibodies and small molecule inhibitors that suppress IGF1R and IR kinase activity. New advances in the molecular basis of anti-IGF1R blocking antibodies reveal they are biased agonists and promote the binding of IGF1 to integrin β3 receptors in some cancer cells. Our recent reports indicate that pharmacological aryl hydrocarbon receptor (AHR ligands inhibit breast cancer cell responses to IGFs, suggesting that targeting AHR may have benefit in cancers whose proliferation and survival are dependent on insulin/IGF signaling. Novel aspects of IGF1R/IR in cancer, such as biased agonism, integrin β3 signaling, AHR and new therapeutic targeting strategies will be discussed.

  14. Insulin-like growth factors and pancreas beta cells.

    NARCIS (Netherlands)

    Haeften, T.W. van; Twickler, M.

    2004-01-01

    Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their

  15. Insulin-like growth factors and pancreas beta cells

    NARCIS (Netherlands)

    van Haeften, T. W.; Twickler, Th B.

    2004-01-01

    Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. As low birth weight has been implicated in the development of obesity and type 2 diabetes, much research has evolved into the importance of IGF and their

  16. Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels1

    Science.gov (United States)

    Tang, Yaxiong; Parmakhtiar, Basmina; Simoneau, Anne R; Xie, Jun; Fruehauf, John; Lilly, Michael; Zi, Xiaolin

    2011-01-01

    Docetaxel is currently the most effective drug for the treatment of castration-resistant prostate cancer (CRPC), but it only extends life by an average of 2 months. Lycopene, an antioxidant phytochemical, has antitumor activity against prostate cancer (PCa) in several models and is generally safe. We present data on the interaction between docetaxel and lycopene in CRPC models. The growth-inhibitory effect of lycopene on PCa cell lines was positively associated with insulin-like growth factor I receptor (IGF-IR) levels. In addition, lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression than on those PCa cell lines with IGF-IR low expression. In a DU145 xenograft tumor model, docetaxel plus lycopene caused tumor regression, with a 38% increase in antitumor efficacy (P = .047) when compared with docetaxel alone. Lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis. Together, the enhancement of docetaxel's antitumor efficacy by lycopene supplementation justifies further clinical investigation of lycopene and docetaxel combination for CRPC patients. CRPC patients with IGF-IR-overexpressing tumors may be most likely to benefit from this combination. PMID:21403837

  17. Blockade of insulin-like growth factor type-1 receptor with cixutumumab (IMC-A12): a novel approach to treatment for multiple cancers.

    Science.gov (United States)

    Rowinsky, Eric K; Schwartz, Jonathan D; Zojwalla, Naseem; Youssoufian, Hagop; Fox, Floyd; Pultar, Philippe; Novosyadlyy, Ruslan; Cosaert, Jan; Ludwig, Dale L

    2011-12-01

    Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.

  18. Insulin-like growth factor II mRNA binding protein 3 (IMP3 is overexpressed in prostate cancer and correlates with higher Gleason scores

    Directory of Open Access Journals (Sweden)

    Mortezavi Ashkan

    2010-06-01

    Full Text Available Abstract Background The oncofetal protein insulin-like growth factor II mRNA binding protein 3 (IMP3 is an important factor for cell-migration and adhesion in malignancies. Recent studies have shown a remarkable overexpression of IMP3 in different human malignant neoplasms and also revealed it as an important prognostic marker in some tumor entities. To our knowledge, IMP3 expression has not been investigated in prostate carcinomas so far. Methods Immunohistochemical stainings for IMP3 were performed on tissue microarray (TMA organized samples from 507 patients: 31 normal prostate tissues, 425 primary carcinomas and 51 prostate cancer metastases or castration-resistant prostate cancers (CRPC. IMP3 immunoreactivity was semiquantitatively scored and correlated with clinical-pathologic parameters including survival. Results IMP3 is significantly stronger expressed in prostate carcinomas compared to normal prostate tissues (p Conclusions Although IMP3 is overexpressed in a significant proportion of prostate cancer cases, which might be of importance for novel therapeutic approaches, it does not appear to possess any immediate diagnostic or prognostic value, limiting its potential as a tissue biomarker for prostate cancer. These results might be corroborated by the fact, that two independent tumor cohorts were separately reviewed.

  19. Expression of estrogen receptors in non-malignant mammary tissue modifies the association between insulin-like growth factor 1 and breast cancer risk.

    Science.gov (United States)

    Samoli, E; Lagiou, A; Zourna, P; Barbouni, A; Georgila, C; Tsikkinis, A; Vassilarou, D; Minaki, P; Sfikas, C; Spanos, E; Trichopoulos, D; Lagiou, P

    2015-04-01

    Several studies have reported that the insulin-like growth factor 1 (IGF-1) is positively associated with estrogen receptor-positive [ER(+)] breast cancer risk, whereas there is little or no association with respect to ER(-) breast cancer. All comparisons of ER(+) breast cancer cases, however, have been made versus healthy controls, for whom there is no information about the ER expression in their mammary gland. In the context of a case-control investigation conducted in Athens, Greece, we studied 102 women with incident ERα(+) breast cancer and compared their IGF-1 blood levels with those of 178 ERα(+) and 83 ERα(-) women with benign breast disease (BBD) who underwent biopsies in the context of their standard medical care. Data were analysed using multiple logistic regression and controlling for potential confounding variables. ERα(+) breast cancer patients had higher IGF-1 levels compared with women with BBD [odds ratio (OR) 1.36, 95% confidence interval (CI): 0.95-1.94, per 1 standard deviation (SD) increase in IGF-1 levels]. When ERα status of women with BBD was taken into account, the difference in IGF-1 levels between ERα(+) breast cancer patients and women with BBD was clearly driven by the comparison with BBD women who were ERα(+) (OR = 1.95, 95% CI: 1.31-2.89 per 1 SD increase in IGF-1 levels), whereas there was essentially no association with IGF-1 levels when ERα(+) breast cancer patients were compared with ERα(-) BBD women. These contrasts were particularly evident among post/peri-menopausal women. We found evidence in support of an interaction of IGF-1 with the expression of ERα in the non-malignant mammary tissue in the context of breast cancer pathogenesis. This is in line with previous evidence suggesting that IGF-1 increases the risk of ER(+) breast cancer. Published by Oxford University Press on behalf of the European Society for Medical Oncology 2014.

  20. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Haruo, E-mail: hal.kato@gunma-u.ac.jp; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-05-22

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling.

  1. Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives

    Directory of Open Access Journals (Sweden)

    Meizhong Jin

    2013-04-01

    Full Text Available Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF- 1R targeted therapies (e.g. monoclonal antibodies and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials.

  2. Association between Insulin Like Growth Factor-1 (IGF-1) gene ...

    African Journals Online (AJOL)

    The insulin-like growth factor-1 (IGF1) is a key regulator of muscle development and metabolism in birds and other vertebrate. Our objective was to determine the association between IGF1 gene polymorphism and carcass traits in FUNAAB Alpha chicken. Genomic DNA was extracted from the blood of 50 normal feathered ...

  3. IGF-1 (Insulin-Like Growth Factor -1) Test

    Science.gov (United States)

    ... High-sensitivity C-reactive Protein (hs-CRP) Histamine Histone Antibody HIV Antibody and HIV Antigen (p24) HIV ... Tests Online adjunct board member. (© 1995-2010). Unit Code 15867: Insulin-Like Growth Factor 1 (IGF-1), ...

  4. Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma.

    LENUS (Irish Health Repository)

    Donohoe, C L

    2012-03-01

    Epidemiological studies have linked obesity with many cancers. The insulin-like growth factor (IGF) 1 axis may be an important mediator in obesity-associated cancer. This study examined the relationship between IGF-1 and its receptor (IGF-1R) in oesophageal adenocarcinoma, a cancer strongly linked to obesity.

  5. Insulin-Like Growth Factor 1/Mammalian Target of Rapamycin and AMP-Activated Protein Kinase Signaling Involved in the Effects of Metformin in the Human Endometrial Cancer.

    Science.gov (United States)

    Cai, Dongge; Sun, Hongli; Qi, Yanhua; Zhao, Xiaogui; Feng, Minjuan; Wu, Xiaoling

    2016-11-01

    Metformin is a well-tolerated biguanide drug used for decades to treat type 2 diabetes mellitus. In recent years, long-term administration of metformin has been found to reduce carcinogenic risk for cancers derived from various tissues. However, its cellular and molecular mechanisms of anticancer action in the endometrial cancer (EC) have not yet been fully elucidated. Sixty patients diagnosed as endometrial carcinoma were grouped into (n = 30) and non-treatment mixed (n = 30) for analysis. Thirty healthy donors are control groups. We attempt to investigate the interaction of metformin, insulin-like growth factor 1 (IGF-1) expression, and phosphorylated mammalian target of rapamycin (p-mTOR) and AMP-activated protein kinase (p-AMPK). We found that high IGF-1 plasma concentrations in women with EC were reversed by conventional antidiabetic doses of metformin in the present work. In parallel, the activation of AMPK and suppression of mTOR seemed to play an important role for the effect of metformin in patients with EC. This pilot trial presents biological evidence consistent with antiproliferative effects of metformin in women with EC in the clinical setting.

  6. Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: Current status and future perspectives

    Directory of Open Access Journals (Sweden)

    Meizhong Jin

    2013-04-01

    Full Text Available Based on over three decades of preclinical data, insulin-like growth factor-1 receptor (IGF-1R signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF- 1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF-1R targeted therapies (e.g. monoclonal antibodies and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such finding have led to the development of small molecule IGF-1R inhibitors which also coinhibit additional targets such as IR and EGFR. Such findings have helped to guide the rationale design of numerous drug combinations which are currently being evaluated in clinical trials.

  7. New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways.

    Science.gov (United States)

    Lam, Thuy Giang; Jeong, Yun Soo; Kim, Soo-A; Ahn, Sang-Gun

    2017-12-29

    Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of the present study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose-dependent way. HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) levels and apoptotic cells with caspase-3 and -9 activation. HL156A inhibited the expression and activation of insulin-like growth factor (IGF)-1 and its downstream proteins, AKT, mammalian target of rapamycin (mTOR), and ERK1/2. In addition, HL156A activated AMP-activated protein kinase/nuclear factor kappa B (AMPK-NF-κB) signaling of FaDu and YD-10B cells. A xenograft mouse model further showed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by down-regulated p-IGF-1, p-mTOR, proliferating cell nuclear antigen (PCNA) and promoted p-AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  8. Insulin-like growth factor family and combined antisense approach in therapy of lung carcinoma.

    OpenAIRE

    Pavelić, Jasminka; Pavelić, Ljubomir; Karadza, Jerolim; Krizanac, Simun; Unesić, Josip; Spaventi, Sime; Pavelić, Kresimir

    2002-01-01

    BACKGROUND: Perturbation in a level of any peptide from insulin-like growth factor (IGF) family (ligands, receptors, and binding proteins) seems to be implicated in lung cancer formation; IGF ligands and IGF-I receptor through their mitogenic and anti-apoptotic action, and the mannose 6-phosphate/insulin-like growth factor II receptor (M6-P/IGF-IIR) possibly as a tumor suppressor. MATERIALS AND METHODS: To determine the identity, role, and mutual relationship of IGFs in lung cancer growth and...

  9. Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study.

    Science.gov (United States)

    Irwin, Melinda L; Varma, Katie; Alvarez-Reeves, Marty; Cadmus, Lisa; Wiley, Andrew; Chung, Gina G; Dipietro, Loretta; Mayne, Susan T; Yu, Herbert

    2009-01-01

    High insulin and insulin-like growth factor-I (IGF-I) levels may be associated with an increased breast cancer risk and/or death. Given the need to identify modifiable factors that decrease insulin, IGF-I, and breast cancer risk and death, we investigated the effects of a 6-month randomized controlled aerobic exercise intervention versus usual care on fasting insulin, IGF-I, and its binding protein (IGFBP-3) in postmenopausal breast cancer survivors. Seventy-five postmenopausal breast cancer survivors were identified from the Yale-New Haven Hospital Tumor Registry and randomly assigned to an exercise (n = 37) or usual care (n = 38) group. The exercise group participated in 150 minutes per week of moderate-intensity aerobic exercise. The usual care group was instructed to maintain their current physical activity level. A fasting blood sample was collected on each study participant at baseline and 6 months. Blood levels of insulin and IGF were measured with ELISA. On average, exercisers increased aerobic exercise by 129 minutes per week compared with 45 minutes per week among usual care participants (P exercise experienced decreases in insulin, IGF-I, and IGFBP-3, whereas women randomized to usual care had increases in these hormones. Between-group differences in insulin, IGF-I, and IGFBP-3 were 20.7% (P = 0.089), 8.9% (P = 0.026), and 7.9% (P = 0.006), respectively. Moderate-intensity aerobic exercise, such as brisk walking, decreases IGF-I and IGFBP-3. The exercise-induced decreases in IGF may mediate the observed association between higher levels of physical activity and improved survival in women diagnosed with breast cancer.

  10. The Insulin-like Growth Factor System: Towards Clinical Applications

    OpenAIRE

    Bach, Leon A.

    2004-01-01

    Insulin-like growth factors (IGF-I and II) are important endocrine, paracrine and autocrine mediators of physiological growth. They promote cellular proliferation, survival and differentiation. Their effects are mediated mainly through the IGF-I receptor, but IGFs also bind to the IGF-II/mannose 6-phosphate and insulin receptors. IGF activity is modulated by a family of six high-affinity IGF binding proteins (IGFBPs); in most situations, IGFBPs inhibit IGF actions but they may also enhance th...

  11. Comparison of radioimmuno and carbon nanotube field-effect transistor assays for measuring insulin-like growth factor-1 in a preclinical model of human breast cancer.

    Science.gov (United States)

    Jones, Laundette P; Stefansson, Steingrimur; Kim, Man S; Ahn, Saeyoung N

    2011-09-02

    To realize the promise of personalized medicine, diagnostic instruments used for detecting and measuring biomarkers must become smaller, faster and less expensive. Although most techniques used currently to detect biomarkers are sensitive and specific, many suffer from several disadvantages including their complexity, high cost and long turnaround time. One strategy to overcome these problems is to exploit carbon nanotube (CNT) based biosensors, which are sensitive, use inexpensive disposable components and can be easily adapted to current assay protocols. In this study we investigated the applicability of using a CNT field-effect transistor (CNT-FET) as a diagnostic instrument for measuring cancer biomarkers in serum using a mouse model of Breast Cancer Susceptibility 1-related breast cancer. Insulin like growth factor-1 (IGF-1) was chosen because it is highly relevant in breast cancer and because measuring serum IGF-1 levels by conventional methods is complicated due to specific IGF-1 serum binding proteins. Our results show that there is good correlation between the two platforms with respect to detecting serum IGF-1. In fact, the CNT-FETs required only one antibody, gave real-time results and required approximately 100-fold less mouse serum than the radioimmunoassay. Both IGF-1 radioimmuno and CNT-FET assays gave comparable results. Indeed, the CNT-FET assay was simpler and faster than the radioimmunoassay. Additionally, the low serum sample required by CNT-FETs can be especially advantageous for studies constricted by limited amount of human clinical samples and for mouse studies, since animals often need to be sacrificed to obtain enough serum for biomarker evaluation.

  12. Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jae-Hyun Park

    2015-05-01

    Full Text Available The stroma of breast cancer can promote the disease’s progression, but whether its composition and functions are shared among different subtypes is poorly explored. We compared stromal components of a luminal [mouse mammary tumor virus (MMTV–Neu] and a triple-negative/basal-like [C3(1–Simian virus 40 large T antigen (Tag] genetically engineered breast cancer mouse model. The types of cytokines and their expression levels were very different in the two models, as was the extent of innate immune cell infiltration; however, both models showed infiltration of innate immune cells that expressed matrix metalloproteinase 9 (MMP9, an extracellular protease linked to the progression of many types of cancer. By intercrossing with Mmp9 null mice, we found that the absence of MMP9 delayed tumor onset in the C3(1-Tag model but had no effect on tumor onset in the MMTV-Neu model. We discovered that protein levels of insulin-like growth factor binding protein-1 (IGFBP-1, an MMP9 substrate, were increased in C3(1-Tag;Mmp9−/− compared to C3(1-Tag;Mmp9+/+ tumors. In contrast, IGFBP-1 protein expression was low in MMTV-Neu tumors regardless of Mmp9 status. IGFBP-1 binds and antagonizes IGFs, preventing them from activating their receptors to promote cell proliferation and survival. Tumors from C3(1-Tag;Mmp9−/− mice had reduced IGF-1 receptor phosphorylation, consistent with slower tumor onset. Finally, gene expression analysis of human breast tumors showed that high expression of IGFBP mRNA was strongly correlated with good prognosis but not when MMP9 mRNA was also highly expressed. In conclusion, MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed.

  13. Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk.

    Directory of Open Access Journals (Sweden)

    Su Yon Jung

    Full Text Available Genetic variants and traits in metabolic signaling pathways may interact with lifestyle factors such as obesity, physical activity, and exogenous estrogen (E, influencing postmenopausal colorectal cancer (CRC risk, but these interrelated pathways are not fully understood. In this case-cohort study, we examined 33 single-nucleotide polymorphisms (SNPs in genes related to insulin-like growth factor-I (IGF-I/ insulin resistance (IR traits and signaling pathways, using data from 704 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying by the lifestyle modifiers, we assessed the effects of IGF-I/IR traits (fasting total and free IGF-I, IGF binding protein-3, insulin, glucose, and homeostatic model assessment-insulin resistance on CRC risk as a mediator or influencing factor. Six SNPs in the INS, IGF-I, and IGFBP3 genes were associated with CRC risk, and those associations differed between non-obese/active and obese/inactive women and between E nonusers and users. Roughly 30% of the cancer risk due to the SNP was mediated by IGF-I/IR traits. Likewise, carriers of 11 SNPs in the IRS1 and AKT1/2 genes (signaling pathway-related genetic variants had different associations with CRC risk between strata, and the proportion of the SNP-cancer association explained by traits varied from 30% to 50%. Our findings suggest that IGF-I/IR genetic variants interact with obesity, physical activity, and exogenous E, altering postmenopausal CRC risk, through IGF-I/IR traits, but also through different pathways. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce CRC risk.

  14. Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis.

    Science.gov (United States)

    Harrison, Sean; Lennon, Rosie; Holly, Jeff; Higgins, Julian P T; Gardner, Mike; Perks, Claire; Gaunt, Tom; Tan, Vanessa; Borwick, Cath; Emmet, Pauline; Jeffreys, Mona; Northstone, Kate; Rinaldi, Sabina; Thomas, Stephen; Turner, Suzanne D; Pease, Anna; Vilenchick, Vicky; Martin, Richard M; Lewis, Sarah J

    2017-06-01

    To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3). Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise. One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk-IGF relationship; 132 examining the IGF-prostate cancer relationship in humans; and 10 animal studies examining the IGF-prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF-I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 -202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF-II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression. IGF-I is a potential mechanism underlying the

  15. Targeting non-small cell lung cancer cells by dual inhibition of the insulin receptor and the insulin-like growth factor-1 receptor.

    Directory of Open Access Journals (Sweden)

    Emma E Vincent

    Full Text Available Phase III trials of the anti-insulin-like growth factor-1 receptor (IGF1R antibody figitumumab in non-small cell lung cancer (NSCLC patients have been discontinued owing to lack of survival benefit. We investigated whether inhibition of the highly homologous insulin receptor (IR in addition to the IGF1R would be more effective than inhibition of the IGF1R alone at preventing the proliferation of NSCLC cells. Signalling through IGF1R and IR in the NSCLC cell lines A549 and Hcc193 was stimulated by a combination of IGF1, IGF2 and insulin. It was inhibited by antibodies that block ligand binding, αIR3 (IGF1R and IR47-9 (IR, and by the ATP-competitive small molecule tyrosine kinase inhibitors AZ12253801 and NVPAWD742 which inhibit both IGF1R and IR tyrosine kinases. The effect of inhibitors was determined by an anchorage-independent proliferation assay and by analysis of Akt phosphorylation. In Hcc193 cells the reduction in cell proliferation and Akt phosphorylation due to anti-IGF1R antibody was enhanced by antibody-mediated inhibition of the IR whereas in A549 cells, with a relatively low IR:IGF1R expression ratio, it was not. In each cell line proliferation and Akt phosphorylation were more effectively inhibited by AZ12253801 and NVPAWD742 than by combined αIR3 and IR47-9. When the IGF1R alone is inhibited, unencumbered signalling through the IR can contribute to continued NSCLC cell proliferation. We conclude that small molecule inhibitors targeting both the IR and IGF1R more effectively reduce NSCLC cell proliferation in a manner independent of the IR:IGF1R expression ratio, providing a therapeutic rationale for the treatment of this disease.

  16. Neurodevelopmental effects of insulin-like growth factor signaling

    Science.gov (United States)

    O’Kusky, John; Ye, Ping

    2012-01-01

    Insulin-like growth factor (IGF) signaling greatly impacts the development and growth of the central nervous system (CNS). IGF-I and IGF-II, two ligands of the IGF system, exert a wide variety of actions both during development and in adulthood, promoting the survival and proliferation of neural cells. The IGFs also influence the growth and maturation of neural cells, augmenting dendritic growth and spine formation, axon outgrowth, synaptogenesis, and myelination. Specific IGF actions, however, likely depend on cell type, developmental stage, and local microenvironmental milieu within the brain. Emerging research also indicates that alterations in IGF signaling likely contribute to the pathogenesis of some neurological disorders. This review summarizes experimental studies and shed light on the critical roles of IGF signaling, as well as its mechanisms, during CNS development. PMID:22710100

  17. Insulin-like growth factor 1 and growth hormone in chronic liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Becker, Povl Ulrik

    1992-01-01

    Somatomedins or insulin-like growth factors (IGF) are peptides synthesized in the liver. IGFs have different anabolic and metabolic actions and are important in normal growth and development. The concentration of insulin-like growth factor 1 (IGF-1) is low in patients with chronic liver disease...

  18. Azathioprine desensitizes liver cancer cells to insulin-like growth factor 1 and causes apoptosis when it is combined with bafilomycin A1

    Energy Technology Data Exchange (ETDEWEB)

    Hernández-Breijo, Borja [Departamento de Biología de Sistemas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad de Alcalá, 28871 Alcalá de Henares (Spain); Monserrat, Jorge [Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, 28871 Alcalá de Henares (Spain); Román, Irene D. [Departamento de Biología de Sistemas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad de Alcalá, 28871 Alcalá de Henares (Spain); González-Rodríguez, Águeda [Departamento de Biomedicina y Biotecnología, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad de Alcalá, 28871 Alcalá de Henares (Spain); Fernández-Moreno, M. Dolores [Departamento de Biología de Sistemas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad de Alcalá, 28871 Alcalá de Henares (Spain); and others

    2013-11-01

    Hepatoblastoma is a primary liver cancer that affects children, due to the sensitivity of this tumor to insulin-like growth factor 1 (IGF-1). In this paper we show that azathioprine (AZA) is capable of inhibiting IGF1-mediated signaling cascade in HepG2 cells. The efficiency of AZA on inhibition of proliferation differs in the evaluated cell lines as follows: HepG2 (an experimental model of hepatoblastoma) > Hep3B (derived from a hepatocellular carcinoma) > HuH6 (derived from a hepatoblastoma) ≫ HuH7 (derived from a hepatocellular carcinoma) = Chang Liver cells (a non-malignant cellular model). The effect of AZA in HepG2 cells has been proven to derive from activation of Ras/ERK/TSC2, leading to activation of mTOR/p70S6K in a sustained manner. p70S6K phosphorylates IRS-1 in serine 307 which leads to the uncoupling between IRS-1 and p85 (the regulatory subunit of PI3K) and therefore causing the lack of response of HepG2 to IGF-1. As a consequence, proliferation induced by IGF-1 is inhibited by AZA and autophagy increases leading to senescence of HepG2 cells. Our results suggest that AZA induces the autophagic process in HepG2 activating senescence, and driving to deceleration of cell cycle but not to apoptosis. However, when simultaneous to AZA treatment the autophagy was inhibited by bafilomycin A1 and the degradation of regulatory proteins of cell cycle (e.g. Rb, E2F, and cyclin D1) provoked apoptosis. In conclusion, AZA induces resistance in hepatoblastoma cells to IGF-1, which leads to autophagy activation, and causes apoptosis when it is combined with bafilomycin A1. We are presenting here a novel mechanism of action of azathioprine, which could be useful in treatment of IGF-1 dependent tumors, especially in its combination with other drugs. - Highlights: • Azathioprine activated Ras/ERK/TSC-2/mTOR/p70S6K signaling pathway in HepG2 cells. • Azathioprine inhibited IGF-1-mediated signaling cascade. • Azathioprine induced autophagy leading to cell cycle

  19. Insulin-like growth factor-I and the liver

    DEFF Research Database (Denmark)

    Bonefeld, Karen; Møller, Søren

    2011-01-01

    . Patients with cirrhosis are characterised by a variety of metabolic disturbances, including nutritional and metabolic complications such as insulin resistance, malnutrition, osteopenia and hypogonadism, all related to IGF-I deficiency. The complex process of hepatic fibrogenesis and the systemic......Insulin-like growth factors (IGFs) play an essential role in growth and development, as well as in the overall cellular regulation and metabolism in the human body. In chronic liver disease, IGF levels are decreased, and the circulating levels correlate to the extent of hepatocellular dysfunction...... has a strong antifibrotic effect that acts directly through the GH/IGF system and indirectly by the regulation of hepatoprotective and profibrogenic factors. It is most likely that IGF-I deficiency contributes to the diverse metabolic complications of cirrhosis. At present, liver transplantation...

  20. Insulin-like growth factors and fish reproduction.

    Science.gov (United States)

    Reinecke, Manfred

    2010-04-01

    Knowledge of fish reproduction is of high relevance to basic fish biology and comparative evolution. Furthermore, fish are excellent biomedical models, and the impact of aquaculture on worldwide food production is steadily increasing. Consequently, research on fish reproduction and the potential modes of its manipulation has become more and more important. Reproduction in fish is regulated by the integration of endogenous neuroendocrine (gonadotropins), endocrine, and autocrine/paracrine signals with exogenous (environmental) factors. The main endocrine regulators of gonadal sex differentiation and function are steroid hormones. However, recent studies suggest that other hormones are also involved. Most prominent among these hormones are the insulin-like growth factors (Igfs), i.e., Igf1, Igf2, and, most recently, Igf3. Thus, the present review deals with the expression patterns and potential physiological functions of Igf1 and Igf2 in male and female gonads. It further considers the potential involvement of growth hormone (Gh) and balances the reasons for endocrine vs. autocrine/paracrine action of the Igfs on the gonads of fish. Finally, this review discusses the early and late development of gonadal Igf1 and Igf2 and whether they are targets of endocrine-disrupting compounds. Future topics for novel research investigation on Igfs and fish reproduction are presented.

  1. Insulin-like growth factor I: a biologic maturation indicator.

    Science.gov (United States)

    Ishaq, Ramy Abdul Rahman; Soliman, Sanaa Abou Zeid; Foda, Manal Yehya; Fayed, Mona Mohamed Salah

    2012-11-01

    Determination of the maturation level and the subsequent evaluation of growth potential during preadolescence and adolescence are important for optimal orthodontic treatment planning and timing. This study was undertaken to evaluate the applicability of insulin-like growth factor I (IGF-I) blood level as a maturation indicator by correlating it to the cervical vertebral maturation index. The study was conducted with 120 subjects, equally divided into 60 males (ages, 10-18 years) and 60 females (ages, 8-16 years). A lateral cephalometric radiograph and a blood sample were taken from each subject. For each subject, cervical vertebral maturation and IGF-I serum level were assessed. Mean values of IGF-I in each stage of cervical vertebral maturation were calculated, and the means in each stage were statistically compared with those of the other stages. The IGF-I mean value at each cervical vertebral maturation stage was statistically different from the mean values at the other stages. The highest mean values were observed in stage 4, followed by stage 5 in males and stage 3 in females. IGF-I serum level is a reliable maturation indicator that could be applied in orthodontic diagnosis. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  2. The Insulin-Like Growth Factor System and Nutritional Assessment

    Directory of Open Access Journals (Sweden)

    Callum Livingstone

    2012-01-01

    Full Text Available Over recent years there has been considerable interest in the role of the insulin-like growth factor (IGF system in health and disease. It has long been known to be dysregulated in states of under- and overnutrition, serum IGF-I levels falling in malnourished patients and responding promptly to nutritional support. More recently, other proteins in this system have been observed to be dysregulated in both malnutrition and obesity. Currently no biochemical marker is sufficiently specific for use in screening for malnutrition, but levels may be valuable in providing information on nutritional status and in monitoring of nutritional support. All have limitations as nutritional markers in that their serum levels are influenced by factors other than nutritional status, most importantly the acute phase response (APR. Levels should be interpreted along with clinical findings and the results of other investigations such as C-reactive protein (CRP. This paper reviews data supporting the use of proteins of the IGF system as nutritional markers.

  3. Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment.

    Science.gov (United States)

    de la Garza, Rocio G; Morales-Garza, Luis Alonso; Martin-Estal, Irene; Castilla-Cortazar, Inma

    2017-04-01

    Cirrhosis represents the final stage of chronic liver damage, which can be due to different factors such as alcohol, metabolic syndrome with liver steatosis, autoimmune diseases, drugs, toxins, and viral infection, among others. Nowadays, cirrhosis is an important health problem and it is an increasing cause of morbidity and mortality, being the 14th most common cause of death worldwide. The physiopathological pathways that lead to fibrosis and finally cirrhosis partly depend on the etiology. Nevertheless, some common features are shared in this complex mechanism. Recently, it has been demonstrated that cirrhosis is a dynamic process that can be altered in order to delay or revert fibrosis. In addition, when cirrhosis has been established, insulin-like growth factor-1 (IGF-1) deficiency or reduced availability is a common condition, independently of the etiology of chronic liver damage that leads to cirrhosis. IGF-1 deprivation seriously contributes to the progressive malnutrition of cirrhotic patient, increasing the vulnerability of the liver to establish an inflammatory and oxidative microenvironment with mitochondrial dysfunction. In this context, IGF-1 deficiency in cirrhotic patients can justify some of the common characteristics of these individuals. Several studies in animals and humans have been done in order to test the replacement of IGF-1 as a possible therapeutic option, with promising results.

  4. Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment

    Science.gov (United States)

    de la Garza, Rocio G.; Morales-Garza, Luis Alonso; Martin-Estal, Irene; Castilla-Cortazar, Inma

    2017-01-01

    Cirrhosis represents the final stage of chronic liver damage, which can be due to different factors such as alcohol, metabolic syndrome with liver steatosis, autoimmune diseases, drugs, toxins, and viral infection, among others. Nowadays, cirrhosis is an important health problem and it is an increasing cause of morbidity and mortality, being the 14th most common cause of death worldwide. The physiopathological pathways that lead to fibrosis and finally cirrhosis partly depend on the etiology. Nevertheless, some common features are shared in this complex mechanism. Recently, it has been demonstrated that cirrhosis is a dynamic process that can be altered in order to delay or revert fibrosis. In addition, when cirrhosis has been established, insulin-like growth factor-1 (IGF-1) deficiency or reduced availability is a common condition, independently of the etiology of chronic liver damage that leads to cirrhosis. IGF-1 deprivation seriously contributes to the progressive malnutrition of cirrhotic patient, increasing the vulnerability of the liver to establish an inflammatory and oxidative microenvironment with mitochondrial dysfunction. In this context, IGF-1 deficiency in cirrhotic patients can justify some of the common characteristics of these individuals. Several studies in animals and humans have been done in order to test the replacement of IGF-1 as a possible therapeutic option, with promising results. PMID:28270882

  5. Insulin-like growth factor-I, physical activity, and control of cellular anabolism.

    Science.gov (United States)

    Nindl, Bradley C

    2010-01-01

    The underlying mechanisms responsible for mediating the beneficial outcomes of exercise undoubtedly are many, but the insulin-like growth factor-I (IGF-I) system is emerging as an important and central hormonal axis that plays a significant role concerning cellular anabolism. This introductory article summarizes the intent and the content for papers presented as part of a 2008 American College of Sports Medicine national symposium entitled "Insulin-like Growth Factor-I, Physical Activity, and Control of Cellular Anabolism." The individual authors and their papers are as follows: Jan Frystyk authoring "The relationship between exercise and the growth hormone/insulin-like growth factor-I axis," Greg Adams authoring "IGF-I signaling in skeletal muscle and the potential for cytokine interactions," and Brad Nindl authoring "Insulin-like growth factor-I as a biomarker of health, fitness, and training status." These papers focus on 1) different assay methodologies for IGF-I within the paradigm of exercise studies, 2) research demonstrating that intracellular signaling components associated with several proinflammatory cytokines have the potential to interact with anabolic signaling processes in skeletal muscle, and 3) an overview of IGF-I as a biomarker related to exercise training, muscle and bone remodeling, body composition, cognition, and cancer. When summed in total, the contribution that these papers will make will undoubtedly involve bringing attention to the vast regulatory complexity of the IGF-I system and will hopefully convince the reader that the IGF-I system warrants further detailed scientific inquiry to resolve many unanswered questions and paradoxical experimental findings. The IGF-I system remains one of the most intriguing and captivating marvels of human physiology that seems central in mediating numerous adaptations from physical activity.

  6. Effects of mixed volatile fatty acid sodium salt on insulin-like growth ...

    African Journals Online (AJOL)

    Effects of mixed volatile fatty acid sodium salt on insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) in plasma and rumen tissue, and rumen epithelium development in lambs.

  7. Human insulin-like growth factor II leader 2 mediates internal initiation of translation

    DEFF Research Database (Denmark)

    Pedersen, Susanne K; Christiansen, Jan; Hansen, Thomas v O

    2002-01-01

    Insulin-like growth factor II (IGF-II) is a fetal growth factor, which belongs to the family of insulin-like peptides. During fetal life, the IGF-II gene generates three mRNAs with different 5' untranslated regions (UTRs), but identical coding regions and 3' UTRs. We have shown previously that IG...

  8. Insulin-like growth factor I - a novel biomarker of abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Lindholt, J S; Martin-Ventura, J L; Urbonavicius, S

    2011-01-01

    The study aimed to test the potential role of insulin-like growth factor I (IGF-I) and IGF-II as biomarkers for abdominal aortic aneurysm (AAA).......The study aimed to test the potential role of insulin-like growth factor I (IGF-I) and IGF-II as biomarkers for abdominal aortic aneurysm (AAA)....

  9. Good growth despite very low levels of insulin-like growth factors.

    Science.gov (United States)

    Dötsch, J; Siebler, T; Blum, W F; Rascher, W; Kiess, W

    1998-09-01

    A 12.5-year-old girl presented with short stature. Insulin-like growth factor 1(IGF-I) and insulin- like growth factor binding protein (IGFBP-3) were below the 0.1 percentile. Growth hormone provocation tests disclosed normal responses to L-arginine and insulin-induced hypoglycaemia. A huge benign mesenteric cyst was discovered by abdominal ultrasound and completely removed. Subsequently, the girl showed a marked catch-up growth; however, IGF-I and IGFBP-3 remained below the 0.1 percentile. These observations imply that growth may take place even with very low levels of insulin-like growth factors. The interpretation of low IGF-I and IGFBP-3 levels in short children still requires good clinical judgement and basic knowledge of their biological action.

  10. Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Kyung-A; Park, Min-Ah; Kang, Nam-Hee; Yi, Bo-Rim; Hyun, Sang-Hwan; Jeung, Eui-Bae; Choi, Kyung-Chul, E-mail: kchoi@cbu.ac.kr

    2013-11-01

    The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERα and IGF-1R and inducing phosphorylation of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERα, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERα and IGF-1R signaling pathways upregulated by BPA or E2.

  11. Risk factors for breast cancer and expression of insulin-like growth factor-2 (IGF-2 in women with breast cancer in Wuhan City, China.

    Directory of Open Access Journals (Sweden)

    Jun Qiu

    Full Text Available PURPOSE: The purpose of this study was to explore the risk factors for breast cancer and establish the expression rate of IGF-2 in female patients. METHODS: A case control study with 500 people in case group and 500 people in control group. A self-administered questionnaire was used to investigate risk factors for breast cancer. All cases were interviewed during a household survey. Immune-histochemical method was used to inspect the expression of IGF-2 in different tissues (benign breast lesions, breast cancer and tumor-adjacent tissue. RESULTS: Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. High body mass index (OR = 1.012,95%CI = 1.008-1.016, working attributes (OR = 1.004, 95%CI = 1.002 = 1.006, long menstrual period (OR = 1.007, 95%CI = 1.005-1.009, high parity OR = 1.003, 95%CI = 1.001-1.005 , frequent artificial abortion (OR = 1.004, 95%CI = 1.001-1.005, family history of cancer (OR = 1.003, 95%CI = 1.000-1.005, period of night shift (OR = 1.003, 95%CI = 1.001-1.006, live in high risk environment (OR = 1.005, 95%CI = 1.002-1.008, and family problems (OR = 1.010, 95%CI = 1.005-1.014 were associated with increased risk for breast cancer. In this study, good sleeping status, positive coping strategies, subjective support, and utility degree of social support were associated with reduced risk for breast cancer (OR = 0.998, 0.997, 0.985, 0.998 respectively; 95%CI = 0.996-1.000, 0.994-1.000, 0.980-0.989, 0.996-1.000, respectively. In benign breast lesions, breast cancer and tumor-adjacent tissue, IGF-2 was mainly expressed in the cytoplasm, but its expression rate was different (p<0.05. CONCLUSIONS: The incidence of breast cancer is a common result of multiple factors. IGF-2 is involved in the development of breast cancer, and its expression varies in different tissues (benign breast lesions

  12. Factors affecting insulin-like growth factor-I concentration in bovine milk.

    Science.gov (United States)

    Collier, R J; Miller, M A; Hildebrandt, J R; Torkelson, A R; White, T C; Madsen, K S; Vicini, J L; Eppard, P J; Lanza, G M

    1991-09-01

    To establish the naturally occurring range of insulin-like growth factor-I concentrations in bovine milk, samples from individual cows (n = 409) managed on five Missouri dairy herds were assayed. Parity, stage of lactation, and farm affected milk insulin-like growth factor-I concentration. Milk insulin-like growth factor-I concentration was higher in early lactation than mid and late lactation with concentrations in multiparous cows exceeding those in primiparous cows. Insulin-like growth factor-I concentration was negatively correlated to milk production the day of sample collection (r = -.15) and not correlated to predicted 305-d milk yields. Unprocessed bulk tank milk samples (n = 100) from a commercial processing plant had a mean concentration of insulin-like growth factor-I in milk of 4.32 ng/ml with a range of 1.27 to 8.10 ng/ml. This distribution was similar to the range detected in samples from individual cows, but values were lower than those reported for human milk. Concentration of insulin-like growth factor-I in milk was not altered by pasteurization (at 79 degrees C for 45 s). However, insulin-like growth factor-I was undetectable in milk heated to temperatures (121 degrees C for 5 min) required for infant formula preparation or in commercially available infant formula. These data indicated that insulin-like growth factor-I is a normal but quantitatively variable component of bovine milk that is not destroyed by pasteurization but is undetectable in infant formula. Concentration of insulin-like growth factor-I in bovine milk is lower than concentrations reported for human milk yet similar to those reported for human saliva.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. A hepatoprotective Lindera obtusiloba extract suppresses growth and attenuates insulin like growth factor-1 receptor signaling and NF-kappaB activity in human liver cancer cell lines

    Directory of Open Access Journals (Sweden)

    Stroh Thorsten

    2011-05-01

    Full Text Available Abstract Background In traditional Chinese and Korean medicine, an aqueous extract derived from wood and bark of the Japanese spice bush Lindera obtusiloba (L.obtusiloba is applied to treat inflammations and chronic liver diseases including hepatocellular carcinoma. We previously demonstrated anti-fibrotic effects of L.obtusiloba extract in hepatic stellate cells. Thus, we here consequently examine anti-neoplastic effects of L.obtusiloba extract on human hepatocellular carcinoma (HCC cell lines and the signaling pathways involved. Methods Four human HCC cell lines representing diverse stages of differentiation were treated with L.obtusiloba extract, standardized according to its known suppressive effects on proliferation and TGF-β-expression. Beside measurement of proliferation, invasion and apoptosis, effects on signal transduction and NF-κB-activity were determined. Results L.obtusiloba extract inhibited proliferation and induced apoptosis in all HCC cell lines and provoked a reduced basal and IGF-1-induced activation of the IGF-1R signaling cascade and a reduced transcriptional NF-κB-activity, particularly in the poorly differentiated SK-Hep1 cells. Pointing to anti-angiogenic effects, L.obtusiloba extract attenuated the basal and IGF-1-induced expression of hypoxia inducible factor-1α, vascular endothelial growth factor, peroxisome proliferator-activated receptor-γ, cyclooxygenase-2 and inducible nitric oxide synthase. Conclusions The traditional application of the extract is confirmed by our experimental data. Due to its potential to inhibit critical receptor tyrosine kinases involved in HCC progression via the IGF-1 signaling pathway and NF-κB, the standardized L.obtusiloba extract should be further analysed for its active compounds and explored as (complementary treatment option for HCC.

  14. Insulin-like growth factor-I in growth and metabolism

    DEFF Research Database (Denmark)

    Backeljauw, P; Bang, P; Dunger, D B

    2010-01-01

    Deficiency of insulin-like growth factor-I (IGF-I) results in growth failure. A variety of molecular defects have been found to underlie severe primary IGF-I deficiency (IGFD), in which serum IGF-I concentrations are substantially decreased and fail to respond to GH therapy. Identification of mor...

  15. Expression of insulin-like growth factor system components in colorectal tissue and its relation with serum IGF levels.

    NARCIS (Netherlands)

    Vrieling, A.; Voskuil, D.W.; Bosma, A.; Majoor, D.M.; Doorn, J. van; Cats, A.; Depla, A.C.; Timmer, R.; Witteman, B.J.; Wesseling, J.; Kampman, E.; Veer, L.J. van 't

    2009-01-01

    CONTEXT: The insulin-like growth factor (IGF)-system has been implicated in colorectal tumor carcinogenesis. Although both tumor expression levels and serum concentrations of IGF-system components are related to colorectal cancer risk, it is unknown whether IGF levels in tissue and serum are

  16. Expression of insulin-like growth factor system components in colorectal tissue and its relation with serum IGF levels

    NARCIS (Netherlands)

    Vrieling, A.; Voskuil, D.W.; Bosma, A.; Majoor, D.M.; Doorn, van J.; Cats, A.; Depla, A.; Timmer, R.; Witteman, B.J.M.; Wesseling, J.; Kampman, E.; van't Veer, L.J.

    2009-01-01

    Context: The insulin-like growth factor (IGF)-system has been implicated in colorectal tumor carcinogenesis. Although both tumor expression levels and serum concentrations of IGF-system components are related to colorectal cancer risk, it is unknown whether IGF levels in tissue and serum are

  17. A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer.

    Science.gov (United States)

    Weickhardt, Andrew; Doebele, Robert; Oton, Ana; Lettieri, Janice; Maxson, DeLee; Reynolds, Michele; Brown, Amy; Jackson, Mary K; Dy, Grace; Adjei, Araba; Fetterly, Gerald; Lu, Xian; Franklin, Wilbur; Varella-Garcia, Marileila; Hirsch, Fred R; Wynes, Murry W; Youssoufian, Hagop; Adjei, Alex; Camidge, D Ross

    2012-02-01

    This phase I/II study evaluated the safety and antitumor effect of the combination of erlotinib with cixutumumab, a recombinant fully humanized anti-insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in advanced non-small cell lung cancer (NSCLC). Patients with advanced NSCLC were treated in an initial safety-lead and drop-down cohorts using erlotinib 150 mg/d with cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an additional cohort (3 + 3 design) with cixutumumab at 15 mg/kg on day 1 in 21-day cycles (cohort 3). Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), whereas at 5 mg/kg, one of eight patients experienced DLT but three of eight patients still required a dose delay during cycle 1. At 15 mg/kg every 21 days, two of four patients experienced DLTs. In all cohorts, DLTs were either G3 rash or fatigue. Five patients had stable disease as best response and 14 patients had progressive disease. The median progression-free survival was 39 days (range 21-432+ days). Biomarkers analyses showed a trend toward better progression-free survival seen with higher free baseline insulin-like growth factor-1 levels as seen with other insulin-like growth factor-1R inhibitors. The combinations of cixutumumab at 6 mg/kg every 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not tolerable in unselected patients with NSCLC, as measured by DLT. Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but dose delays were common. Efficacy in unselected patients with NSCLC seems to be low.

  18. Insulin-like growth factor 1 and growth hormone in chronic liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Becker, Povl Ulrik

    1992-01-01

    mainly due to the decreased liver function. Low levels of somatomedins are also seen in patients with growth hormone (GH) insufficiency, renal impairment, and malnutrition. GH stimulates the production of IGF-1, and both are part of a negative feedback system acting on hepatic, pituitary......Somatomedins or insulin-like growth factors (IGF) are peptides synthesized in the liver. IGFs have different anabolic and metabolic actions and are important in normal growth and development. The concentration of insulin-like growth factor 1 (IGF-1) is low in patients with chronic liver disease......, and hypothalamic levels. The basal and stimulated GH concentration is pathologically elevated in patients with chronic liver disease and may be due to a disturbed regulation. Alterations in liver IGF receptors in patients with chronic liver disease still require investigation as they may be important for the liver...

  19. Circulating insulin-like growth factor I and cognitive function : Neuromodulation throughout the lifespan

    NARCIS (Netherlands)

    Aleman, Andre; Torres-Aleman, Ignacio

    2009-01-01

    Insulin-like growth factor I (IGF-I) is central to the somatotropic (growth hormone) axis. It promotes tissue growth and continues to have anabolic effects in adulthood. Accumulating evidence from the last decade, however, reveals that circulating levels of IGF-I also significantly affects cognitive

  20. The roles of the insulin-like growth factor system and leptin as ...

    African Journals Online (AJOL)

    The roles of the insulin-like growth factor system and leptin as possible mediators of the effects of nutritional restriction on age at puberty and compensatory growth in ... and IGFBP-3 are affected by nutritional restriction and repletion, and may contribute in some measure to the endocrine regulation of compensatory growth.

  1. Insulin-like growth factor binding protein 3 in inflammatory bowel disease

    DEFF Research Database (Denmark)

    Kirman, Irena; Whelan, Richard Larry; Jain, Suvinit

    2005-01-01

    Epithelial cell growth regulation has been reported to be altered in inflammatory bowel disease (IBD) patients. The cell growth regulatory factor, insulin-like growth factor binding protein 3 (IGFBP-3), may be partly responsible for this phenomenon. So far, IGFBP-3 levels have been assessed as va...

  2. Type-I Insulin-Like Growth Factor Receptor (IGF1R)-Estrogen Receptor (ER) Crosstalk Contributes to Antiestrogen Therapy Resistance in Breast Cancer Cells

    Science.gov (United States)

    2013-02-01

    consequences that can be treated using metformin (18). Thus, the clinical benefit of using lGFlR/IR tyrosine kinase inhibitors(TKI) may outweigh their...d IG F-JJ-stimu la ted proliferation in MCF-7L and T47D (data not shown) cells a nd insu lin and I G F-ll -stimu lated proli feration in...opausal women wit h horm one-receptor positive (HR +) metastat ic (M) or locally advanced ( LA ) breast cancer (BC). Cancer Res 2010;70:76s

  3. Insulin-Like Growth Factor 2 - The Oncogene and its Accomplices.

    Science.gov (United States)

    Kessler, Sonja M; Haybaeck, Johannes; Kiemer, Alexandra K

    2016-01-01

    The era of personalized medicine for cancer treatment has just begun opening up novel molecular targets improving cancer therapy. Members of the insulin-like growth factor 2 (IGF2) axis have been described to be altered and to have prognostic relevance in several different tumor identities. IGF2 belongs to the most complexly regulated growth factors known. As an imprinted gene it is controlled by epigenetic alterations. IGF2 mRNA binding proteins (IMPs/IGF2BPs) further regulate its translation. IGF2 activity is contained through IGF binding proteins (IGFBPs) and differential expression of the target receptors. The necessity of such a complex regulation implies pathophysiological effects of a deregulated expression of IGF2. This review attempts to summarize the different levels of IGF2 regulation, especially in the context of cancer. Members of the IGF2 axis are enlightened from the perspective of novel molecular targets for cancer therapy. Preclinical as well as experimental therapeutic interventions targeting IGF2 in cancer will be surveyed.

  4. Differential effects of insulin-like growth factor binding protein-6 (IGFBP-6 on migration of two ovarian cancer cell lines

    Directory of Open Access Journals (Sweden)

    Zhiyong eYang

    2015-01-01

    Full Text Available IGFBP-6 inhibits angiogenesis as well as proliferation and survival of rhabdomyosarcoma cells. However, it promotes migration of these cells in an IGF-independent manner. The IGF system is implicated in ovarian cancer, so we studied the effects of IGFBP-6 in ovarian cancer cells.Methods: The effects of wild type (wt and a non-IGF-binding mutant (m of IGFBP-6 on migration of HEY and SKOV-3 ovarian cancer cells, which respectively represent aggressive and transitional cancers, were studied. ERK and JNK phosphorylation were measured by Western blotting.Results: IGF-II, wt- and mIGFBP-6 each promoted SKOV3 cell migration by 77-98% (p<0.01. In contrast, IGF-II also increased HEY cell migration to 155 ± 13% of control (p<0.001, but wtIGFBP-6 and mIGFBP-6 decreased migration to 62 ± 5% and 66 ± 3% respectively (p<0.001. In these cells, coincubation of IGF-II with wt but not mIGFBP-6 increased migration. MAP kinase pathways are involved in IGFBP-6-induced rhabdomyosarcoma cell migration, so activation of these pathways in HEY and SKOV3 cells was studied. wt and mIGFBP-6 increased ERK phosphorylation by 62-99% in both cell lines (p<0.05. wtIGFBP-6 also increased JNK phosphorylation by 139-153% in both cell lines (p<0.05, but the effect of mIGFBP-6 was less clear. ERK and JNK inhibitors partially inhibited the migratory effects of wt and mIGFBP-6 in SKOV3 cells, whereas the ERK inhibitor partially restored wt and mIGFBP-6-induced inhibition of HEY cell migration. The JNK inhibitor had a lesser effect on the actions of wtIGFBP-6 and no effect on the actions of mIGFBP-6 in HEY cells.Conclusions: IGFBP-6 has opposing effects on migration of HEY and SKOV3 ovarian cancer cells, but activates MAP kinase pathways in both. Delineating the pathways underlying the differential effects on migration will increase our understanding of ovarian cancer metastasis and shed new light on the IGF-independent effects of IGFBP-6.

  5. Insulin-like growth factors, insulin-like growth factor-binding proteins, insulin-like growth factor-binding protein-3 protease, and growth hormone-binding protein in lipodystrophic human immunodeficiency virus-infected patients

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte Rønde

    2004-01-01

    Human immunodeficiency virus (HIV)-lipodystrophy is associated with impaired growth hormone (GH) secretion. It remains to be elucidated whether insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), IGFBP-3 protease, and GH-binding protein (GHBP) are abnormal in HIV......-lipodystrophy. These parameters were measured in overnight fasting serum samples from 16 Caucasian males with HIV-lipodystrophy (LIPO) and 15 Caucasian HIV-infected males without lipodystrophy (NONLIPO) matched for age, weight, duration of HIV infection, and antiretroviral therapy. In LIPO, abdominal fat mass and insulin...... concentration were increased (>90%, P protease were similar between groups (all P > .5), whereas, in LIPO, IGFBP-1 and IGFBP-2 were reduced (-36%, P

  6. Therapy of Prostate Cancer Using a Human Antibody Targeting the Type 1 Insulin-Like Growth Factor Receptor (IGF-IR)

    Science.gov (United States)

    2009-09-01

    Prostate Cancer, IGF-IR, monoclonal antibody 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF...J Cell Biochem 2006;99:392^401. 40. Dumontet C, Jaffrezou JP,Tsuchiya E, et al. Resis- tance to microtubule-targeted cytotoxins in a K562 leukemia ...by screening a naBve bacteriophage Fab library (28). A12 does not cross-react with the insulin receptor (28). In vivo study. To study the in vivo

  7. Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells.

    Science.gov (United States)

    Attias-Geva, Zohar; Bentov, Itay; Ludwig, Dale L; Fishman, Ami; Bruchim, Ilan; Werner, Haim

    2011-07-01

    Specific insulin-like growth factor-I receptor (IGF-IR) targeting emerged in recent years as a promising therapeutic strategy in cancer. Endometrial cancer is the most common gynaecological cancer in the Western world. The aim of this study was to evaluate the potential of cixutumumab (IMC-A12, ImClone Systems), a fully human monoclonal antibody against the IGF-IR, to inhibit IGF-I-mediated biological actions and cell signalling events in four endometrial carcinoma-derived cell lines (ECC-1, Ishikawa, USPC-1 and USPC-2). Our results demonstrate that cixutumumab was able to block the IGF-I-induced autophosphorylation of the IGF-IR. In addition, the PI3K and MAPK downstream signalling pathways were also inactivated by cixutumumab in part of the cell lines. Prolonged (24h and 48h) exposures to cixutumumab reduced IGF-IR expression. Furthermore, confocal microscopy of GFP-tagged receptors shows that cixutumumab treatment led to IGF-IR redistribution from the cell membrane to the cytoplasm. Antiapoptotic effects were evaluated by cleavage of caspase 3 and PARP, and mitogenicity and transformation by proliferation and cell cycle assays. Results obtained showed that cixutumumab abrogated the IGF-I-stimulated increase in proliferation rate, and increased caspase-3 and PARP cleavage, two markers of apoptosis. Of importance, cixutumumab had no effect neither on insulin receptor (IR) expression nor on IGF-I activation of IR. In summary, in a cellular model of endometrial cancer cixutumumab was able to inhibit the IGF-I-induced activation of intracellular cascades, apoptosis and proliferation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Insulin-like Growth Factor I and its Binding Proteins in Health, Aging and Disease

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph)

    1998-01-01

    textabstractThe insulin-like growth factors (IGFs) were discovered in 1956 by William D. Salmon Jr. and William H. Daughaday at Washington University, St Louis, USA. Initially IGFs were called sulfation factors because they were able to replace the sulfation factor activity of growth hormone

  9. Diminished concentrations of insulin-like growth factor I in cystic fibrosis

    DEFF Research Database (Denmark)

    Laursen, Erik; Juul, A; Lanng, S

    1995-01-01

    Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data...

  10. Detection of polymorphism of the insulin-like growth factor-I (IGF-I ...

    African Journals Online (AJOL)

    Molecular genetic selection on individual genes is a promising method to genetically improve economically important traits in chickens. The insulin-like growth factor-I (IGF-I) gene may play important roles in growth of multiple tissues, including muscle cells, cartilage and bone. In the present study, polymorphism of the ...

  11. Evaluation of insulin-like growth factor-I gene polymorphism in ...

    African Journals Online (AJOL)

    The genetic improvement of production traits can be developed through marker assisted selection. Insulin-like growth factor I (IGF-I) is a member of the somatotrophic axis which has a remarkable variation of its biological effect including protein synthesis and skeletal growth. This study aimed to detect the genetic ...

  12. Circulating concentrations of insulin-like growth factor-1 in dogs with naturally occurring mitral regurgitation

    DEFF Research Database (Denmark)

    Pedersen, Henrik Duelund; Falk, Bo Torkel; Häggström, Jens

    2005-01-01

    Insulin-like growth factor-1 (IGF-1), which mediates most effects of growth hormone, has effects on cardiac mass and function, and plays an important role in the regulation of vascular tone. In humans, an inverse relationship between degree of heart failure (HF) and circulating IGF-1 concentratio...

  13. The roles of the insulin-like growth factor system and leptin as ...

    African Journals Online (AJOL)

    Unknown

    Abstract. The aim of this experiment was to determine to what extent changes in the blood concentrations of insulin- like growth factor-1 (IGF-1), IGF binding proteins (IGFBPs), leptin and glucose are associated with compensatory growth and age at puberty in Friesian heifers. Twelve heifers (6 months old; 179.8 kg body ...

  14. Insulin-like growth factor 2 in development and disease: a mini-review.

    Science.gov (United States)

    Bergman, Daniel; Halje, Matilda; Nordin, Matilda; Engström, Wilhelm

    2013-01-01

    Insulin-like growth factor 2 (IGF2) is a protein hormone known to regulate cell proliferation, growth, migration, differentiation and survival. The gene is parentally imprinted in the sense that transcripts are almost exclusively derived from the paternal allele. Loss of imprinting of the IGF2 gene is a recurrent observation in growth disorders that combine overgrowth with a variety of malignant tumours. Moreover, IGF2 has been proposed to play a role in the development of a variety of seemingly unrelated cancers that play an important role in geriatric medicine, e.g., breast cancer, colon cancer and lung cancer. Finally, IGF2 has been implicated in cardiovascular disease, since, for example, IGF2 has been shown to influence the size of atherosclerotic lesions. To summarize current knowledge about IGF2, its interactions with binding proteins and receptors and connections with key diseases. The contents of this paper were based on reviews of existing literature within the field. There is a substantial amount of research linking IGF2 to growth disorders, cancer and to a much lesser degree cardiovascular disease. Some of the studies on IGF2 and tumour growth have yielded conflicting results, for instance regarding its effect on apoptosis. Today, our knowledge on how IGF2 is composed and interacts with receptors has come a long way. However, there is comparatively little information on how IGF2 affects tumour growth and cardiovascular diseases such as atherosclerosis. Thus, further research will be needed to elucidate the impact of IGF2 on key diseases. Copyright © 2012 S. Karger AG, Basel.

  15. Hormones and diet: low insulin-like growth factor-I but normal bioavailable androgens in vegan men

    Science.gov (United States)

    Allen, N E; Appleby, P N; Davey, G K; Key, T J

    2000-01-01

    Mean serum insulin-like growth factor-I was 9% lower in 233 vegan men than in 226 meat-eaters and 237 vegetarians (P = 0.002). Vegans had higher testosterone levels than vegetarians and meat-eaters, but this was offset by higher sex hormone binding globulin, and there were no differences between diet groups in free testosterone, androstanediol glucuronide or luteinizing hormone. © 2000 Cancer Research Campaign PMID:10883675

  16. The Insulin-like Growth Factor-I–mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth

    NARCIS (Netherlands)

    Floyd, Suzanne; Favre, Cedric; Lasorsa, Francesco M.; Leahy, Madeline; Trigiante, Giuseppe; Stroebel, Philipp; Marx, Alexander; Loughran, Gary; O’Callaghan, Katie; Marobbio, Carlo M.T.; Slotboom, Dirk J.; Kunji, Edmund R.S.; Palmieri, Ferdinando; O’Connor, Rosemary

    2007-01-01

    The insulin/insulin-like growth factor (IGF) signaling pathway to mTOR is essential for the survival and growth of normal cells and also contributes to the genesis and progression of cancer. This signaling pathway is linked with regulation of mitochondrial function, but how is incompletely

  17. Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer.

    Science.gov (United States)

    Reidy, Diane Lauren; Vakiani, Efsevia; Fakih, Marwan G; Saif, Muhammad Wasif; Hecht, Joel Randolph; Goodman-Davis, Noah; Hollywood, Ellen; Shia, Jinru; Schwartz, Jonathan; Chandrawansa, Kumari; Dontabhaktuni, Aruna; Youssoufian, Hagop; Solit, David B; Saltz, Leonard B

    2010-09-20

    To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti-epidermal growth factor receptor (EGFR) mAb colorectal cancer. A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m(2) IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R. Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients). IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors.

  18. The Expression of Insulin-like Growth Factor and Insulin-like Growth Factor Binding Protein mRNAs in Mouse Placenta

    DEFF Research Database (Denmark)

    Carter, Anthony M.; Nygard, K.; Mazzuca, D.M.

    2006-01-01

    Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) are paracrine regulators of tissue growth and development, and are expressed at the sites of biological action. To study the role of the IGFs and IGFBPs in mouse placental development, we determined the temporal and spatial...... in endothelium of maternal blood vessels, and IGFBP-2 and -6 mRNAs in myometrium, where IGFBPs may play a critical role in regulating trophoblast invasion. These findings suggest possible biological roles of the peptides at the feto-maternal interface....

  19. Insulin-like growth factor-I in growth and metabolism

    DEFF Research Database (Denmark)

    Backeljauw, P; Bang, P; Dunger, D B

    2010-01-01

    Deficiency of insulin-like growth factor-I (IGF-I) results in growth failure. A variety of molecular defects have been found to underlie severe primary IGF-I deficiency (IGFD), in which serum IGF-I concentrations are substantially decreased and fail to respond to GH therapy. Identification of more...... for proper interpretation of data. Recombinant human IGF-I (rhIGF-I) treatment improves stature in patients with severe primary IGFD, and has also been shown to improve glycaemic control and insulin sensitivity in patients with severe insulin resistance. Ongoing studies of patients receiving rh...

  20. The human insulin-like growth factor II gene contains two development-specific promoters

    NARCIS (Netherlands)

    Pagter-Holthuizen, P. de; Jansen, M.; Schaik, F.M.A.; Kammen, R. van der; Oosterwijk, C.; Brande, J.L. van den; Sussenbach, J.S.

    1987-01-01

    The insulin-like growth factors (IGF) play an important role in fetal and postnatal development. Recently, the nucleotide sequences of the cDNAs encoding IGF-I and IGF-II and part of the human IGF genes were reported. In this communication we describe two distinct IGF-II cDNAs isolated from a human

  1. Neuroprotective Effect of Insulin-like Growth Factor-II on 1- Methyl-4 ...

    African Journals Online (AJOL)

    Purpose: To evaluate the receptor-mediated neuroprotective effect of insulin-like growth factor-II (IGFII) on 1-methyl-4-phenyl pyridinium (MPP) induced oxidative damage in adult cortical neuronal cultures. Methods: Adult rats were randomly divided into 5 groups. Cortical neurons were prepared from rats. The cells were ...

  2. Insulin-like growth factor system in serum and cerebrospinal fluid in patients with multiple sclerosis

    NARCIS (Netherlands)

    Wilczak, N; Schaaf, M; Bredewold, R; Streefland, C; Teelken, A; De Keyser, J

    1998-01-01

    The insulin-like growth factor (IGF) system influences oligodendrocyte survival, myelination, and immune functions. We examined whether alterations in the circulating IGF system occur in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. We measured

  3. Leptin, insulin like growth factor-1 and thyroid profile in a studied ...

    African Journals Online (AJOL)

    Background: Several mechanisms have been suggested for obesity in Down syndrome. Aim of the study: Assessment of serum levels of leptin, insulin like growth factor-I (IGF-I), thyroid stimulating hormone (TSH) and free thyroxin (FT4) in a prepubertal Egyptian sample of children with DS compared to their age and sex ...

  4. Lower insulin-like growth factor-1 concentrations in women with premenstrual dysphoric disorder.

    Science.gov (United States)

    Thys-Jacobs, Susan; McMahon, Don; Bilezikian, John P

    2008-05-01

    Recent evidence suggests that abnormalities in calcium metabolism may be responsible for the luteal phase symptoms in women experiencing premenstrual syndrome. Our objective was to measure the cyclic variations in bone turnover across the menstrual cycle in women with and without luteal phase symptoms consistent with severe premenstrual syndrome or premenstrual dysphoric disorder. We measured the indices of bone metabolism, N-telopeptide, osteocalcin and insulin-like growth factor-1 in women with and without premenstrual dysphoric disorder using a cross-sectional and prospective design. Participating women underwent 2 months of self-assessment symptom screening and 1 month of hormonal evaluation. Overall serum insulin-like growth factor-1 (mean +/- standard deviation) was significantly lower in the premenstrual dysphoric disorder group compared with controls (205.7 +/- 56.8 vs 240.2 +/- 76.9 ng/ mL, P = .01) and was significantly lower throughout all 5 phases of the menstrual cycle in the premenstrual dysphoric disorder group compared with controls. In both groups of women, serum insulin-like growth factor-1 concentrations were highest and urinary N-telopeptide levels were lowest during the luteal phase. Bone remodeling indices of formation and resorption during the menstrual cycle were greater and appeared earlier in the control compared with the premenstrual dysphoric disorder group. Significantly lower insulin-like growth factor-1 concentrations in premenstrual dysphoric disorder subjects compared with controls may hold insights about how premenstrual dysphoric disorder subjects differ from asymptomatic controls.

  5. Effect of Insulin Infusion on insulin-like growth factor I (IGF-I) during Hemodialysis

    DEFF Research Database (Denmark)

    Reinhard, Mark; Frystyk, Jan; Bjerre, Mette

    2012-01-01

    Background: Hemodialysis (HD) is a catabolic procedure probably contributing to the high frequency of protein-energy wasting among patients on maintenance HD. The aim was to investigate the effect of insulin infusion on insulin-like growth factor I (IGF-I) during HD compared with a meal alone...

  6. Endonucleolysis in the turnover of insulin-like growth factor II mRNA

    DEFF Research Database (Denmark)

    Nielsen, F C; Christiansen, Jan

    1992-01-01

    The overlapping transcription units constituting the rat insulin-like growth factor II (IGF-II) locus generate multiple mRNAs by using different promoters. Three promoters have been identified, giving rise to 4.6-, 3.8-, and 3.6-kilobase mRNAs. The latter, originating from promoter P3, is the most...

  7. Neuroprotective Effect of Insulin-like Growth Factor-II on 1- Methyl-4 ...

    African Journals Online (AJOL)

    oxidative stress markers, antioxidant enzymes, mitochondrial functional markers were analyzed in the. MPP-treated neuronal ... Keywords: Insulin-like growth factor-II, Neuronal cells, 1-Methyl-4-phenyl pyridinium, Mitochondrial markers, Oxidative stress ..... processes, such as memory [17], and neuro- protection against ...

  8. Downregulation of Insulin-like growth factor binding protein 6 is associated with ACTH-secreting pituitary adenoma growth.

    Science.gov (United States)

    Yang, Yakun; Sheng, Miaomiao; Huang, Fengming; Bu, Dechao; Liu, Xiaohai; Yao, Yong; Dai, Congxin; Sun, Bowen; Zhu, Jindong; Jiao, Yonghui; Wei, Zhenqing; Zhu, Huijuan; Lu, Lin; Zhao, Yi; Jiang, Chengyu; Wang, Renzhi

    2014-12-01

    Adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome, called Cushing disease, is caused by a corticotroph tumor of the pituitary gland. Insulin-like growth factor binding protein 6 (IGFBP6), which regulates insulin-like growth factor (IGF) activity and inhibits several IGF2-dependent cancer growths, plays a pivotal role in the tumorigenesis of malignancy, but its roles in ACTH-secreting pituitary adenomas remain unclear. To investigate IGFBP6 expression in ACTH-secreting pituitary adenomas, and its involvement in tumor growth. Sporadic ACTH-secreting pituitary adenomas specimens (n = 41) and adjacent non-tumorous pituitary tissues (n = 9) were collected by transphenoidal surgery. IGFBP6 expression was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and validated by Western blotting. Associations of IGFBP6 expression with maximum tumor diameter or Ki-67 labeling index were evaluated in ACTH-secreting pituitary adenomas. IGFBP6 mRNA and protein expression were both decreased in ACTH-secreting pituitary adenomas, compared to adjacent non-tumorous pituitary tissues (P pituitary adenomas. IGFBP6 attenuation in ACTH-secreting pituitary adenomas is associated with tumor growth, through activation of PI3K-AKT-mTOR pathway. The finding underlies IGFBP6 roles in Cushing disease and would potentially provide a novel target of medical therapies.

  9. Low fat diet with omega-3 fatty acids increases plasma insulin-like growth factor concentration in healthy postmenopausal women

    Science.gov (United States)

    The insulin-like growth factor pathway plays a central role in the normal and abnormal growth of tissues; however, the nutritional determinants of insulin-like growth factor I (IGF-I) and its binding proteins in normal individuals are not well-defined. The purpose of this study was to determine the ...

  10. Stimulation of body weight increase and epiphyseal cartilage growth by insulin like growth factor

    Science.gov (United States)

    Ellis, S.

    1981-01-01

    The ability of insulin-like growth factor (IGF) to induce growth in hypophysectomized immature rats was tested by continuous infusion of the partially purified factor at daily doses of 6, 21, and 46 mU for an 8-day period. A dose-dependent growth of the proximal epiphyseal cartilage of the tibia and an associated stimulation of the primary spongiosa were produced by these amounts of IGF. The two highest doses of IGF also resulted in dose-dependent increases of body weight. Gel permeation of the sera at neutrality showed that the large-molecular-weight IGF binding protein was not induced by the infusion of IGF, whereas it ws generated in the sera of hypophysectomized rats that were infused with daily doses of 86 mU of human growth hormone.

  11. Effects of Hypergravity Rearing on Growth Hormone and Insulin-Like Growth Factor in Rat Pups

    Science.gov (United States)

    Baer, L. A.; Chowdhury, J. H.; Grindeland, R. E.; Wade, C. E.; Ronca, A. E.

    2003-01-01

    Body weights of rat pups reared during exposure to hypergravity (hg) are significantly reduced relative to 1 g controls. In the present study, we examined in hg-reared rat pups two major contributors to growth and development, namely growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Beginning on Gestational day (G)11 of the rats 22 day pregnancy, rat dams and their litters were continuously exposed to either 1.5-g or 2.0-g. On Postnatal day (P)l0, plasma GH and IGF-1 were analyzed using radioimmunoassay (RIA). Both hormones were significantly elevated in hg pups relative to 1-g control pups. Together, these findings suggest that GH and IGF-1 are not primary determinants of reduced body weights observed in hg-reared pups. The significant elevations in pup GH and IGF-1 may be related to increased physical stimulation in hypergravity.

  12. Serum insulin-like growth factor-I adult reference values for an ...

    African Journals Online (AJOL)

    Analysis of insulin-like growth factor I (IGF-I) in serum is fundamental in order to aid in the diagnosis of growth hormone (GH)-related disorders, as well as in the diagnosis and follow-up of other diseases. Considering the importance of IGF-I local normal range, the aim of this study was to determine reference values for IGF-I ...

  13. Paternal Insulin-like Growth Factor 2 (Igf2 Regulates Stem Cell Activity During Adulthood

    Directory of Open Access Journals (Sweden)

    Vilma Barroca

    2017-02-01

    Full Text Available Insulin-like Growth Factor 2 (IGF2 belongs to the IGF/Insulin pathway, a highly conserved evolutionarily network that regulates growth, aging and lifespan. Igf2 is highly expressed in the embryo and in cancer cells. During mouse development, Igf2 is expressed in all sites where hematopoietic stem cells (HSC successively expand, then its expression drops at weaning and becomes undetectable when adult HSC have reached their niches in bones and start to self-renew. In the present study, we aim to discover the role of IGF2 during adulthood. We show that Igf2 is specifically expressed in adult HSC and we analyze HSC from adult mice deficient in Igf2 transcripts. We demonstrate that Igf2 deficiency avoids the age-related attrition of the HSC pool and that Igf2 is necessary for tissue homeostasis and regeneration. Our study reveals that the expression level of Igf2 is critical to maintain the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSC and their niche. Our data have major clinical interest for transplantation: understanding the changes in adult stem cells and their environments will improve the efficacy of regenerative medicine and impact health- and life-span.

  14. Adult growth hormone deficiency treatment with a combination of growth hormone and insulin-like growth factor-1 resulting in elevated sustainable insulin-like growth factor-1 and insulin-like growth factor binding protein 3 plasma levels: a case report

    Directory of Open Access Journals (Sweden)

    Madigan Margaret

    2010-09-01

    Full Text Available Abstract Introduction Adult Growth hormone Deficiency is a well known phenomenon effecting both males and females. Adult Growth Hormone Deficiency is marked by a number of neuropsychiatric, cognitive performance, cardiac, metabolic, muscular, and bone symptoms and clinical features. There is no known standardized acceptable therapeutic modality to treat this condition. A recent meta-analysis found that after 16 years of Growth Hormone replacement therapy a large proportion of the patients still had Growth Hormone associated symptoms especially related to executive functioning. A major goal is to increase plasma levels of both insulin-like growth factor (insulin-like growth factor-1 and insulin-like growth factor binding protein 3. Case Presentation We report a case of a 45-year-old caucasian woman with early ovarian failure for 2 years and amenorrhea since the age of 43, who presented with Adult Growth Hormone Deficiency and an IGF-1 of 126 ng/mL. Since her insulin-like growth factor-1 was lowest at 81 ng/mL, she was started on insulin-like growth factor-1 Increlex at 0.2 mg at bedtime, which immediately raised her insulin-like growth factor-1 levels to 130 ng/mL within 1 month, and 193 ng/mL, 249 ng/mL, and 357 ng/mL, after 3, 4, and 5 months, respectively, thereafter. Her insulin-like growth factor binding protein 3 continued to decrease. It was at this point when we added back the Growth Hormone and increased her Increlex dosage to 1.3 - 1.5 mg that her insulin-like growth factor binding protein 3 began to increase. Conclusion It appears that in some patients with Adult Growth Hormone Deficiency, insulin-like growth factor-1 elevation is resistant to direct Growth Hormone treatment. Furthermore, the binding protein may not rise with insulin-like growth factor-1. However, a combination of Growth Hormone and insulin-like growth factor-1 treatment may be a solution.

  15. CDNA cloning and mRNA expression of the six mouse insulin-like growth factor binding proteins

    NARCIS (Netherlands)

    A.G.P. Schuller (Alwin); C. Groffen (Cora); J.W. van Neck (Han); E.C. Zwarthoff (Ellen); S.L.S. Drop (Stenvert)

    1994-01-01

    textabstractThe insulin-like growth factor binding proteins (IGFBPs) comprise a family of six distinct proteins which modulate insulin-like growth factor action. We have isolated cDNAs encoding the six mouse IGFBPs (mIGFBPs). In addition, we studied the mRNA expression of the six mIGFBPs during

  16. Expression of insulin-like growth factor-1 and insulin-like growth factor-1 receptors in EL4 lymphoma cells overexpressing growth hormone.

    Science.gov (United States)

    Weigent, Douglas A; Arnold, Robyn E

    2005-03-01

    Almost all of the previous studies with growth hormone (GH) have been done with exogenously supplied GH and, therefore, involve actions of the hormone through its receptor. However, the actions of endogenous or lymphocyte GH are still unclear. In a previous study, we showed that overexpression of GH (GHo) in a lymphoid cell line resulted in protection of the cells to apoptosis mediated by nitric oxide (NO). In the present study, we show that the protection from apoptosis could be transferred to control cells with culture fluids obtained from GHo cells and blocked by antibodies to the insulin-like growth factor-1 (IGF-1) or antibodies to the IGF-1-receptor (IGF-1R). Northern and Western blot analysis detected significantly higher levels of IGF-1 in cells overexpressing GH. An increase in the expression of the IGF-1R in GHo cells was also detected by Western blot analysis, (125)I-IGF-1 binding and analysis of IGF-1R promoter luciferase constructs. Transfection of GHo cells with a dominant negative IGF-1R mutant construct blocked the generation of NO and activation of Akt seen in GHo cells compared to vector alone control EL4 cells. The results suggest that one of the consequences of the overexpression of GH, in cells lacking the GH receptor, is an increase in the expression of IGF-1 and the IGF-1R which mediate the protection of EL4 lymphoma cells from apoptosis.

  17. Insulin Like Growth Factor System: How Does it Affect Neonatal Anthropometry?

    Directory of Open Access Journals (Sweden)

    Emine Kacar

    2016-09-01

    Full Text Available Aim: The present study aims to clarify the role of insulin like growth factor-1 (IGF-1, insulin like growth factor binding protein-3 (IGFBP-3, ghrelin, and insulin in fetal growth. Material and Method: Based on Turkish standards, 14 newborns were defined as small for gestational age (SGA, 33 newborns were described as appropriate for gestational age (AGA, and 13 newborns were identified as large for gestational age (LGA. IGF-1, IGFBP-3, ghrelin, and insulin levels were measured in umbilical cord and maternal serum. Results: The LGA group had significantly higher levels of IGF-1, IGFBP-3, ghrelin, and insulin in umbilical cord and maternal serum than the SGA group. Umbilical cord and maternal serum levels of IGF-1 and IGFBP-3 correlated significantly and positively with body weight, body length, head circumference, and abdominal circumference of the neonates. Discussion: Based on the findings of the present study, it may be postulated that insulin like growth factor system has a role in fetal growth.

  18. Type I insulin-like growth factor as a liver reserve assessment tool in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Abdel-Wahab R

    2015-09-01

    Full Text Available Reham Abdel-Wahab,1,2 Samir Shehata,2 Manal M Hassan,1 Mouhammed A Habra,3 Ghazaleh Eskandari,4 Peggy T Tinkey,5 Jennifer Mitchell,5 Ju-Seog Lee,6 Hesham M Amin,4,7 Ahmed O Kaseb11Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Clinical Oncology, Assiut University Hospital, Assiut, Egypt; 3Department of Endocrinology, 4Department of Hematopathology, 5Department of Veterinary Medicine and Surgery, 6Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 7Graduate School of Biomedical Sciences, Houston, TX, USAAbstract: Chronic liver diseases (CLDs encompass a wide range of illnesses, including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and viral hepatitis. Deterioration of liver capacity, with subsequent progression into cirrhosis and hepatocellular carcinoma (HCC, ultimately leads to a further decrease in the hepatic reserve. The Child–Turcotte–Pugh scoring system is the standard tool for assessing underlying liver reserve capacity in routine practice and in clinical trials of CLD and HCC. In this review, we highlight the clinical significance of insulin-like growth factor-I (IGF-I and the growth hormone (GH signaling pathway in HCC. IGF-I could be a marker for liver reserve capacity in CLDs and HCC in clinical practice. This approach could improve the risk assessment and stratifications of patients on the basis of their underlying liver reserve, either before active treatment in routine practice or before they are enrolled in clinical trials.Keywords: IGF-I, growth hormone, chronic liver disease

  19. Serum free and total insulin-like growth factor-1, insulin-like growth factor binding protein-1 and insulin-like growth factor binding protein-3 levels in healthy elderly individuals - Relation to self-reported duality of health and disability

    NARCIS (Netherlands)

    Janssen, JAMJL; Stolk, RP; Pols, HAP; Grobbee, DE; Lamberts, SWJ

    1998-01-01

    Background: Little is known about the influence of the free insulin-like growth factor-I/insulin-like growth factor binding protein (IGF-I/IGFBP) system on the quality of health and on disability in the elderly population. Design: In a cross-sectional population based study of 218 healthy elderly

  20. Tumour suppression associated with expression of human insulin-like growth factor II.

    OpenAIRE

    Schofield, P. N.; Lee, A.; Hill, D. J.; Cheetham, J. E.; James, D.; Stewart, C.

    1991-01-01

    Recent circumstantial evidence has implicated Insulin-like growth factor II in the genesis of several tumour types, notably developmental tumours (Scott et al., 1985; Schofield & Tate, 1987; Wilkins et al., 1989). This type of tumour, thought to originate during the defective differentiation of organ precursors (Miereau et al., 1987), often expresses greatly elevated levels of mRNA for IGF-II, a known mitogen for these cells and abundantly expressed in their presumed normal counterparts (Scot...

  1. The Insulin-Like Growth Factor System in the Long-Lived Naked Mole-Rat.

    Directory of Open Access Journals (Sweden)

    Malene Brohus

    Full Text Available Naked mole-rats (Heterocephalus glaber (NMRs are the longest living rodents known. They show negligible senescence, and are resistant to cancers and certain damaging effects associated with aging. The insulin-like growth factors (IGFs have pluripotent actions, influencing growth processes in virtually every system of the body. They are established contributors to the aging process, confirmed by the demonstration that decreased IGF signaling results in life-extending effects in a variety of species. The IGFs are likewise involved in progression of cancers by mediating survival signals in malignant cells. This report presents a full characterization of the IGF system in the NMR: ligands, receptors, IGF binding proteins (IGFBPs, and IGFBP proteases. A particular emphasis was placed on the IGFBP protease, pregnancy-associated plasma protein-A (PAPP-A, shown to be an important lifespan modulator in mice. Comparisons of IGF-related genes in the NMR with human and murine sequences indicated no major differences in essential parts of the IGF system, including PAPP-A. The protease was shown to possess an intact active site despite the report of a contradictory genome sequence. Furthermore, PAPP-A was expressed and translated in NMRs cells and retained IGF-dependent proteolytic activity towards IGFBP-4 and IGF-independent activity towards IGFBP-5. However, experimental data suggest differential regulatory mechanisms for PAPP-A expression in NMRs than those described in humans and mice. This overall description of the IGF system in the NMR represents an initial step towards elucidating the complex molecular mechanisms underlying longevity, and how these animals have evolved to ensure a delayed and healthy aging process.

  2. Insulin-like growth factor-I, insulin-like growth factor binding protein-3 and the risk of fibrocystic breast conditions among Chinese women.

    Science.gov (United States)

    Chen, Chu; Doherty, Jennifer A; Lewis, S Kay; Ray, Roberta M; Gao, Dao Li; Stalsberg, Helge; Feng, Ziding; Thomas, David B

    2006-05-01

    We investigated whether circulating insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels are associated with the risk of fibrocystic breast conditions (FBC), in a case-control study nested within a randomized trial of breast self-examination conducted in Shanghai, China. Participants were enrolled during 1989-1991 and were followed over 10 years for the development of breast diseases. Controls (n = 897) were frequency-matched by age to cases (n = 451), who were diagnosed with FBC between 1995 and 2000. Circulating IGF-I and IGFBP-3 levels and their molar ratio were positively associated with risk of FBC. The odds ratios (ORs) and 95% confidence intervals (CI) for the upper fourth of the distribution compared to the lowest fourth for IGF-I, IGFBP3 and their molar ratio were 3.02 (2.02-4.52), 1.92 (1.37-2.71) and 2.26 (1.52-3.36), respectively. The strength of the association between IGF-I levels and FBC was attenuated after adjustment for IGFBP-3 and that for IGFBP-3 was largely eliminated after adjustment for IGF-I. Increasing levels of IGF-I were particularly associated with increasing risk of FBC with proliferative elements (ORs and 95% CIs for the 2nd, 3rd and upper fourth of the distribution of IGF-I: 3.13 (1.50-6.53), 4.57 (2.22-9.39) and 6.30 (3.08-12.89), compared with the lowest fourth. Our results suggest that elevated levels of IGF-I may contribute to the development of FBC. 2005 Wiley-Liss, Inc.

  3. Cow placenta extract promotes murine hair growth through enhancing the insulin - like growth factor-1

    Directory of Open Access Journals (Sweden)

    Dongliang Zhang

    2011-01-01

    Full Text Available Background: Hair loss is seen as an irreversible process. Most research concentrates on how to elongate the anagen, reduce the negative factors of obstructing hair growth and improve the hair number and size. Aim: In our experiment, we tried to prove that the cow placenta extract can promote hair growth by elongating hair shaft and increasing hair follicle number. Materials and Methods: Cow placenta extract (CPE, water and minoxidil applied separately on the back of depilated B57CL/6 mice for the case, negative and positive control respectively. We checked the proliferation of cells which are resident in hair sheath, and the expression of a few growth factors which stimulate hair growth. Results: Result shows that placenta extract more efficiently accelerates cell division and growth factor expression, by raising the insulin-like growth factor (IGF-1 mRNA and protein level to increase HF size and hair length. Conclusions: The extract is not a purified product; so, it is less effective than minoxidil, which is approved by the US FDA for the treatment of male pattern baldness. If refinement is done, the placenta extract would be a good candidate medicine for hair loss.

  4. Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Pedersen, S B

    1997-01-01

    PURPOSE: To investigate the effects of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) on the rat prostate. In addition, we investigated the effect of ornithine decarboxylase (ODC) inhibition with alpha-diflouromethylornitine (DFMO) on the expected growth of the prostate.MA...

  5. Serum concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein-2 and -3 in eight hoofstock species.

    Science.gov (United States)

    Govoni, Kristen E; Goodman, Danielle; Maclure, Rebecca M; Penfold, Linda M; Zinn, Steven A

    2011-01-01

    The somatotropic axis, which includes growth hormone, insulin-like growth factor (IGF)-I, and IGF binding proteins (IGFBP), is involved in the regulation of growth and metabolism. Measures of the somatotropic axis can be predictive of nutritional status and growth rate that can be utilized to identify nutritional status of individual animals. Before the somatotropic axis can be a predictive tool, concentrations of hormones of the somatotropic axis need to be established in healthy individuals. To begin to establish these data, we quantified IGF-I, IGFBP-2, and IGFBP-3 in males and females of eight threatened hoofstock species at various ages. Opportunistic blood samples were collected from Bos javanicus (Java banteng), Tragelaphus eurycerus isaaci (bongo), Gazella dama ruficollis (addra gazelle), Taurotragus derbianus gigas (giant eland), Kobus megaceros (Nile lechwe), Hippotragus equines cottoni (roan antelope), Ceratotherium simum simum (white rhinoceros), and Elephas maximus (Asian elephant). Serum IGF-I and IGFBPs were determined by radioimmunoassay and ligand blot, respectively. Generally, IGF-I and IGFBP-3 were greater in males, and IGFBP-2 was greater in females. In banteng (P = 0.08) and male Nile lechwe (P age, but decreased in rhinoceros (P = 0.07) and female Nile lechwe (P banteng, IGFBP-3 was greater (P Determination of concentrations of hormones in the somatotropic axis in healthy animals makes it possible to develop models that can identify the nutritional status of these threatened hoofstock species. © 2010 Wiley-Liss, Inc.

  6. Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis*

    Science.gov (United States)

    Jepsen, Malene R.; Kløverpris, Søren; Mikkelsen, Jakob H.; Pedersen, Josefine H.; Füchtbauer, Ernst-Martin; Laursen, Lisbeth S.; Oxvig, Claus

    2015-01-01

    Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system. PMID:25533459

  7. Childhood Exposure to Phthalates: Associations with Thyroid Function, Insulin-like Growth Factor I, and Growth

    Science.gov (United States)

    Boas, Malene; Frederiksen, Hanne; Feldt-Rasmussen, Ulla; Skakkebæk, Niels E.; Hegedüs, Laszlo; Hilsted, Linda; Juul, Anders; Main, Katharina M.

    2010-01-01

    Background Phthalates are widely used chemicals, and human exposure is extensive. Recent studies have indicated that phthalates may have thyroid-disrupting properties. Objective We aimed to assess concentrations of phthalate metabolites in urine samples from Danish children and to investigate the associations with thyroid function, insulin-like growth factor I (IGF-I), and growth. Methods In 845 children 4–9 years of age, we determined urinary concentrations of 12 phthalate metabolites and serum levels of thyroid-stimulating hormone, thyroid hormones, and IGF-I. Results Phthalate metabolites were detected in all urine samples, of which monobutyl phthalate was present in highest concentration. Phthalate metabolites were negatively associated with serum levels of free and total triiodothyronine, although statistically significant primarily in girls. Metabolites of di(2-ethylhexyl) phthalate and diisononyl phthalate were negatively associated with IGF-I in boys. Most phthalate metabolites were negatively associated with height, weight, body surface, and height gain in both sexes. Conclusions Our study showed negative associations between urinary phthalate concentrations and thyroid hormones, IGF-I, and growth in children. Although our study was not designed to reveal the mechanism of action, the overall coherent negative associations between urine phthalate and thyroid and growth parameters may suggest causative negative roles of phthalate exposures for child health. PMID:20621847

  8. Osteocalcin induces growth hormone/insulin-like growth factor-1 system by promoting testosterone synthesis in male mice.

    Science.gov (United States)

    Li, Y; Li, K

    2014-10-01

    Osteocalcin has been shown to enhance testosterone production in men. In the present study, we investigated the effects of osteocalcin on testosterone and on induction of the growth hormone/insulin-like growth factor-1 axis. Osteocalcin injection stimulated growth, which could be inhibited by castration. In addition, osteocalcin induced testosterone secretion in testes both in vivo and in vitro. Using real-time polymerase chain reaction and Western blotting, we showed that growth hormone expression was significantly increased in the pituitary after osteocalcin injection (pGrowth hormone expression in CLU401 mouse pituitary cells was also significantly stimulated (pgrowth hormone receptor and insulin-like growth factor-1 (pgrowth hormone receptor and insulin-like growth factor-1 expression in NCTC1469 cells. These results suggest that the growth-stimulating activities of osteocalcin are mediated by testicular testosterone secretion, and thus provide valuable information regarding the regulatory effects of osteocalcin expression on the growth hormone/insulin-like growth factor-1 axis via reproductive activities. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Insulin-like growth factor Ⅰ, osteocalcin and skeletal quality: an invited review

    OpenAIRE

    Sugiyama, Toshihiro

    2003-01-01

    Osteoporosis is a major public health problem, but its pathogenesis remains unclear. For example, the precise functions of insulin-like growth factor I (IGF-I) and osteocalcin in skeleton have been poorly understood, although it is well known that growth-hormore IGF-I axis plays a critical role in bone health and that serum concentration of osteocalcin in one of the most utilized biological markers for the clinical assessment of metabolic bone diseases. This brief review focuses on the involv...

  10. Growth hormone and insulin-like growth factor 1 affect the severity of Graves' disease.

    Science.gov (United States)

    Di Cerbo, Alfredo; Pezzuto, Federica; Di Cerbo, Alessandro

    2017-01-01

    Graves' disease, the most common form of hyperthyroidism in iodine-replete countries, is associated with the presence of immunoglobulins G (IgGs) that are responsible for thyroid growth and hyperfunction. In this article, we report the unusual case of a patient with acromegaly and a severe form of Graves' disease. Here, we address the issue concerning the role of growth hormone (GH) and insulin-like growth factor 1 (IGF1) in influencing thyroid function. Severity of Graves' disease is exacerbated by coexistent acromegaly and both activity indexes and symptoms and signs of Graves' disease improve after the surgical remission of acromegaly. We also discuss by which signaling pathways GH and IGF1 may play an integrating role in regulating the function of the immune system in Graves' disease and synergize the stimulatory activity of Graves' IgGs. Clinical observations have demonstrated an increased prevalence of euthyroid and hyperthyroid goiters in patients with acromegaly.The coexistence of acromegaly and Graves' disease is a very unusual event, the prevalence being Graves' disease associated with acromegaly and show that surgical remission of acromegaly leads to a better control of symptoms of Graves' disease.

  11. The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2010-05-01

    To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational age at delivery.

  12. Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma

    NARCIS (Netherlands)

    Hartog, Hermien; Horlings, Hugo M; van der Vegt, Bert; Kreike, Bas; Ajouaou, Abderrahim; van de Vijver, Marc J; Boezen, Hendrika; de Bock, Geertruida H; van der Graaf, Wilhelmina; Wesseling, Jelle

    2011-01-01

    The insulin-like growth factor type 1 receptor (IGF1R) is involved in progression of breast cancer and resistance to systemic treatment. Targeting IGF1R signaling may, therefore, be beneficial in systemic treatment. We report the effect of IGF1R expression on prognosis in invasive ductal breast

  13. Chronic alterations in growth hormone/insulin-like growth factor-I signaling lead to changes in mouse tendon structure

    DEFF Research Database (Denmark)

    Nielsen, R H; Clausen, N M; Schjerling, P

    2014-01-01

    The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis is an important stimulator of collagen synthesis in connective tissue, but the effect of chronically altered GH/IGF-I levels on connective tissue of the muscle-tendon unit is not known. We studied three groups of mice; 1) giant...

  14. The effect of long-term prednisone treatment on growth hormone and insulin-like growth factor-1

    NARCIS (Netherlands)

    Prummel, M. F.; Wiersinga, W. M.; Oosting, H.; Endert, E.

    1996-01-01

    Due to a lack of longitudinal data the precise effect of long-term corticosteroid treatment on serum levels of the anabolic hormones Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1) is unknown. Therefore, we prospectively followed GH and IGF-1 levels over a six month period in 18

  15. The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities

    Directory of Open Access Journals (Sweden)

    Youngman Oh

    2012-03-01

    Full Text Available The growth hormone–insulin-like growth factor–insulin-like growth factor binding protein (GH–IGF–IGFBP axis plays a critical role in the maintenance of normal renal function and the pathogenesis and progression of chronic kidney disease (CKD. Serum IGF-I and IGFBPs are altered with different stages of CKD, the speed of onset, the amount of proteinuria, and the potential of remission. Recent studies demonstrate that growth failure in children with CKD is due to a relative GH insensitivity and functional IGF deficiency. The functional IGF deficiency in CKD results from either IGF resistance due to increased circulating levels of IGFBPs or IGF deficiency due to increased urinary excretion of serum IGF–IGFBP complexes. In addition, not only GH and IGFs in circulation, but locally produced IGFs, the high-affinity IGFBPs, and low-affinity insulin-like growth factor binding protein-related proteins (IGFBP-rPs may also affect the kidney. With respect to diabetic kidney disease, there is growing evidence suggesting that GH, IGF-I, and IGFBPs are involved in the pathogenesis of diabetic nephropathy (DN. Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I and IGFBP actions also may offer a way to inhibit the development or progression of DN. Furthermore, it is well accepted that the systemic inflammatory response is a key player for progression of CKD, and how to prevent and treat this response is currently of great interest. Recent studies demonstrate existence of IGF-independent actions of high-affinity and low-affinity-IGFBPs, in particular, antiinflammatory action of IGFBP-3 and profibrotic action of IGFBP-rP2/CTGF. These findings reinforce the concept in support of the clinical significance of the IGF-independent action of IGFBPs in the assessment of pathophysiology of kidney disease and its

  16. Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

    Science.gov (United States)

    Misra, Uma Kant; Pizzo, Salvatore Vincent

    2015-01-01

    Ligation of cell surface GRP78 by activated α2-macroglobulin (α2M*) promotes cell proliferation and suppresses apoptosis. α2M*-treated human prostate cancer cells exhibit a 2–3-fold increase in glucose uptake and lactate secretion, an effect similar to insulin treatment. In both α2M* and insulin-treated cells, the mRNA levels of SREBP1-c, SREBP2, fatty-acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, and Glut-1 were significantly increased together with their protein levels, except for SREBP2. Pretreatment of cells with α2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these α2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. α2M* induces a 2–3-fold increase in lipogenesis as determined by 6-[14C]glucose or 1-[14C]acetate incorporation into free cholesterol, cholesterol esters, triglycerides, free fatty acids, and phosphatidylcholine, which is blocked by inhibitors of fatty-acid synthase, PI 3-kinase, mTORC, or an antibody against the carboxyl-terminal domain of GRP78. We also assessed the incorporation of [14CH3]choline into phosphatidylcholine and observed similar effects. Lipogenesis is significantly affected by pretreatment of prostate cancer cells with fatostatin A, which blocks sterol regulatory element-binding protein proteolytic cleavage and activation. This study demonstrates that α2M* functions as a growth factor, leading to proliferation of prostate cancer cells by promoting insulin-like responses. An antibody against the carboxyl-terminal domain of GRP78 may have important applications in prostate cancer therapy. PMID:25720493

  17. Collagen and Stretch Modulate Autocrine Secretion of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Proteins from Differentiated Skeletal Muscle Cells

    Science.gov (United States)

    Perrone, Carmen E.; Fenwick-Smith, Daniela; Vandenburgh, Herman H.

    1995-01-01

    Stretch-induced skeletal muscle growth may involve increased autocrine secretion of insulin-like growth factor-1 (IGF-1) since IGF-1 is a potent growth factor for skeletal muscle hypertrophy, and stretch elevates IGF-1 mRNA levels in vivo. In tissue cultures of differentiated avian pectoralis skeletal muscle cells, nanomolar concentrations of exogenous IGF-1 stimulated growth in mechanically stretched but not static cultures. These cultures released up to 100 pg of endogenously produced IGF-1/micro-g of protein/day, as well as three major IGF binding proteins of 31, 36, and 43 kilodaltons (kDa). IGF-1 was secreted from both myofibers and fibroblasts coexisting in the muscle cultures. Repetitive stretch/relaxation of the differentiated skeletal muscle cells stimulated the acute release of IGF-1 during the first 4 h after initiating mechanical activity, but caused no increase in the long-term secretion over 24-72 h of IGF-1, or its binding proteins. Varying the intensity and frequency of stretch had no effect on the long-term efflux of IGF-1. In contrast to stretch, embedding the differentiated muscle cells in a three-dimensional collagen (Type I) matrix resulted in a 2-5-fold increase in long-term IGF-1 efflux over 24-72 h. Collagen also caused a 2-5-fold increase in the release of the IGF binding proteins. Thus, both the extracellular matrix protein type I collagen and stretch stimulate the autocrine secretion of IGF-1, but with different time kinetics. This endogenously produced growth factor may be important for the growth response of skeletal myofibers to both types of external stimuli.

  18. Growth hormone, insulin-like growth factor-1 and the aging brain.

    Science.gov (United States)

    Ashpole, Nicole M; Sanders, Jessica E; Hodges, Erik L; Yan, Han; Sonntag, William E

    2015-08-01

    Growth hormone (GH) and insulin-like growth factor (IGF)-1 regulate the development and function of cells throughout the body. Several clinical diseases that result in a decline in physical and mental functions are marked by mutations that disrupt GH or IGF-1 signaling. During the lifespan there is a robust decrease in both GH and IGF-1. Because GH and IGF-1 are master regulators of cellular function, impaired GH and IGF-1 signaling in aging/disease states leads to significant alterations in tissue structure and function, especially within the brain. This review is intended to highlight the effects of the GH and IGF-1 on neuronal structure, function, and plasticity. Furthermore, we address several potential mechanisms through which the age-related reductions in GH and IGF-1 affect cognition. Together, the studies reviewed here highlight the importance of maintaining GH and IGF-1 signaling in order to sustain proper brain function throughout the lifespan. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor-Binding Protein 3 in Relation to the Risk of Type 2 Diabetes Mellitus: Results From the EPIC-Potsdam Study.

    Science.gov (United States)

    Drogan, Dagmar; Schulze, Matthias B; Boeing, Heiner; Pischon, Tobias

    2016-03-15

    Higher levels of insulin-like growth factor-binding protein 3 (IGFBP-3) might raise the risk of type 2 diabetes mellitus (T2DM) via binding of insulin-like growth factor 1 (IGF-1), an insulin-like hormone that is involved in glucose homeostasis. We investigated serum concentrations of IGF-1 and IGFBP-3 and their molar ratio in relation to T2DM incidence in a nested case-cohort study within the European Prospective Investigation Into Cancer and Nutrition-Potsdam Study. We included a randomly selected subcohort of persons without T2DM at the time of blood sampling (n = 2,269) and 776 individuals with incident T2DM identified between 1994 and 2005. For the highest quartile versus lowest, the multivariable-adjusted hazard rate ratios were 0.91 (95% confidence interval (CI): 0.68, 1.23; P for trend = 0.31) for IGF-1, 1.33 (95% CI: 1.00, 1.76; P for trend = 0.04) for IGFBP-3, and 0.77 (95% CI: 0.57, 1.03; P for trend = 0.03) for IGF-1:IGFBP-3 ratio. IGFBP-3 level remained positively associated with T2DM incidence-and the ratio of IGF-1 to IGFBP-3 was inversely related with T2DM incidence--in models that included adjustment for IGF-1 concentrations (P for trend < 0.05). Therefore, our findings do not confirm an association between total IGF-1 concentrations and risk of T2DM in the general study population, although higher IGFBP-3 levels might raise T2DM risk independent of IGF-1 levels. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Insulin-like growth factor binding protein-2 as a regulator of IGF actions in CNS : Implications in multiple sclerosis

    NARCIS (Netherlands)

    Chesik, Daniel; De Keyser, Jacques; Wilczak, Nadine

    2007-01-01

    Insulin-like growth factors (IGFs) are indispensable peptide hormones for proper development of the central nervous system (CNS). Because IGF-1 exhibits neuroprotective and myelinogenetic effects, it possesses therapeutic potential in treating neurodegenerative demyelinating diseases such as

  1. Insulin-like growth factor I and anthropometric parameters in a Danish population

    DEFF Research Database (Denmark)

    Friedrich, N; Jørgensen, Torben; Juul, A

    2012-01-01

    During the last decade several studies indicated that low insulin-like growth factor (IGF) I levels are related to higher risk of cardiovascular disease and mortality. Obesity represents one further main cardiovascular risk factor which might also be related to IGF-I. The objective of the present...... study was to analyse the associations between anthropometric measures and IGF-I levels in a population-based sample. From the Danish cross-sectional Health2006 study 3,328 subjects (1,835 women; 1,493 men) aged 19-72 years were included in the analyses. Serum IGF-I levels were determined...

  2. Expression, content, and localization of insulin-like growth factor I in human achilles tendon

    DEFF Research Database (Denmark)

    Olesen, Jens L; Heinemeier, Katja M; Langberg, Henning

    2006-01-01

    In animals insulin-like growth factor I (IGF-I) stimulates collagen production by fibroblasts and is expressed in tendons together with its binding protein 4 (IGFBP-4). However, the presence of IGF-I and IGFBP-4 in human tendon tissue is not described. Tissue IGF-I content was examined by immunof...... the tendon fibroblasts and that mRNA for IGF-I and IGFBP-4 can be determined in human tendon tissue. The present study adds support for the roles of IGF-I and IGFBP-4 in the regulation of tendon adaptive responses to mechanical loading....

  3. Relationship between leptin, insulin resistance, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in patients with chronic kidney disease.

    Science.gov (United States)

    Atamer, A; Alisir Ecder, S; Akkus, Z; Kocyigit, Y; Atamer, Y; Ilhan, N; Ecder, T

    2008-01-01

    This study examined the relationship between leptin, insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3) and insulin resistance in patients with chronic kidney disease (CKD). Levels of leptin, insulin, IGF-1, IGFBP-3 and common routine parameters were measured in 45 patients (23 males and 22 females) with CKD and 45 healthy controls matched for age, gender and body mass index. IGF-1 and IGFBP-3 levels were measured using a two-site immunoradiometric assay. Leptin levels were measured using an enzyme-linked immunosorbent assay. A homeostasis model assessment computer-solved model was used to assess insulin resistance (HOMA-IR). Levels of serum leptin, insulin, IGF-1, IGFBP-3 and HOMA-IR were significantly increased in patients with CKD compared with healthy subjects, whereas fasting blood glucose was not significantly different between the two groups. In patients with CKD, the serum leptin level was significantly correlated with IGF-1, IGFBP-3 and HOMA-IR. In conclusion, this study suggests that there is an interaction between leptin, IGF-1, IGFBP-3 and insulin resistance in patients with CKD.

  4. Antepartal insulin-like growth factor 1 and insulin-like growth factor binding protein 2 concentrations are indicative of ketosis in dairy cows.

    Science.gov (United States)

    Piechotta, M; Mysegades, W; Ligges, U; Lilienthal, J; Hoeflich, A; Miyamoto, A; Bollwein, H

    2015-05-01

    A study involving a small number of cows found that the concentrations of insulin-like growth hormone 1 (IGF1) may be a useful predictor of metabolic disease. Further, IGF1 may provide also a pathophysiological link to metabolic diseases such as ketosis. The objective of the current study was to test whether the low antepartal total IGF1 or IGF1 binding protein (IGFBP) concentrations might predict ketosis under field conditions. Clinical examinations and blood sampling were performed antepartum (262-270 d after artificial insemination) on 377 pluriparous pregnant Holstein Friesian cows. The presence of postpartum diseases were recorded (ketosis, fatty liver, displacement of the abomasum, hypocalcemia, mastitis, retention of fetal membranes, and clinical metritis or endometritis), and the concentrations of IGF1, IGFBP2, IGFBP3, and nonesterified fatty acids were measured. Cows with postpartum clinical ketosis had lower IGF1 concentrations antepartum than healthy cows. The sensitivity of antepartal IGF1 as a marker for postpartum ketosis was 0.87, and the specificity was 0.43; a positive predictive value of 0.91 and a negative predictive value of 0.35 were calculated. The cows with ketosis and retained fetal membranes had lower IGFBP2 concentrations compared with the healthy cows. It can be speculated that lower IGF1 production in the liver during late pregnancy may increase growth hormone secretions and lipolysis, thereby increasing the risk of ketosis. Lower IGFBP2 concentrations may reflect the suppression of IGFBP2 levels through higher growth hormone secretion. In conclusion, compared with nonesterified fatty acids as a predictive parameter, IGF1 and IGFBP2 may represent earlier biomarkers of inadequate metabolic adaptation to the high energy demand required postpartum. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  5. Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development.

    Science.gov (United States)

    Hellström, Ann; Ley, David; Hansen-Pupp, Ingrid; Hallberg, Boubou; Löfqvist, Chatarina; van Marter, Linda; van Weissenbruch, Mirjam; Ramenghi, Luca A; Beardsall, Kathryn; Dunger, David; Hård, Anna-Lena; Smith, Lois E H

    2016-06-01

    Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin-like growth factor 1 (IGF-1) axis is the major hormonal mediator of growth in utero, and levels of IGF-1 are often very low after preterm birth. We reviewed the role of IGF-1 in foetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF-1 deficiency in preterm morbidities. There is a rationale for clinical trials to evaluate the potential benefits of IGF-1 replacement in very preterm infants. ©2016 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.

  6. Age-related changes in Serum Growth Hormone, Insulin-like Growth Factor-1 and Somatostatin in System Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Malemud Charles J

    2004-10-01

    Full Text Available Abstract Background Systemic lupus erythematosus is an age- and gender-associated autoimmune disorder. Previous studies suggested that defects in the hypothalamic/pituitary axis contributed to systemic lupus erythematosus disease progression which could also involve growth hormone, insulin-like growth factor-1 and somatostatin function. This study was designed to compare basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels in female systemic lupus erythematosus patients to a group of normal female subjects. Methods Basal serum growth hormone, insulin-like growth factor-1 and somatostatin levels were measured by standard radioimmunoassay. Results Serum growth hormone levels failed to correlate with age (r2 = 3.03 in the entire group of normal subjects (i.e. 20 – 80 years. In contrast, serum insulin-like growth factor-1 levels were inversely correlated with age (adjusted r2 = 0.092. Of note, serum growth hormone was positively correlated with age (adjusted r2 = 0.269 in the 20 – 46 year range which overlapped with the age range of patients in the systemic lupus erythematosus group. In that regard, serum growth hormone levels were not significantly higher compared to either the entire group of normal subjects (20 – 80 yrs or to normal subjects age-matched to the systemic lupus erythematosus patients. Serum insulin-like growth factor-1 levels were significantly elevated (p 55 yrs systemic lupus erythematosus patients. Conclusions These results indicated that systemic lupus erythematosus was not characterized by a modulation of the growth hormone/insulin-like growth factor-1 paracrine axis when serum samples from systemic lupus erythematosus patients were compared to age- matched normal female subjects. These results in systemic lupus erythematosus differ from those previously reported in other musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, fibromyalgia, diffuse idiopathic skeletal

  7. Induction of Regulatory T Cells and Its Regulation with Insulin-like Growth Factor/Insulin-like Growth Factor Binding Protein-4 by Human Mesenchymal Stem Cells.

    Science.gov (United States)

    Miyagawa, Ippei; Nakayamada, Shingo; Nakano, Kazuhisa; Yamagata, Kaoru; Sakata, Kei; Yamaoka, Kunihiro; Tanaka, Yoshiya

    2017-09-01

    Human mesenchymal stem cells (MSCs) are multipotent and exert anti-inflammatory effects, but the underlying mechanism remains to be elucidated. In the current study, we investigated the regulatory mechanism of regulatory T cell (Treg) induction through the growth factors released by human MSCs. Human naive CD4 + T cells were stimulated with anti-CD3/28 Abs and cocultured with human MSC culture supernatant for 48 h. The proliferation and cytokine production of CD4 + T cells and surface molecule expression on CD4 + T cells were evaluated. The proliferation of anti-CD3/28 Abs-stimulated CD4 + T cells was suppressed by the addition of human MSC culture supernatant; in addition, the production of IL-10 and IL-4 increased. The human MSC culture supernatant induced CD4 + FOXP3 + Tregs that expressed CD25, CTLA-4, glucocorticoid-induced TNFR-related protein, insulin-like growth factor (IGF)-1R, and IGF-2R, showing antiproliferative activity against CD4 + T cells. In addition, the induction of Tregs by human MSC culture supernatant was enhanced by the addition of IGF and suppressed by the inhibition of IGF-1R. In contrast, a significant amount of IGF binding protein (IGFBP)-4, an inhibitor of IGF action, was detected in the human MSC culture supernatant. After neutralization of IGFBP-4 in the human MSC culture supernatant by anti-IGFBP-4 Ab, Treg numbers increased significantly. Thus, our results raise the possibility that human MSC actions also involve a negative-regulatory mechanism that suppresses Treg proliferation by releasing IGFBP-4. The results of this study suggest that regulation of IGF may be important for treatments using human MSCs. Copyright © 2017 by The American Association of Immunologists, Inc.

  8. Serum Growth Hormone and Insulin-Like Growth Factor-1 Levels in Women with Postadolescent Acne

    Directory of Open Access Journals (Sweden)

    Mualla Polat

    2010-06-01

    Full Text Available Background and Design: Acne vulgaris is an inflammatory disease of pilosebaceous unit. It usually starts after puberty but may continue into adulthood. We studied Growth hormone (GH and insulin-like growth factor (IGF-1 levels in women patients with acne vulgaris in whom all other hormon levels were normal. We aimed to show any relation of the acne vulgaris lesion type and GH and IGF-1 levels. Material and Method: The study conducted on the postadolesance period woman patients applying to out patient dermatology department with complaint of acne symptoms between Semtember 2005 and July 2006. All other hormonal parameters were normal in patients. 25 healthy similar age women were accepted as control. IGF-I and GH were quantified by solid-phase competitive chemiluminescence assays. Results: There was no difference according to age between the groups (p=0.726. The mean IGF-1 level was 336.5±112.88 ng/ml in patients and 194±31.32 ng/ml in control; the difference was significantly important (p=0.000. The mean GH level was 3.16±4.35 µIU/ml in patients and 1.15±1.21 µIU/ml in control; and the diffrence was not found as important (p=0.03. IGF-1 level was significantly important in patients with noduler involvement (p=0.015, and GH level was also significantly important in patients with cystic involvement (p=0.05. Conclusion: We supported the hypothesis that GH and IGF-1 levels were important in postadolasence period women patients with acne vulgaris. We recommend new studies comparing GH and IGF-1 levels in adolesence and postadolesence period women patients in order to support the role of these hormones in pathogenesis of acne vulgaris.

  9. Insulin-like growth factor binding protein 3 in inflammatory bowel disease

    DEFF Research Database (Denmark)

    Kirman, Irena; Whelan, Richard Larry; Jain, Suvinit

    2005-01-01

    was measured in ELISA. Western blot analysis, which distinguishes between intact and cleaved IGFBP-3, was performed in order to determine the ratio of intact to total protein; this ratio was used to calculate the concentration of intact IGFBP-3. The profile of plasma proteases was evaluated in zymography......Epithelial cell growth regulation has been reported to be altered in inflammatory bowel disease (IBD) patients. The cell growth regulatory factor, insulin-like growth factor binding protein 3 (IGFBP-3), may be partly responsible for this phenomenon. So far, IGFBP-3 levels have been assessed...... as values of total protein, which is a sum of bioactive intact 43- to 45-kDa protein and its inactive proteolytic cleavage fragments. We aimed to assess the levels of intact IGFBP-3 and its cleaving protease MMP-9 in IBD. Patients with IBD and controls were included. Total plasma IGFBP-3 concentration...

  10. The pubertal spurt: effects of sex steroids on growth hormone and insulin-like growth factor I.

    Science.gov (United States)

    Caufriez, A

    1997-02-01

    In puberty, the growth spurt and the appearance of secondary sex characteristics occur concomitantly with an increase of sex steroids, growth hormone (GH) and insulin-like growth factor I (IGF-I). A number of experiments indicate that sex steroids exert a stimulatory action on the somatotropic axis. This effect is due to an amplifying action of oestradiol (secreted by the ovaries or after testosterone aromatization) on the neuroendocrine regulation of pulsatile GH release.

  11. Early diet, insulin-like growth factor-1, growth and later obesity.

    Science.gov (United States)

    Michaelsen, Kim F; Larnkjaer, Anni; Molgaard, Christian

    2013-01-01

    There is increasing evidence that factors in early life are important for the risk of developing overweight and obesity later in childhood. Among the postnatal factors, breastfeeding and complementary feeding are especially interesting because the pattern of these two factors can be changed. Breastfeeding has been shown to reduce the risk of later obesity, although the effect is not substantial. Complementary feeding also seems to play a role. There is some evidence that a high protein intake is associated with a higher risk of obesity later in childhood, whereas a high fat intake during the complementary feeding period does not seem to be a risk factor for later obesity. Thus, the dietary pattern during this period is different from the pattern seen in older children and adults where a high fat intake is associated with a higher risk of obesity and a high protein intake in some studies seems to protect against obesity. A few studies have also suggested that early introduction of complementary foods (before age 4 months) is associated with an increased risk of later obesity. A high weight gain during early life, especially the first 6 months, is associated with a higher risk of developing obesity. However, some studies suggest that weight gain during the 6- to 12-month age period, when complementary feeding is introduced, is not associated with later obesity. Insulin-like growth factor-1 (IGF-1) values and body composition both play a role in the complex pattern between early diet and later obesity, but our present knowledge about how these factors are influenced by diet during infancy is limited. Future studies should include longitudinal data on IGF-1 and body composition during infancy to improve our understanding of how diet in early life can play a role in prevention of later obesity. Copyright © 2013 S. Karger AG, Basel.

  12. Insulin-like growth factor I enhances collagen synthesis in engineered human tendon tissue

    DEFF Research Database (Denmark)

    Herchenhan, Andreas; Bayer, Monika L.; Eliasson, Pernilla

    2015-01-01

    investigated the influence of insulin-like growth factor I (IGF-I) on tendon construct formation in 3D cell culture. DESIGN: Tendon constructs were grown in 0.5 or 10% FBS with or without IGF-I (250 mg/ml) supplementation. Collagen content (fluorometric), mRNA levels (PCR) and fibril diameter (transmission...... of fibril diameter (day 14), collagen content (at days 21 and 28) and mRNA expression for collagen, tenomodulin and scleraxis. CONCLUSION: IGF-I supplementation promotes early onset of tensile load induced collagen formation and tendon structural arrangement, whereas the FBS concentration routinely used......OBJECTIVE: Isolated human tendon cells form 3D tendon constructs that demonstrate collagen fibrillogenesis and feature structural similarities to tendon when cultured under tensile load. The exact role of circulating growth factors for collagen formation in tendon is sparsely examined. We...

  13. The Insulin-Like Growth Factor System in Obesity, Insulin Resistance and Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Moira S. Lewitt

    2014-12-01

    Full Text Available The insulin-like growth factor (IGF system, acting in concert with other hormone axes, is important in normal metabolism. In obesity, the hyperinsulinaemia that accompanies peripheral insulin resistance leads to reduced growth hormone (GH secretion, while total IGF-I levels are relatively unchanged due to increased hepatic GH sensitivity. IGF-binding protein (IGFBP-1 levels are suppressed in relation to the increase in insulin levels in obesity and low levels predict the development of type 2 diabetes several years later. Visceral adiposity and hepatic steatosis, along with a chronic inflammation, contribute to the IGF system phenotype in individuals with metabolic syndrome and type 2 diabetes mellitus, including changes in the normal inverse relationship between IGFBP-1 and insulin, with IGFBP-1 concentrations that are inappropriately normal or elevated. The IGF system is implicated in the vascular and other complications of these disorders and is therefore a potential therapeutic target.

  14. Specific immunoradiometric assay of insulin-like growth factor I with use of monoclonal antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Scott, M.G.; Cuca, G.C.; Petersen, J.R.; Lyle, L.R.; Burleigh, B.D.; Daughaday, W.H.

    1987-11-01

    We identified two monoclonal antibodies that bind spatially distinct epitopes on insulin-like growth factor I (IGF-I). Using these two antibodies, we developed a simultaneous, two-site immunoradiometric assay (IRMA) specific for IGF-I. This IRMA has no detectable cross reactivity with insulin, proinsulin, prolactin, or somatotropin, and less than 2% crossreactivity with IGF-II. The assay response varies linearly with IGF-I concentrations of 0-800 micrograms/L in serum; the detection limit is about 10 micrograms/L. A comparison of 26 IGF-I serum values from the IRMA and from a previously reported IGF-I specific RIA gave a correlation coefficient of 0.96 with no substantial bias (slope = 1.10). IGF-I values for serum, as an aid in assessing growth abnormalities, are easily (only three pipetting steps) obtained in less than 4 h.

  15. Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults

    DEFF Research Database (Denmark)

    Juul, A; Bang, P; Hertel, Niels

    1994-01-01

    Serum levels of insulin-like growth factor-I (IGF-I) increase with age and pubertal development. The large variation in circulating IGF-I levels in adolescence makes it difficult to use the IGF-I value of a single child in the assessment of his growth status. In addition, the interference of IGF......-binding proteins in many IGF-I assays contributes to this problem. We measured IGF-I in acid-ethanol-extracted serum from 1030 healthy children, adolescents, and adults, employing a RIA that reduces interference of IGF-binding proteins by using monoiodinated Tyr31-[125I]des-(1-3)IGF-I as radioligand. Mean serum...

  16. Growth hormone-insuline-like growth factor-I system in pejerrey Odontesthes bonariensis (Atheriniformes

    Directory of Open Access Journals (Sweden)

    S.E. Arranz

    2008-07-01

    Full Text Available Using biotechnology to increase the growth rates of fish is likely to reduce production costs per unit of food. Among vertebrates, fish appear to occupy a unique position, when growth patterns are considered. With few exceptions, fish species tend to grow indeterminately, implying that size is never fixed. Both hyperplasia and hypertrophy contribute to post-larval muscle growth in fish. Growth hormone (GH - Insulin-like Growth Factor I (IGF-I is the most important growth axis in fish. Our experimental model, the pejerrey, Odontesthes bonariensis (Ateriniformes is a South American inland water fish considered to be a promising species for intensive aquaculture. However, one major drawback to achieve this goal is its slow growth in captivity. In order to understand how growth is regulated in this species, our first objective was to characterized pejerrey GH- IGF-I axis. We first cloned and characterized pejerrey (pj GH, IGF-I and the growth hormone receptors (GHRs I and II. In addition to providing valuable data for evolutionary comparison of GH, investigation of GH action in teleosts is particularly important because of its potential application in aquaculture. GH can not only promote the somatic growth in fish but also lower dietary protein requirements. A prerequisite for providing sufficient amounts of GH for basic research and aquaculture application is a large-scale production of GH. For that purpose, recombinant pjGH was expressed in a bacterial system. Protocols for solubilization and proper folding were achieved. Activity of recombinant pjGH was assessed in fish by measuring the liver IGF-I response to different doses of GH. IGF-I transcript was measured in the liver after pjGHr in vivo stimulation by means of quantitative real-time PCR assays. A dose-dependent response of IGF-I mRNA was observed after pjGHr administration, and reached a 6 fold IGF-I maximum increase over control group when 2.5 µg pjGH /g-body weight were injected

  17. Insulin-like growth factor binding protein-6 delays replicative senescence of human fibroblasts

    DEFF Research Database (Denmark)

    Micutkova, Lucia; Diener, Thomas; Li, Chen

    2011-01-01

    extracellular proteins with significantly different abundance in conditioned media from young and senescent fibroblasts. Among these was insulin-like growth factor binding protein-6 (IGFBP-6), which was chosen for further analysis. When IGFBP-6 gene expression was downregulated, cell proliferation was inhibited...... and apoptotic cell death was increased. Furthermore, downregulation of IGFBP-6 led to premature entry into cellular senescence. Since IGFBP-6 overexpression increased cellular lifespan, the data suggest that IGFBP-6, in contrast to other IGF binding proteins, is a negative regulator of cellular senescence......Cellular senescence can be induced by a variety of mechanisms, and recent data suggest a key role for cytokine networks to maintain the senescent state. Here, we have used a proteomic LC-MS/MS approach to identify new extracellular regulators of senescence in human fibroblasts. We identified 26...

  18. Serum insulin-like growth factor 1 in the aging horse

    DEFF Research Database (Denmark)

    Lygren, Tone; Hansen, Sanni; Langberg, Henning

    2014-01-01

    BACKGROUND: Insulin-like growth factor 1 (IGF-1) has important roles in anabolic processes in the musculoskeletal system and has been reported to decrease with age in both people and horses. OBJECTIVES: The objective of this study was to determine serum IGF-1 levels in the aging horse from early...... to late adulthood (age range 5-27 years). METHODS: Healthy horses (n = 72) were used in a cross-sectional study, while 37 paired serum samples were available for a longitudinal study. Serum IGF-1 protein was determined using an ELISA kit validated for use in equine samples. RESULTS: No association...... was found between serum IGF-1 levels and age in the cross-sectional study. In the longitudinal study, a latent variable model fitted to the data revealed that horses in general experienced a 5.2% increase of serum IGF-1 levels over a 5-year period, but horses crossing a change point around 9 years of age...

  19. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

    DEFF Research Database (Denmark)

    Pouladi, Mahmoud A; Xie, Yuanyun; Skotte, Niels Henning

    2010-01-01

    Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement...

  20. Epidermal growth factor and insulin-like growth factor I upregulate the expression of the epidermal growth factor system in rat liver

    DEFF Research Database (Denmark)

    Bor, M V; Sørensen, B S; Vinter-Jensen, L

    2000-01-01

    BACKGROUND/AIM: Both epidermal growth factor and insulin-like growth factor I play a role in connection with the liver. In the present study, the possible interaction of these two growth factor systems was studied by investigating the effect of epidermal growth factor or insulin-like growth factor...... I treatment on the expression of the epidermal growth factor receptor, and its activating ligands, transforming growth factor-alpha and epidermal growth factor. METHODS: Fifty-five male rats received no treatment, human recombinant epidermal growth factor or human recombinant insulin-like growth...... factor I for either 3 or 7 days. The amount of epidermal growth factor receptor, transforming growth factor-alpha, and epidermal growth factor mRNA was quantitated by a calibrated user-friendly RT-PCR assay (CURT-PCR), and the expression of transforming growth factor-alpha and epidermal growth factor...

  1. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease

    OpenAIRE

    Kythreotis, Prokopis; Kokkini, Ageliki; Avgeropoulou, Stavrina; Hadjioannou, Argyro; Anastasakou, Efgenia; Rasidakis, Antonis; Bakakos, Petros

    2009-01-01

    Abstract Background Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether the...

  2. Insulin-Insulin-like Growth Factors Hybrids as Molecular Probes of Hormone:Receptor Binding Specificity.

    Science.gov (United States)

    Křížková, Květoslava; Chrudinová, Martina; Povalová, Anna; Selicharová, Irena; Collinsová, Michaela; Vaněk, Václav; Brzozowski, Andrzej M; Jiráček, Jiří; Žáková, Lenka

    2016-05-31

    Insulin, insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively), and their receptors (IR and IGF-1R) are the key elements of a complex hormonal system that is essential for the development and functioning of humans. The C and D domains of IGFs (absent in insulin) likely play important roles in the differential binding of IGF-1 and -2 to IGF-1R and to the isoforms of IR (IR-A and IR-B) and specific activation of these receptors. Here, we attempted to probe the impact of IGF-1 and IGF-2 D domains (DI and DII, respectively) and the IGF-2 C domain (CII) on the receptor specificity of these hormones. For this, we made two types of insulin hybrid analogues: (i) with the C-terminus of the insulin A chain extended by the amino acids from the DI and DII domains and (ii) with the C-terminus of the insulin B chain extended by some amino acids derived from the CII domain. The receptor binding affinities of these analogues and their receptor autophosphorylation potentials were characterized. Our results indicate that the DI domain has a more negative impact than the DII domain does on binding to IR, and that the DI domain Pro-Leu-Lys residues are important factors for a different IR-A versus IR-B binding affinity of IGF-1. We also showed that the additions of amino acids that partially "mimic" the CII domain, to the C-terminus of the insulin B chain, change the binding and autophosphorylation specificity of insulin in favor of the "metabolic" IR-B isoform. This opens new venues for rational enhancement of insulin IR-B specificity by modifications beyond the C-terminus of its B chain.

  3. Stimulation of myenteric plexus neurite outgrowth by insulin and insulin-like growth factors I and II.

    Science.gov (United States)

    Mulholland, M W; Romanchuk, G; Simeone, D M; Flowe, K

    1992-01-01

    A defined culture medium containing insulin, insulin-like growth factor I (IGF-I) or insulin-like growth factor II (IGF-II) supported morphological development of myenteric plexus neurons derived from neonatal guinea pigs. Insulin increased neurite outgrowth 3-fold at concentrations as low as 0.2 nM. Similar significant and dose-dependent increases in neurite outgrowth were noted with IGF-I and IGF-II. Stimulation of neurite outgrowth was abolished by exposure to cytosine arabinofuranoside, an agent toxic to non-neuronal cells, implying that trophic effects of insulin or insulin-like growth factors require the presence of non-neuronal elements in culture.

  4. Insulin-like growth factor II: complexity of biosynthesis and receptor binding

    DEFF Research Database (Denmark)

    Gammeltoft, S; Christiansen, Jan; Nielsen, F C

    1991-01-01

    , Man-6-P induces cellular responses. We have studied rat brain neuronal precursor cells where Man-6-P acted as a mitogen suggesting that phosphomannosylated proteins may act as growth factors via the Man-6-P/IGF-II receptor. In conclusion, the gene expression and mechanism of action of IGF-II is very......Insulin-like growth factor II (IGF-II) belongs to the insulin family of peptides and acts as a growth factor in many fetal tissues and tumors. The gene expression of IGF-II is initiated at three different promoters which gives rise to multiple transcripts. In a human rhabdomyosarcoma cell line...... the 4.8-kb mRNA is translated to IGF-II. The cell line secretes two forms of immunoreactive and bioactive IGF-II to the medium of molecular size 10 kd and 7.5 kd which may be involved in autocrine control of cell growth. IGF-II binds to two receptors on the surface of many cell types: the IGF-I receptor...

  5. Prediction of the outcome of growth hormone provocative testing in short children by measurement of serum levels of insulin-like growth factor I and insulin-like growth factor binding protein 3

    DEFF Research Database (Denmark)

    Juul, A; Skakkebaek, N E

    1997-01-01

    Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) reflect the secretion of endogenous growth hormone (GH) in healthy children and exhibit little diurnal variation, which makes them potential candidates for screening of GH deficiency (GHD...... the positive predictive value and in 10- to 20-year-old children was 52.3% for IGF-I and 56.5% for IGFBP-3. Combination use of IGF-I and IGFBP-3 gave additional diagnostic information. We conclude that a subnormal IGF-I level, and especially a subnormal IGFBP-3 level, are highly predictive of a subnormal GH...

  6. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease

    DEFF Research Database (Denmark)

    Juul, Anders; Scheike, Thomas Harder; Davidsen, Michael

    2002-01-01

    Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD).......Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD)....

  7. Insulin-like growth factor-1 overexpression in cardiomyocytes diminishes ex vivo heart functional recovery after acute ischemia.

    Science.gov (United States)

    Prêle, Cecilia M; Reichelt, Melissa E; Mutsaers, Steven E; Davies, Marilyn; Delbridge, Lea M; Headrick, John P; Rosenthal, Nadia; Bogoyevitch, Marie A; Grounds, Miranda D

    2012-01-01

    Acute insulin-like growth factor-1 administration has been shown to have beneficial effects in cardiac pathological conditions. The aim of the present study was to assess the structural and ex vivo functional impacts of long-term cardiomyocyte-specific insulin-like growth factor-1 overexpression in hearts of transgenic αMHC-IGF-1 Ea mice. Performance of isolated transgenic αMHC-IGF-1 Ea and littermate wild-type control hearts was compared under baseline conditions and in response to 20-min ischemic insult. Cardiac desmin and laminin expression patterns were determined histologically, and myocardial hydroxyproline was measured to assess collagen content. Overexpression of insulin-like growth factor-1 did not modify expression patterns of desmin or laminin but was associated with a pronounced increase (∼30%) in cardiac collagen content (from ∼3.7 to 4.8 μg/mg). Baseline myocardial contractile function and coronary flow were unaltered by insulin-like growth factor-1 overexpression. In contrast to prior evidence of acute cardiac protection, insulin-like growth factor-1 overexpression was associated with significant impairment of acute functional response to ischemia-reperfusion. Insulin-like growth factor-1 overexpression did not modify ischemic contracture development, but postischemic diastolic dysfunction was aggravated (51±5 vs. 22±6 mmHg in nontransgenic littermates). Compared with wild-type control, recovery of pressure development and relaxation indices relative to baseline performance were significantly reduced in transgenic αMHC-IGF-1 Ea after 60-min reperfusion (34±7% vs. 62±7% recovery of +dP/dt; 35±11% vs. 57±8% recovery of -dP/dt). Chronic insulin-like growth factor-1 overexpression is associated with reduced functional recovery after acute ischemic insult. Collagen deposition is elevated in transgenic αMHC-IGF-1 Ea hearts, but there is no change in expression of the myocardial structural proteins desmin and laminin. These findings suggest

  8. Regulation of insulin-like growth factor-I in skeletal muscle and muscle cells.

    Science.gov (United States)

    Frost, R A; Lang, C H

    2003-03-01

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are potent regulators of muscle mass. Transgenic mice that over-express these proteins exhibit dramatically enlarged skeletal muscles. In contrast, malnutrition, critical illness, sepsis, and aging are all associated with a dramatic reduction in muscle mass and function. The circulating concentration of IGF-I and the expression of IGF-I in skeletal muscle are also reduced during catabolic states. Consequently, GH has been used clinically to increase lean body mass in patients with muscle wasting. Likewise, delivery of IGF-I specifically into muscle has been proposed as a genetic therapy for muscle disorders. A better understanding of the regulation of IGF-I expression in skeletal muscle and muscle cells is therefore of importance. Yet, our knowledge in this area has been limited by a lack of GH responsive muscle cells. In addition the IGF-I gene spans over 90 kb of genomic DNA and it exhibits a very complex regulatory pattern. This review will summarize our knowledge of the control of muscle mass by GH, IGF-I, anabolic steroids, exercise and other growth enhancing hormones. We will also highlight recent advances in the regulation of IGF-I and signal transducers and activators of transcription (Stats) by GH. A special emphasis will be placed on the interaction of IGF-I and proinflammatory cytokines in skeletal muscle and muscle cells.

  9. Insulin-like growth factor II: complexity of biosynthesis and receptor binding

    DEFF Research Database (Denmark)

    Gammeltoft, S; Christiansen, Jan; Nielsen, F C

    1991-01-01

    Insulin-like growth factor II (IGF-II) belongs to the insulin family of peptides and acts as a growth factor in many fetal tissues and tumors. The gene expression of IGF-II is initiated at three different promoters which gives rise to multiple transcripts. In a human rhabdomyosarcoma cell line...... the 4.8-kb mRNA is translated to IGF-II. The cell line secretes two forms of immunoreactive and bioactive IGF-II to the medium of molecular size 10 kd and 7.5 kd which may be involved in autocrine control of cell growth. IGF-II binds to two receptors on the surface of many cell types: the IGF-I receptor...... and the mannose-6-phosphate (Man-6-P)/IGF-II receptor. There is consensus that the cellular effects of IGF-II are mediated by the IGF-I receptor via activation of its intrinsic tyrosine kinase. The Man-6-P/IGF-II receptor is involved in endocytosis of lysosomal enzymes and IGF-II. In selected cell types, however...

  10. Early nutrition impact on the insulin-like growth factor axis and later health consequences.

    Science.gov (United States)

    Larnkjær, Anni; Mølgaard, Christian; Michaelsen, Kim F

    2012-05-01

    There is increasing interest in the role of insulin-like growth factor-I (IGF-I) in the relation between early growth and later risk of noncommunicable diseases (NCDs). This review presents and discusses a selection of recent publications on this topic. Nutrition during pregnancy and in preterm infants has an influence on IGF-I. Breastfeeding is associated with lower IGF-I values and the effect of early protein intake was confirmed in a large intervention study. IGF-I levels are associated with early obesity, but the relation is complex and differs with age. Further studies and reviews support that there is a programming of the IGF axis, with higher levels during early life being associated with lower levels in adulthood, which is likely to influence the risk of NCDs later in life. Recent studies support that IGF-I plays an important role in the complex association between early diet, growth and later health, but more studies are needed to better understand the role of IGF-I, especially in the early development of obesity. Studies with data on how IGF-I is influenced by early diet in studies of preterm infants and young children with undernutrition from low-income countries will be helpful in recommending optimal diets.

  11. The role of insulin-like growth factor in prediction and prevention of preterm delivery

    Directory of Open Access Journals (Sweden)

    Bogavac Mirjana

    2010-01-01

    Full Text Available Background/Aim. Prediction and prevention of preterm delivery remain great challenge. It is important to include in everyday medical practice determination of certain markers that could help identifying pregnant women with preterm delivery. Insulin like growth factor (IGF is involved in the control mechanism of fetal and placental growth and development. The aim of this study was to examine the presence of insulin-like growth factor binding protein 1 (IGFBP-1 in cervicovaginal secretion of pregnant women with symptoms of preterm labor, but with apparently intact fetal membranes and to point out a possible application of the strip test for detection of phIGFBP-1 in diagnosis of preterm premature rupture of total membranes (PPROM in everyday medical practice. Methods. The study was performed at the Department for Obstetrics and Gynecology, Clinical Center of Vojvodina between October 2008 and May 2009. The study included 54 pregnant women between 20-35 weeks of gestation (WG, divided into two groups: the study group (16 pregnant women with symptoms of preterm delivery that gave birth before 37 WG and the control group (38 pregnant women with the normal course of pregnancy that gave birth on term. In cervicovaginal secretion of the examined pregnant women the level of IGFBP-1 was determined by the immunochromatographic assay with monoclonal antibodies 6303 as a detecting antibody (Actim PROM test, Medix Biochemica, Kauniainen, Finland. Results. Gestational age (GA at delivery in the study group was 32.6 WG and in the control group it was 38.4 WG. Weight of newborns in the study group was 2,021 g and in the control group 3,430 g. IGFBP test was positive in 15 women (93.75% of the study group, while in the control group it was positive only in 1 woman (2.63%. Conclusion. Test on phIGFBP-1 in cervicovaginal mucus was positive in 93.75% women with preterm delivery, suggesting that this test could be used in diagnosis of silent rupture of fetal

  12. Insulin-like growth factor 2 axis supports the serum-independent growth of malignant rhabdoid tumor and is activated by microenvironment stress

    Science.gov (United States)

    Li, Ting; Wang, Jin; Liu, Pengfei; Chi, Jiadong; Yan, Han; Lei, Lei; Li, Zexing; Yang, Bing; Wang, Xi

    2017-01-01

    Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers. Here, we evaluated the role of IGF2 axis in MRT cell proliferation. We showed that microenvironment stress, including starvation treatment and chemotherapy exposure, lead to elevated expression of IGF2 in the SNF5-deficient MRT cell line. The autocrine IGF2, in turn, activated insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), followed by PI3K/AKT pathway and RAS/ERK pathway to promote cancer cell proliferation and survival. We further demonstrated that impairment of IGF2 signaling by IGF2 neutralizing antibody, IGF1R inhibitor NVP-AEW541 or AKT inhibitor MK-2206 2HCl treatment prevented MRT cell growth in vitro. Taken together, our characterization of this axis defines a novel mechanism for MRT cell growth in the microenvironment of stress. Our results also demonstrated the necessity to test the treatment effect targeting this axis in future research. PMID:28521298

  13. Human conditions of insulin-like growth factor-I (IGF-I deficiency

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    Puche Juan E

    2012-11-01

    Full Text Available Abstract Insulin-like growth factor I (IGF-I is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions. IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.

  14. Human conditions of insulin-like growth factor-I (IGF-I) deficiency

    Science.gov (United States)

    2012-01-01

    Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range. PMID:23148873

  15. Insulin-like growth factor binding protein-3 in preterm infants with retinopathy of prematurity

    Directory of Open Access Journals (Sweden)

    Manizheh Mostafa Gharehbaghi

    2012-01-01

    Full Text Available Background: Retinopathy of prematurity (ROP is the main cause of visual impairment in preterm newborn infants. Objective: This study was conducted to determine whether insulin-like growth factor binding protein -3 (IGFBP-3 is associated with proliferative ROP and has a role in pathogenesis of the disease in premature infants. Materials and Methods: A total of 71 preterm infants born at or before 32 weeks of gestation participated in this study. Studied patients consisted of 41 neonates without vaso-proliferative findings of ROP as the control group and 30 preterm infants with evidence of severe ROP in follow up eye examination as the case group. Blood samples obtained from these infants 6-8 weeks after birth and blood levels of IGFBP-3 were measured using enzyme-linked immunosorbent assay (ELISA. Results: The mean gestation age and birth weight of the studied patients were 28.2±1.6 weeks and 1120.7±197 gram in the case group and 28.4±1.6 weeks and 1189.4±454 gram in the control group (P=0.25 and P=0.44 respectively. The infants in the case group had significantly lower Apgar score at first and 5 min after birth. Insulin-like growth factor binding protein -3 (IGFBP-3 was significantly lower in the patients with proliferative ROP than the patients without ROP [592.5±472.9 vs. 995.5±422.2 ng/ml (P=0.009]. Using a cut-off point 770.45 ng/ml for the plasma IGFBP-3, we obtained a sensitivity of 65.9% and a specificity of 66.7% in the preterm infants with vasoproliferative ROP. Conclusion: Our data demonstrated that the blood levels IGFBP-3 was significantly lower in the patients with ROP and it is suspected that IGFBP-3 deficiency in the premature infants may have a pathogenetic role in proliferative ROP.

  16. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Gallardo-Escarate, C. [Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Molina, A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile)

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  17. Diversification of the insulin-like growth factor 1 gene in mammals.

    Directory of Open Access Journals (Sweden)

    Peter Rotwein

    Full Text Available Insulin-like growth factor 1 (IGF1, a small, secreted peptide growth factor, is involved in a variety of physiological and patho-physiological processes, including somatic growth, tissue repair, and metabolism of carbohydrates, proteins, and lipids. IGF1 gene expression appears to be controlled by several different signaling cascades in the few species in which it has been evaluated, with growth hormone playing a major role by activating a pathway involving the Stat5b transcription factor. Here, genes encoding IGF1 have been evaluated in 25 different mammalian species representing 15 different orders and ranging over ~180 million years of evolutionary diversification. Parts of the IGF1 gene have been fairly well conserved. Like rat Igf1 and human IGF1, 21 of 23 other genes are composed of 6 exons and 5 introns, and all 23 also contain recognizable tandem promoters, each with a unique leader exon. Exon and intron lengths are similar in most species, and DNA sequence conservation is moderately high in orthologous exons and proximal promoter regions. In contrast, putative growth hormone-activated Stat5b-binding enhancers found in analogous locations in rodent Igf1 and in human IGF1 loci, have undergone substantial variation in other mammals, and a processed retro-transposed IGF1 pseudogene is found in the sloth locus, but not in other mammalian genomes. Taken together, the fairly high level of organizational and nucleotide sequence similarity in the IGF1 gene among these 25 species supports the contention that some common regulatory pathways had existed prior to the beginning of mammalian speciation.

  18. Effects of immune challenge on concentrations of serum insulin-like growth factor-I and growth performance in pigs.

    OpenAIRE

    Hevener, W; Routh, P A; Almond, G W

    1999-01-01

    This study was designed to determine the long-term effects of repeated endotoxin treatment or immunization against human serum albumin on concentrations of serum insulin-like growth factor-I (IGF-I) and other indicators of growth performance in growing pigs. Thirty gilts (38.5 +/- 0.9 kg) were randomly assigned to 5 treatment groups (n = 6 animals/group): 1) lipopolysaccharide injections, 2) lipopolysaccharide pair-fed, 3) human serum albumin immunization, 4) human serum albumin pair-fed, and...

  19. Local administration of insulin-like growth factor-I (IGF-I) stimulates tendon collagen synthesis in humans

    DEFF Research Database (Denmark)

    Hansen, M; Boesen, A; Holm, L

    2013-01-01

    Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. In animals, injections of insulin-like growth factor I (IGF-I) has been shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing...

  20. Insulin-like growth factor II receptors in human brain and their absence in astrogliotic plaques in multiple sclerosis

    NARCIS (Netherlands)

    Wilczak, N; De Bleser, P; Luiten, P; Geerts, A; Teelken, A; De Keyser, J

    2000-01-01

    Insulin-like growth factor (IGF) II receptors were studied in human adult brain by using autoradiography with [(125)I]IGF-II. Receptors were found to be widely distributed throughout all neuronal regions. The highest densities were found in plexus choroideus, granular layer of the cerebellar cortex,

  1. Expression of the insulin-like growth factor (IGF) system and steroidgenic enzymes in canine testis tumors

    NARCIS (Netherlands)

    Peters, M.A.J.; Mol, J.A.; Wolferen, van M.E.; Oosterlaken-Dijksterhuis, M.A.; Teerds, K.J.; Sluijs, van F.J.

    2003-01-01

    Testis tumors occur frequently in dogs. The main types of tumors are Sertoli cell tumors, seminomas, and Leydig cell tumors. Mixed tumors and bilateral occurrence of tumors may be encountered frequently. To elucidate the possible relationship between the insulin-like growth factor (IGF) system and

  2. 'Big'-insulin-like growth factor-II signaling is an autocrine survival pathway in gastrointestinal stromal tumors.

    NARCIS (Netherlands)

    Rikhof, B.; Graaf, W.T.A. van der; Suurmeijer, A.J.H.; Doorn, J. van; Meersma, G.J.; Groenen, P.J.T.A.; Schuuring, E.M.; Meijer, C.; Jong, S. de

    2012-01-01

    New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor

  3. 'Big'-Insulin-Like Growth Factor-II Signaling Is an Autocrine Survival Pathway in Gastrointestinal Stromal Tumors

    NARCIS (Netherlands)

    Rikhof, Bart; van der Graaf, Winette T. A.; Suurmeijer, Albert J. H.; van Doorn, Jaap; Meersma, Gert Jan; Groenen, Patricia J. T. A.; Schuuring, Ed M. D.; Meijer, Coby; de Jong, Steven

    New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor

  4. Associations between genetic polymorphisms of insulin-like growth factor axis genes and risk for age-related macular degeneration

    Science.gov (United States)

    Purpose: Our objective was to investigate if insulin-like growth factor (IGF) axis genes affect the risk for age-related macular degeneration (AMD). Methods: 864 Caucasian non-diabetic participants from the Age-Related Eye Disease Study (AREDS) Genetic Repository were used in this case control st...

  5. Developmental changes of Insulin-like growth factors in the liver and muscle of chick embryos.

    Science.gov (United States)

    Liu, Yanli; Guo, Wei; Pu, Zhenyu; Li, Xueyuan; Lei, Xinyu; Yao, Junhu; Yang, Xiaojun

    2016-06-01

    The insulin-like growth factors ( IGFS: ) are synthesized in tissues and play an important role in embryonic development of avian via autocrine/paracrine mechanisms. In the study, mRNA expression of IGFs were detected by real-time PCR in the muscle and liver from d 10 to 20 of chick embryo ( E10: to E20: ). Methylation of IGF1 promoter in the muscle was analyzed by bisulfite sequencing PCR as well as IGF2 promoter in the liver. These results showed that there was obviously IGF1 expression in liver at E19 and E20. The higher IGF1 expression in muscle was found during E15 to E18 with the peak on E17, and then declined. Correspondingly, the lowest methylation level of IGF1 promoter was detectable on the same embryonic d 17. Expression of IGF2 in muscle increased gradually during embryonic growth and showed higher level in the later stages (E17 to E20) when IGF1 expression began to decrease. IGF2 expression in liver reached the first peak on E14, then declined but gradually elevated from E17. IGF2 promoter methylation in liver showed gradual decline on d 12, 15, 17 and 19 of incubation, meanwhile IGF2 expression of liver increased gradually. These results suggested that IGF1 and IGF2 might separately be more important for muscle and liver growth in chick embryonic development. Variation of IGFs expression during the incubation might be concerned with the methylation of gene promoter. The profile of IGFs expression in chick embryonic tissues may be meaningful for understanding organ growth and embryonic development in chick. © 2016 Poultry Science Association Inc.

  6. Prognostic value of insulin- like growth factor-I receptor expression in renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Sichani Mehrdad

    2010-01-01

    Full Text Available The Insulin-Like growth factor-I receptor (IGF-IR, a tyrosine-kinas receptor over expressed in many tumor cell lines and in some human tumors, plays a critical role in trans-formation, tumorigenicity and metastasis. The aim of the present study is to investigate the role of IGF-IR expression as a prognostic factor in RCC. This study was conducted in a historical cohort of 82 patients who had RCC treated with radical nephrectomy from 1994 to 2005. Specimens were reevaluated with regard to histological subtype, nuclear grade, stage and IGF-IR expression. The IGF-IR stain was semi- quantitatively evaluated using the Allred score system. Kaplan-Meier analysis demonstrated a significant positive correlation between Fuhrman nuclear grade and IGF-IR Allred score (P< 0.0001. Survival in patients with score IGF-I ≤ 4 was 90.21 month and in patients with score IGF-1R> 4 was 33.39 month (P Value < 0.0001. Cox regression analysis in-dicated that expression of IGF-IR is a prognostic factor in patients with RCC (P Value < 0.0001, odds Ratio = 2.38. In conclusion, a statistically significant correlation was demonstrated between IGF-IR expression and Fuhrman nuclear grading and survival in patients with RCC. In stage-by-stage and grade-by-grade analysis; however, it seems that we cannot consider IGF-IR as an inde-pendent prognostic factor.

  7. Prognostic value of insulin- like growth factor-I receptor expression in renal cell carcinoma.

    Science.gov (United States)

    Sichani, Mehrdad Mohammadi; Yazdi, Fateme Sarreshtedar; Moghaddam, Noushin Afshar; Chehrei, Ali; Kabiri, Mahmud; Naeimi, Amin; Taheri, Diana

    2010-01-01

    The insulin-like growth factor-I receptor (IGF-IR), a tyrosine kinase receptor over expressed in many tumor cell lines and in some human tumors, plays a critical role in transformation, tumorigenicity and metastasis. The aim of the present study is to investigate the role of IGF-IR expression as a prognostic factor in RCC. This study was conducted in a historical cohort of 82 patients who had RCC treated with radical nephrectomy from 1994 to 2005. Specimens were reevaluated with regard to histological subtype, nuclear grade, stage and IGF-IR expression. The IGF-IR stain was semi-quantitatively evaluated using the Allred score system. Kaplan-Meier analysis demonstrated a significant positive correlation between Fuhrman nuclear grade and IGF-IR Allred score (P 4 was 33.39 month (P Value < 0.0001). Cox regression analysis indicated that expression of IGF-IR is a prognostic factor in patients with RCC (P Value < 0.0001, odds Ratio = 2.38). In conclusion, a statistically significant correlation was demonstrated between IGF-IR expression and Fuhrman nuclear grading and survival in patients with RCC. In stage-by-stage and grade-by-grade analysis; however, it seems that we cannot consider IGF-IR as an independent prognostic factor.

  8. Insulin-Like Growth Factor I Does Not Drive New Bone Formation in Experimental Arthritis.

    Directory of Open Access Journals (Sweden)

    Melissa N van Tok

    Full Text Available Insulin like growth factor (IGF-I can act on a variety of cells involved in cartilage and bone repair, yet IGF-I has not been studied extensively in the context of inflammatory arthritis. The objective of this study was to investigate whether IGF-I overexpression in the osteoblast lineage could lead to increased reparative or pathological bone formation in rheumatoid arthritis and/or spondyloarthritis respectively.Mice overexpressing IGF-I in the osteoblast lineage (Ob-IGF-I+/- line 324-7 were studied during collagen induced arthritis and in the DBA/1 aging model for ankylosing enthesitis. Mice were scored clinically and peripheral joints were analysed histologically for the presence of hypertrophic chondrocytes and osteocalcin positive osteoblasts.90-100% of the mice developed CIA with no differences between the Ob-IGF-I+/- and non-transgenic littermates. Histological analysis revealed similar levels of hypertrophic chondrocytes and osteocalcin positive osteoblasts in the ankle joints. In the DBA/1 aging model for ankylosing enthesitis 60% of the mice in both groups had a clinical score 1<. Severity was similar between both groups. Histological analysis revealed the presence of hypertrophic chondrocytes and osteocalcin positive osteoblasts in the toes in equal levels.Overexpression of IGF-I in the osteoblast lineage does not contribute to an increase in repair of erosions or syndesmophyte formation in mouse models for destructive and remodeling arthritis.

  9. Imprinting and Promoter Usage of Insulin-Like Growth Factor II in Twin Discordant Placenta

    Directory of Open Access Journals (Sweden)

    Yan-Min Luo

    2010-01-01

    Full Text Available Case reports from infant twins suggest that abnormal genomic imprinting may be one of the important causes of twin discordance, but it is unknown whether abnormal genomic imprinting occurs in the placenta. Therefore, we sought to determine the relationship between the imprinting of insulin-like growth factor II (IGF-II in placenta and twin discordance. We analyzed the imprinting and promoter usage of IGF-II in placenta of normal twins (T0 group, weight discordance (T1 group, and phenotype discordance (T2 group. We found the incidence of loss of imprinting (LOI for IGF-II was higher in the T2 group than that in the T0 and T1 groups, while there was no difference between T0 and T1 groups. The transcripts of promoter 3 were lower in the T2 group than in the T0 and T1 groups, and lower in the twin placenta with LOI than in those with normal imprinting. Our findings indicate that the promoter 3 specific LOI of the IGF-II gene may be closely related with phenotype discordance, not weight discordance.

  10. The Effect of Insulin Like Growth Factor-1 on Recovery of Facial Nerve Crush Injury.

    Science.gov (United States)

    Bayrak, Asuman Feda; Olgun, Yuksel; Ozbakan, Ayla; Aktas, Safiye; Kulan, Can Ahmet; Kamaci, Gonca; Demir, Emine; Yilmaz, Osman; Olgun, Levent

    2017-12-01

    The aim of this study is to investigate the efficacy of locally applied insulin-like growth factor 1 (IGF-1) on the recovery of facial nerve functions after crush injury in a rabbit model. The rabbits were randomly assigned into three groups. Group 1 consisted of the rabbits with crush injury alone; group 2, the animals applied saline solution onto the crushed facial nerve and group 3, IGF-1 implemented to the nerve in the same manner. Facial nerve injury was first electrophysiologically studied on 10th and 42nd days of the procedure. The damage to the facial nerves was then investigated histopathologically, after sacrification of the animals. In the electrophysiological study, compound muscle action potential amplitudes of the crushed nerves in the second group were decreased. In pathological specimens of the first and second groups, the orders of axons were distorted; demyelination and proliferation of Schwann cells were observed. However, in IGF-1 treated group axonal order and myelin were preserved, and Schwann cell proliferation was close to normal (Precovery of the facial nerve crush injury in rabbits. IGF-1 was considered worthy of being tried in clinical studies in facial nerve injury cases.

  11. Bioaktivitas insulin Like Growth Factor-I complex plasma seminalis kambing terhadap kualitas spermatozoa hasil sentrifugasi

    Directory of Open Access Journals (Sweden)

    Suherni Susilowati

    2012-02-01

    Full Text Available Series of exploratived laboratory experiment have been conducted to analysed the bioactifity of Insulin Like Growth Factor – I (IGF-I Complex protein of goat seminal plasm on the membran plasm and acrosom cap of centrifugation sperm. First experiment was conducted to identificatify and isolate IGF –I Complex of goat seminal plasm by using Native - Polyacrylamide gel electroforesis. The result of analysis of Native – PAGE indicated that IGF-I Complex have molecular weight of 150 kDa. Second experiment was conducted to role of IGF-I Complex protein on the membrane plasm and acrosom cap of centrifugation sperm. Semen was collected by using artificial vagina from eight mature goat. Immediately after initial evaluation, semen was centrifugated with Bracket and Oliphant’s (BO for 5 minutes 1800 rpm. And then divided two groups. Each group was supplemented with 3 × 106 of sperm concentration and then into group I was supplemented with BO medium and group two was supplemented with IGF-I Complex protein. The result of this experiment indicated that percentages of intact plasm membrane and intact acrosom cap were significantly (p < 0.05, between BO medium and IGF-I protein. In conclusion, IGF- I Complex protein is the optimal in improving plasm membran and acrosom cap of centrifugation sperm

  12. Targeting insulin-like growth factor 1 leads to amelioration of inflammatory demyelinating disease.

    Directory of Open Access Journals (Sweden)

    Matthew F Cusick

    Full Text Available In patients with multiple sclerosis (MS and in mice with experimental autoimmune encephalomyelitis (EAE, proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK, a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.

  13. Targeting insulin-like growth factor 1 leads to amelioration of inflammatory demyelinating disease.

    Science.gov (United States)

    Cusick, Matthew F; Libbey, Jane E; Trede, Nikolaus S; Fujinami, Robert S

    2014-01-01

    In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK), a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.

  14. Distribution and mRNA expression of insulin-like growth factor system in pulmonary lymphangioleiomyomatosis.

    Science.gov (United States)

    Valencia, J C; Matsui, K; Bondy, C; Zhou, J; Rasmussen, A; Cullen, K; Yu, Z X; Moss, J; Ferrans, V J

    2001-09-01

    Insulin-like growth factors (IGF-1 and IGF-2), the IGF-1 receptor (IGF-1R), and IGF-binding proteins (IGFBPs) are involved in normal pulmonary development and in the pathogenesis of smooth muscle cell tumors. To evaluate the role of the IGF system in lymphangioleiomyomatosis (LAM), we used immunohistochemical and in situ hybridization techniques to characterize the expression of IGF-1, IGF-2, IGF-1R, and IGFBP-2, -4, -5, and -6 in lung tissue from 18 LAM patients. IGF-1, ICGF-2, IGF-1R, IGFBP-1, IGFBP-2, IGFBP-4, IGFBP-5, and IGFBP-6 were expressed by LAM cells. Reactivity and mRNA expression for IGF-2 were observed in LAM cells and resembled that found in normal smooth muscle cells during pulmonary development as well as in smooth muscle cell tumors. IGFBP-2, IGFBP-4, and IGFBP-6 were associated with spindle-shaped LAM cells, whereas IGFBP-5 was associated mainly with epithelioid LAM cells. These findings suggest that the IGFBPs modulate the effects of the IGFs on LAM cells. Thus, the patterns of localization and expression of components of the IGF system in LAM strongly suggest that these agents are involved in the proliferation of LAM cells.

  15. Growth and Growth hormone - Insulin Like Growth Factor -I (GH-IGF-I) Axis in Chronic Anemias.

    Science.gov (United States)

    Soliman, Ashraf T; De Sanctis, Vincenzo; Yassin, Mohamed; Adel, Ashraf

    2017-04-28

    Anaemia is a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic development. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children. Iron deficiency anaemia (IDA) was considered to be among the most important contributing factors to the global burden of disease. Prolonged and/or chronic anemia has a negative effect on linear growth especially during the rapid phases (infancy and puberty). Additionally infants with chronic IDA have delayed cognitive, motor, and affective development that may be long-lasting. In view of the significant impact of chronic anemias on growth, pediatricians endocrinologists and hematologists should advocate primary prevention and screening for growth disturbance in these forms of anemias. The extent of the negative effect of different forms of chronic anemias on linear growth and its possible reversibilty is addressed in this review. The possible mechanisms that may impair growth in the different forms of anemias are addressed with special attention to their effect on the growth hormone (GH) - insulin like growth factor -I (IGF-I).

  16. Transforming growth factor-beta1 stimulates the production of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in human bone marrow stromal osteoblast progenitors

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Flyvbjerg, Allan; Eriksen, E F

    2001-01-01

    While transforming growth factor-beta1 (TGF-beta1) regulates proliferation and differentiation of human osteoblast precursor cells, the mechanisms underlying these effects are not known. Several hormones and locally acting growth factors regulate osteoblast functions through changes in the insulin......-like growth factors (IGFs) and IGF-binding proteins (IGFBPs). Thus, we studied the effects of TGF-beta1 on IGFs and IGFBPs in human marrow stromal (hMS) osteoblast precursor cells. TGF-beta1 increased the steady-state mRNA level of IGF-I up to 8.5+/-0.6-fold (P...

  17. HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924.

    Science.gov (United States)

    Haluska, Paul; Carboni, Joan M; TenEyck, Cynthia; Attar, Ricardo M; Hou, Xiaonan; Yu, Chunrong; Sagar, Malvika; Wong, Tai W; Gottardis, Marco M; Erlichman, Charles

    2008-09-01

    We have reported previously the activity of the insulin-like growth factor-I (IGF-IR)/insulin receptor (InsR) inhibitor, BMS-554417, in breast and ovarian cancer cell lines. Further studies indicated treatment of OV202 ovarian cancer cells with BMS-554417 increased phosphorylation of HER-2. In addition, treatment with the pan-HER inhibitor, BMS-599626, resulted in increased phosphorylation of IGF-IR, suggesting a reciprocal cross-talk mechanism. In a panel of five ovarian cancer cell lines, simultaneous treatment with the IGF-IR/InsR inhibitor, BMS-536924 and BMS-599626, resulted in a synergistic antiproliferative effect. Furthermore, combination therapy decreased AKT and extracellular signal-regulated kinase activation and increased biochemical and nuclear morphologic changes consistent with apoptosis compared with either agent alone. In response to treatment with BMS-536924, increased expression and activation of various members of the HER family of receptors were seen in all five ovarian cancer cell lines, suggesting that inhibition of IGF-IR/InsR results in adaptive up-regulation of the HER pathway. Using MCF-7 breast cancer cell variants that overexpressed HER-1 or HER-2, we then tested the hypothesis that HER receptor expression is sufficient to confer resistance to IGF-IR-targeted therapy. In the presence of activating ligands epidermal growth factor or heregulin, respectively, MCF-7 cells expressing HER-1 or HER-2 were resistant to BMS-536924 as determined in a proliferation and clonogenic assay. These data suggested that simultaneous treatment with inhibitors of the IGF-I and HER family of receptors may be an effective strategy for clinical investigations of IGF-IR inhibitors in breast and ovarian cancer and that targeting HER-1 and HER-2 may overcome clinical resistance to IGF-IR inhibitors.

  18. Cycle modulation of insulin-like growth factor-binding protein 1 in human endometrium

    Directory of Open Access Journals (Sweden)

    Corleta H.

    2000-01-01

    Full Text Available Endometrium is one of the fastest growing human tissues. Sex hormones, estrogen and progesterone, in interaction with several growth factors, control its growth and differentiation. Insulin-like growth factor 1 (IGF-1 interacts with cell surface receptors and also with specific soluble binding proteins. IGF-binding proteins (IGF-BP have been shown to modulate IGF-1 action. Of six known isoforms, IGF-BP-1 has been characterized as a marker produced by endometrial stromal cells in the late secretory phase and in the decidua. In the current study, IGF-1-BP concentration and affinity in the proliferative and secretory phase of the menstrual cycle were measured. Endometrial samples were from patients of reproductive age with regular menstrual cycles and taking no steroid hormones. Cytosolic fractions were prepared and binding of 125I-labeled IGF-1 performed. Cross-linking reaction products were analyzed by SDS-polyacrylamide gel electrophoresis (7.5% followed by autoradiography. 125I-IGF-1 affinity to cytosolic proteins was not statistically different between the proliferative and secretory endometrium. An approximately 35-kDa binding protein was identified when 125I-IGF-1 was cross-linked to cytosol proteins. Secretory endometrium had significantly more IGF-1-BP when compared to proliferative endometrium. The specificity of the cross-linking process was evaluated by the addition of 100 nM unlabeled IGF-1 or insulin. Unlabeled IGF-1 totally abolished the radioactivity from the band, indicating specific binding. Insulin had no apparent effect on the intensity of the labeled band. These results suggest that IGF-BP could modulate the action of IGF-1 throughout the menstrual cycle. It would be interesting to study this binding protein in other pathologic conditions of the endometrium such as adenocarcinomas and hyperplasia.

  19. Insulin-like growth factor-I (IGF-I) and clinical nutrition.

    Science.gov (United States)

    Livingstone, Callum

    2013-09-01

    IGF-I (insulin-like growth factor-I) is a peptide hormone, produced predominantly by the liver in response to pituitary GH (growth hormone), which is involved in a wide variety of physiological processes. It acts in an endocrine, paracrine and autocrine manner to promote growth. The production of IGF-I signals the availability of nutrients needed for its anabolic actions. Recently, there has been growing interest in its role in health and disease. IGF-I has long been known to be regulated by nutrition and dysregulated in states of under- and over-nutrition, its serum concentrations falling in malnutrition and responding promptly to refeeding. This has led to interest in its utility as a nutritional biomarker. A considerable evidence base supports utility for measurement of IGF-I in nutritional contexts. Its concentration may be valuable in providing information on nutritional status, prognosis and in monitoring nutritional support. However, it is insufficiently specific for use as a screening test for under nutrition as its serum concentration is influenced by many factors other than nutritional status, notably the APR (acute-phase response) and endocrine conditions. Concentrations should be interpreted along with clinical findings and the results of other investigations such as CRP (C-reactive protein). More recently, there has been interest in free IGF-I which holds promise as a nutritional marker. The present review covers nutritional regulation of IGF-I and its dysregulation in disease, then goes on to review recent studies supporting its utility as a nutritional marker in clinical contexts. Although not currently recommended by clinical guidelines, it is likely that, in time, measurement of IGF-I will become a routine part of nutritional assessment in a number of these contexts.

  20. [Insulin-like growth factor I (IGF-I) and liver cirrhosis].

    Science.gov (United States)

    Conchillo, M; Prieto, J; Quiroga, J

    2007-03-01

    Insulin-like growth factor I (IGF-I) is a polypeptide hormone secreted by multiple tissues in response to growth hormone (GH). It is partly responsible for GH activity, and also has glucose-lowering and anabolizing effects. Ninety percent of circulating IGF-I originates in the liver and has autocrine, paracrine, and endocrine effects, the latter on multiple tissues. Liver cirrhosis results in a progressive decline of hepatic IGF-I output, and this factor may become undetectable in advanced disease. Some cirrhosis complications, mainly those nutritional and metabolic in nature (insuline resistance, malnutrition, osteopenia, hypogonadism, intestinal disorders), may be at least partly related to this IGF-I deficiency, since some IGF-I effects represent a reverse image of cirrhosis complications. Despite this, IGF-I replacement therapy has been never suggested for cirrhosis. A number of experimental studies in cirrhotic rats showed that therapy using low-dose recombinant IGF-I exerts two types of effect on experimental cirrhosis: a) liver improvement driven by improved hepatocellular function, portal hypertension, and liver fibrosis; and b) cirrhosis-related extrahepatic disorder improvement driven by improved food efficiency, muscle mass, bone mass, gonadal function and structure, and intestinal function and structure, with a normalization of sugar and amino acid malabsorption, and improved intstinal barrier function, manifested by reduced endotoxemia and bacterial translocation. Subsequently, the first randomized, double-blind, placebo-controlled, pilot clinical trial in a small number of cirrhotic patients showed increased serum albumin and improved energy metabolism as a result of IGF-I use. Further clinical trials are needed to identify adequate IGF-I doses, administration duration and frequency, and the subgroup of cirrhotic patients who will benefit most from this replacement therapy.

  1. Association between insulin-like growth factor-1 and cognitive functions in alcohol-dependent patients.

    Science.gov (United States)

    Han, Changwoo; Kim, Dai Jin; Bae, Hwallip; Won, Sung-Doo; Lee, Hae Kook

    2014-11-07

    Studies in alcohol-dependent patients show that cognitive function can be influenced by chronic use of alcohol. Alcohol is a known neurotoxin that induces neurodegeneration in the brain. Although there are various causes of cognitive deficiency in alcohol-dependent patients, in this study we focus on the role of corticosteroids. The hypothalamus-pituitary-adrenal system (i.e., the HPA axis) plays a part in the control of corticosteroids. Recent studies show that insulin-like growth factor-1 (IGF-1) reflects the status of growth hormones under the action of the HPA axis. Therefore, IGF-1 is a potential indicator that reflects activity of the HPA axis, and a biomarker that may reflect the decline of cognitive function associated with alcohol-induced hypercortisolism. The purposes of this study are to identify an association between cognitive function and IGF-1, and to investigate IGF as the biological marker of cognitive decline in alcohol-dependent patients. Forty alcohol-dependent patients were selected as the subjects of this study. IGF-1 was measured through an enzyme-linked immunosorbent assay (ELISA). Clinical features were examined using the Korean version of the alcohol dependence scale (ADS-K). Cognitive functions were measured using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Comparative analysis was utilized to identify an association between CERAD measurement items and IGF-1. Alcohol-dependent patients demonstrated stable performance of most of the CERAD measures. Among the measures of the CERAD, only trail making test A showed a correlation to IGF-1. Compared to trail making test B, trail making test A is assumed to reflect basic cognitive functions including psychomotor speed, visual search and sequencing in alcohol-dependent patients, regardless of demographic characteristics such as the level of education of patients. Therefore, IGF-1 seems to play an important role in detecting the decline of basic cognitive functions in

  2. Isolation and Characterization of Vitreous Insulin-like Growth Factor Binding Proteins

    Science.gov (United States)

    King, Jeffery L.

    2011-01-01

    Purpose. Previous studies from this laboratory revealed that vitreous insulin-like growth factor (IGF) biological activity increases in proliferative diabetic retinopathy and that this activity is normally attenuated by IGFBPs. The goal of this study was to identify and characterize the species involved. Methods. Human and porcine vitreous, plasma, recombinant IGFBP-2, and IGFBP-3 were separated by gel electrophoresis. Functional IGFBPs were detected in Western ligand blots with biotinylated IGF-II. IGFBPs were identified using IGFBP-specific antibodies. Results. Western ligand blots of normal vitreous and plasma detected two major proteins at ∼35 kDa and ∼29 kDa. Western blot analysis of human and porcine vitreous and plasma confirmed the identity of the ∼35-kDa band as IGFBP-2 and the ∼29-kDa band as a fragment of IGFBP-3. Western blot and Western ligand blot analyses of vitreous and plasma proteins separated by two-dimensional gel electrophoresis revealed that the IGFBP-3 fragments in vitreous and plasma have virtually identical profiles. Lyase digestion revealed that the ∼29-kDa IGFBP-3 fragment is a glycoprotein with a peptide core of ∼25 kDa. N-terminal sequence data obtained from vitreous IGFBP-3 revealed that the protein is proteolytically truncated at the C terminus. Conclusions. Normal human and porcine vitreous contain two major IGFBPs, IGFBP-2 and an ∼29-kDa fragment of IGFBP-3. Both IGFBPs retain biological activity, and IGFBP-3 has one or more glycosylation sites with a protein core of ∼25 kDa. Systematic comparisons indicate that the vitreous IGFBP-3 is similar to and perhaps identical with a previously described IGFBP-3 fragment in plasma with reduced growth factor affinities. PMID:20811046

  3. Low serum Insulin Like Growth Factor - 1 in patients with Stress Urinary Incontinence

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    Emin Ozbek

    Full Text Available ABSTRACT Objective: SUI, involuntary loss of urine, occurs when intra abdominal pressure exceeds urethral pressure in women. Recent animal study has shown that there are therapeutic effects of Insulin-like growth factors (IGF-1 on stress urinary incontinence in rats with simulated childbirth trauma. IGF-1 is an important mediator of cell growth, differentiation and transformation in various tissues and stimulates fibroblast proliferation and enhances collagen synthesis. The purpose of the current study was to determine the association between IGF-1 levels and SUI. Materials and Methods: All patients were evaluated for SUI and divided into two groups: 116 women with SUI and 76 women without SUI. Diagnosis of SUI was based on the International Consultation on Incontinence Questionnaire-Short Form (ICIQSF. Levels of IGF-1 were measured in serum by enzyme-linked immunosorbent assay. The relationship between IGF-1 levels and SUI in patients was evaluated statisticaly. Results: The mean age of patients wiyh SUI was 49.9±8.6 and 48.7±7.8 in control group. Plasma IGF-1 levels were significantly lower in SUI than in control group (106.5±26.4 and 133.3±37.1ng/mL, respectively, P <0.001. Body mass indexes were higher in women with SUI than women without SUI. Conclusion: In this study lower serum IGF-1 levels were found to be associated with SUI. Serum IGF-1 level appears to be a specific predictor of SUI, and it may be used in early prediction of SUI in female population.

  4. Impact of insulin like growth factor-1 in development of coronary artery ectasia

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    Ibrahim Faruk Akturk

    2014-09-01

    Full Text Available Coronary artery ectasia (CAE is characterized by inappropriate dilatation of the coronary vasculature. The mechanisms of CAE are not well known. Insulin-like growth factor-1 (IGF-1 may make endothelial cells and smooth muscle cells more sensitive to the effects of growth hormone. In the present study, we hypothesized that IGF-1 may have an impact on the formation of ectasia and aneurysm in arterial system, and aimed to investigate the associations between the presence of CAE and serum IGF-1 levels in patients undergoing coronary angiography. The study included 2.980 subjects undergoing elective diagnostic coronary angiography. We selected 40 patients diagnosed with CAE as CAE group and 44 subjects with absolutely normal coronary arteries were assigned as normal control group. IGF-1 levels were measured in both groups of patients. Groups were similar in terms of age, sex and coronary artery disease risk factors. The serum IGF-1 levels were significantly higher in CAE patients with 109.64±54.64 ng/mL than in controls with 84.76±34.01 ng/mL (p=0.016. HDL levels were lower in ectasia group with 41.5±10.7 mg/dL than controls with 47.7±10.4 mg/dL (p=0.018. By means of logistic regression analysis, high IGF-1 and low HDL levels were found to be independent risk factors for the presence of CAE (p<0.02, p<0.016, respectively. The study revealed that there was a positive correlation between serum IGF-1 levels and presence of CAE, and high IGF-1 levels and low HDL levels were independent risk factors for the presence of CAE. Future studies are needed to confirm these results.

  5. Effects of spaceflight and Insulin-like Growth Factor-1 on rat bone properties

    Energy Technology Data Exchange (ETDEWEB)

    Bateman, T.A.; Ayers, R.A.; Spetzler, M.L.; Simske, S.J. [BioServe Space Technologies University of Colorado Boulder, Colorado80309-0429 (United States); Zimmerman, R.J. [Chiron Corporation 4560 Horton Street Emeryville, California94608-2916 (United States)

    1997-01-01

    Spaceflight induces bone degradation which is analogous to an accelerated onset of osteoporosis in humans (Tilton {ital et al.}, 1980). In rats, decreased bone formation is indicative of reduced osteoblast activity (Morey and Baylink, 1978). Chiron Corporation (Emeryville, CA) is interested in using the microgravity environment of low-Earth-orbit to test its therapeutic drug, Insulin-like Growth Factor-1 (IGF-1). This pharmaceutic is known to promote osteoblast activity (Schmid {ital et al.}, 1984) and therefore may encourage bone growth in rats. Chiron sponsored the Immune.3 payload on STS-73 (May 19{endash}29, 1996) through its Center for Space Commercialization (CSC) partner BioServe Space Technologies (University of Colorado and Kansas State University) to investigate the effects of IGF-1 on mitigating the skeletal degradation that affects rats and humans during spaceflight. Twelve rats were flown for 10 days using two Animal Enclosure Modules (AEMs) provided by NASA Ames Research Center. Of the twelve, six received 1.4 mg/day of IGF-1; the other six saline. Sixteen vivarium ground controls received the same treatment on a one day delay. Rat femora and tibiae were examined for bone mineral density via DXA scan. Femora and humeri were measured for physical and compositional properties, as well as mechanically tested in three point flexure. Quantitative histomorphometric examination of tibiae, humeri, fibulae, ribs and cranial bone; and microhardness testing on tibiae and humeri are currently in progress. Flight humeri and vivarium femora were significantly larger than their counterparts; however, significant differences in mechanical properties and mineral density were not concurrent to these mass changes. {copyright} {ital 1997 American Institute of Physics.}

  6. Expression of insulin-like growth factor-2 receptors on EL4 lymphoma cells overexpressing growth hormone.

    Science.gov (United States)

    Farmer, John T; Weigent, Douglas A

    2007-01-01

    In the present study, we report the upregulation of functional IGF-2Rs in cells overexpressing growth hormone (GH). EL4 lymphoma cells stably transfected with an rGH cDNA overexpression vector (GHo) exhibited an increase in the binding of (125)I-IGF-2 with no change in the binding affinity compared to vector alone controls. An increase in the expression of the insulin-like growth factor-2 receptor (IGF-2R) in cells overexpressing GH was confirmed by Western blot analysis and IGF-2R promoter luciferase assays. EL4 cells produce insulin-like growth factor-2 (IGF-2) as detected by the reverse transcription-polymerase chain reaction (RT-PCR); however, no IGF-2 protein was detected by Western analysis. The increase in the expression of the IGF-2R resulted in greater levels of IGF-2 uptake in GHo cells compared to vector alone controls. The data suggest that one of the consequences of the overexpression of GH is an increase in the expression of the IGF-2R.

  7. CLINICAL IMPLICATIONS OF INSULIN-LIKE GROWTH FACTORS (IGF AND IGF-BINDING PROTEINS INVESTIGATION IN PATIENTS WITH OVARIAN NEOPLASMS

    Directory of Open Access Journals (Sweden)

    E. S. Gershteyn

    2015-01-01

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

  8. Insulin-Like Growth Factor-1-Mediated DNA Repair in Irradiated Salivary Glands Is Sirtuin-1 Dependent.

    Science.gov (United States)

    Meyer, S; Chibly, A M; Burd, R; Limesand, K H

    2017-02-01

    Ionizing radiation is one of the most common cancer treatments; however, the treatment leads to a wide range of debilitating side effects. In patients with head and neck cancer (HNC), the surrounding normal salivary gland is extremely sensitive to therapeutic radiation, and damage to this tissue results in various oral complications and decreased quality of life (QOL). In the current study, mice treated with targeted head and neck radiation showed a significant increase in double-stranded breaks (DSB) in the DNA of parotid salivary gland cells immediately after treatment, and this remained elevated 3 h posttreatment. In contrast, mice pretreated with insulin-like growth factor-1 (IGF-1) showed resolution of the same amount of initial DNA damage by 3 h posttreatment. At acute time points (30 min to 2 h), irradiated parotid glands had significantly decreased levels of the histone deactylase Sirtuin-1 (SirT-1) which has been previously shown to function in DNA repair. Pretreatment with IGF-1 increased SirT-1 protein levels and increased deacetylation of SirT-1 targets involved in DNA repair. Pharmacological inhibition of SirT-1 activity decreased the IGF-1-mediated resolution of DSB. These data suggest that IGF-1 promotes DNA repair in irradiated parotid glands through the maintenance and activation of SirT-1.

  9. Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin

    Directory of Open Access Journals (Sweden)

    Michael G. Kemp

    2017-02-01

    Full Text Available The growing incidence of non-melanoma skin cancer (NMSC necessitates a thorough understanding of its primary risk factors, which include exposure to ultraviolet (UV wavelengths of sunlight and age. Whereas UV radiation (UVR has long been known to generate photoproducts in genomic DNA that promote genetic mutations that drive skin carcinogenesis, the mechanism by which age contributes to disease pathogenesis is less understood and has not been sufficiently studied. In this review, we highlight studies that have considered age as a variable in examining DNA damage responses in UV-irradiated skin and then discuss emerging evidence that the reduced production of insulin-like growth factor-1 (IGF-1 by senescent fibroblasts in the dermis of geriatric skin creates an environment that negatively impacts how epidermal keratinocytes respond to UVR-induced DNA damage. In particular, recent data suggest that two principle components of the cellular response to DNA damage, including nucleotide excision repair and DNA damage checkpoint signaling, are both partially defective in keratinocytes with inactive IGF-1 receptors. Overcoming these tumor-promoting conditions in aged skin may therefore provide a way to lower aging-associated skin cancer risk, and thus we will consider how dermal wounding and related clinical interventions may work to rejuvenate the skin, re-activate IGF-1 signaling, and prevent the initiation of NMSC.

  10. Fetal alcohol exposure and mammary tumorigenesis in offspring: role of the estrogen and insulin-like growth factor systems.

    Science.gov (United States)

    Cohick, Wendie S; Crismale-Gann, Catina; Stires, Hillary; Katz, Tiffany A

    2015-01-01

    Fetal alcohol spectrum disorders affect a significant number of live births each year, indicating that alcohol consumption during pregnancy is an important public health issue. Environmental exposures and lifestyle choices during pregnancy may affect the offspring's risk of disease in adulthood, leading to the idea that a woman's risk of breast cancer may be pre-programmed prior to birth. Exposure of pregnant rats to alcohol increases tumorigenesis in the adult offspring in response to mammary carcinogens. The estrogen and insulin-like growth factor (IGF-I) axes occupy central roles in normal mammary gland development and breast cancer. 17-β estradiol (E2) and IGF-I synergize to regulate formation of terminal end buds and ductal elongation during pubertal development. The intracellular signaling pathways mediated by the estrogen and IGF-I receptors cross-talk at multiple levels through both genomic and non-genomic mechanisms. Several components of the E2 and IGF-I systems are altered in early development in rat offspring exposed to alcohol in utero, therefore, these changes may play a role in the enhanced susceptibility to mammary carcinogens observed in adulthood. Alcohol exposure in utero induces a number of epigenetic alterations in non-mammary tissues in the offspring and other adverse in utero exposures induce epigenetic modifications in the mammary gland. Future studies will determine if fetal alcohol exposure can induce epigenetic modifications in genes that regulate E2/IGF action at key phases of mammary development, ultimately leading to changes in susceptibility to carcinogens.

  11. Relationships between performance traits and the expressions of growth hormone, insulin-Like growth facto -I, and insulin in pigs selected for growth or leanness

    NARCIS (Netherlands)

    Pas, te M.F.W.; Gerritsen, C.L.M.; Visscher, A.H.; Greef, de K.H.

    2003-01-01

    Selection for growth rate or backfat thickness (BFT) in pigs is related with changes in the blood plasma concentrations of growth hormone (GH) and insulin-like growth factor-I (IGF-I). Two experimental pig selection lines based upon a common commercial Large White (LW) selection line were selected

  12. Predicting growth in angus bulls: the use of GHRH challenge, insulin-like growth factor-I, and insulin-like growth factor binding proteins.

    Science.gov (United States)

    Connor, E E; Barao, S M; Kimrey, A S; Parlier, A B; Douglass, L W; Dahl, G E

    2000-11-01

    Plasma IGF-I, IGF binding protein-2 (IGFBP-2), and IGFBP-3 were quantified in growing Angus bulls (n = 56) to determine their relationship with postweaning growth and carcass ultrasound measurements. In addition, GH response to GHRH challenge (area-under-the-curve GH [AUC-GH) was determined for each bull as part of a previous study. Blood was collected by jugular venipuncture at the start of a 140-d postweaning growth performance test and at 28 d intervals for plasma IGF-I determination by RIA. Plasma IGFBP-2 and -3 content was measured at the start of the study, on d 70, and d 140 by Western ligand blotting. Individual weights and hip heights were measured every 28 d during the study and carcass longissimus muscle area, intramuscular fat percentage, and carcass backfat were estimated by ultrasound on d 140. Greater plasma IGF-I at the start of the performance test was associated with reduced postweaning ADG and increased longissimus area. Throughout the performance test period, the correlations between plasma IGF-I and hip height were consistently positive, ranging from 0.10 to 0.38, but the correlations between ADG and IGF-I varied from -0.32 to 0.31. Age-adjusted d-1 plasma IGFBP-2 was related to ADG during the performance test, explaining nearly 30% of the variation in ADG. A model combining weaning age, IGFBP-2, and AUC-GH showed a strong relationship with ADG (R2 = 0.40). Plasma IGFBP-2 and -3 were not related to carcass characteristics, and IGFBP-3 was not related to growth rates. This study provides additional evidence for the variable relationship between plasma IGF-I and growth rates in cattle. A significant positive relationship between plasma IGFBP-2, AUC-GH, and postweaning ADG warrants further investigation.

  13. Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats

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    Predrag Šerbedzija

    2012-01-01

    Full Text Available There are an estimated 36 million dementia patients worldwide. The anticipated tripling of this number by year 2050 will negatively impact the capacity to deliver quality health care. The epidemic in diabetes is particularly troubling, because diabetes is a substantial risk factor for dementia independently of cerebrovascular disease. There is an urgent need to elucidate the pathogenesis of progressive brain atrophy, the cause of dementia, to allow rational design of new therapeutic interventions. This review summarizes recent tests of the hypothesis that the concomitant loss of insulin and insulin-like growth factors (IGFs is the dominant cause for age-dependent, progressive brain atrophy with degeneration and cognitive decline. These tests are the first to show that insulin and IGFs regulate adult brain mass by maintaining brain protein content. Insulin and IGF levels are reduced in diabetes, and replacement of both ligands can prevent loss of total brain protein, widespread cell degeneration, and demyelination. IGF alone prevents retinal degeneration in diabetic rats. It supports synapses and is required for learning and memory. Replacement doses in diabetic rats can cross the blood-brain barrier to prevent hippocampus-dependent memory impairment. Insulin and IGFs are protective despite unabated hyperglycemia in diabetic rats, severely restricting hyperglycemia and its consequences as dominant pathogenic causes of brain atrophy and impaired cognition. These findings have important implications for late-onset Alzheimer′s disease (LOAD where diabetes is a major risk factor, and concomitant decline in insulin and IGF activity suggest a similar pathogenesis for brain atrophy and dementia.

  14. Association Between Omentin, Visfatin and Insulin-Like Growth Factor-1 in Women With Metabolic Syndrome

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    Goodarzi

    2014-12-01

    Full Text Available Background Adipokines that are produced by adipose tissue have extensive effects on carbohydrate and lipid metabolism and also on the pathogenesis of the metabolic syndrome (MetS. Objectives This study aimed to measure the concentrations of omentin-1, visfatin and insulin-like growth factor-1 (IGF-1 as likely markers of metabolic syndrome and also to demonstrate their associations in women with MetS. Materials and Methods Eighty women with MetS and eighty healthy women as controls participated in this study. Blood pressure, waist circumference, body mass index (BMI, and serum biochemical parameters were determined in all subjects. The serum level of IGF-1, omentin-1 and visfatin were assessed using the enzyme linked immunosorbent assay (ELISA. The association between omentin, visfatin and IGF-1 was also determined in these women. Results Significantly lower levels of omentin-1 and IGF-1 were observed in MetS subjects compared to the controls (P = 0.009 and < 0.001 respectively. However, a significant difference was not observed in visfatin concentration between the two studied groups (P = 0.67. A positive association was observed between omentin-1, visfatin and IGF-1 in the MetS group. Conclusions Our findings indicated a lower level of both omentin-1 and IGF-1 in women with MetS; this might play a role in the pathogenesis of MetS. Furthermore, the main finding of the current investigation was the association between omentin, visfatin and IGF-1; however determining the molecular mechanism of the observed relationships needs further studies.

  15. Little effects of Insulin-like Growth Factor-I on testicular atrophy induced by hypoxia

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    Casares Amelia

    2006-02-01

    Full Text Available Abstract Background Insulin-like Growth Factor-I (IGF-I supplementation restores testicular atrophy associated with advanced liver cirrhosis that is a condition of IGF-I deficiency. The aim of this work was to evaluate the effect of IGF-I in rats with ischemia-induced testicular atrophy (AT without liver disease and consequently with normal serum level of IGF-I. Methods Testicular atrophy was induced by epinephrine (1, 2 mg/Kg intra-scrotal injection five times per week during 11 weeks. Then, rats with testicular atrophy (AT were divided into two groups (n = 10 each: untreated rats (AT receiving saline sc, and AT+IGF, which were treated with IGF-I (2 μg.100 g b.w.-1.day-1, sc. for 28d. Healthy controls (CO, n = 10 were studied in parallel. Animals were sacrificed on day 29th. Hypophyso-gonadal axis, IGF-I and IGFBPs levels, testicular morphometry and histopathology, immuno-histochemical studies and antioxidant enzyme activity phospholipid hydroperoxide glutathione peroxidase (PHGPx were assessed. Results Compared to controls, AT rats displayed a reduction in testicular size and weight, with histological testicular atrophy, decreased cellular proliferation and transferrin expression, and all of these alterations were slightly improved by IGF-I at low doses. IGF-I therapy increased signifincantly steroidogenesis and PHGPx activity (p Conclusion In testicular atrophy by hypoxia, condition without IGF-I deficiency, IGF-treatment induces only partial effects. These findings suggest that IGF-I therapy appears as an appropriate treatment in hypogonadism only when this is associated to conditions of IGF-I deficiency (such as Laron Syndrom or liver cirrhosis.

  16. Insulin-like growth factor-II receptors in cultured rat hepatocytes: regulation by cell density

    Energy Technology Data Exchange (ETDEWEB)

    Scott, C.D.; Baxter, R.C.

    1987-12-01

    Insulin-like growth factor-II (IGF-II) receptors in primary cultures of adult rat hepatocytes were characterized and their regulation by cell density examined. In hepatocytes cultured at 5 X 10(5) cells per 3.8 cm2 plate (/sup 125/I)IGF-II bound to specific, high affinity receptors (Ka = 4.4 +/- 0.5 X 10(9) l/mol). Less than 1% cross-reactivity by IGF-I and no cross-reactivity by insulin were observed. IGF-II binding increased when cells were permeabilized with 0.01% digitonin, suggesting the presence of an intracellular receptor pool. Determined by Scatchard analysis and by polyacrylamide gel electrophoresis after affinity labeling, the higher binding was due solely to an increase in binding sites present on 220 kDa type II IGF receptors. In hepatocytes cultured at low densities, the number of cell surface receptors increased markedly, from 10-20,000 receptors per cell at a culture density of 6 X 10(5) cells/well to 70-80,000 receptors per cell at 0.38 X 10(5) cells/well. The increase was not due simply to the exposure of receptors from the intracellular pool, as a density-related increase in receptors was also seen in cells permeabilized with digitonin. There was no evidence that IGF binding proteins, either secreted by hepatocytes or present in fetal calf serum, had any effect on the measurement of receptor concentration or affinity. We conclude that rat hepatocytes in primary culture contain specific IGF-II receptors and that both cell surface and intracellular receptors are regulated by cell density.

  17. Repopulation of the atrophied thymus in diabetic rats by insulin-like growth factor I

    Energy Technology Data Exchange (ETDEWEB)

    Binz, K.; Joller, P.; Froesch, P.; Binz, H.; Zapf, J.; Froesch, E.R. (University Hospital, Zurich (Switzerland))

    1990-05-01

    Atrophy of the thymus is one of the consequences of severe insulin deficiency. The authors describe here that the weight and the architecture of the thymus of diabetic rats is restored towards normal not only by insulin but also by insulin-like growth factor I (IGF-I) treatment. In contrast to insulin, this effect of IGF-I occurs despite persisting hyperglycemia and adrenal hyperplasia. They also investigated the in vivo effect of IGF-I on replication and differentiation of thymocytes from streptozotocin-induced diabetic rats. Thymocytes from diabetic rats incorporated less ({sup 3}H)thymidine than did thymocytes from healthy rats. Insulin, as well as IGF-I treatment of diabetic rats increased ({sup 3}H)thymidine incorporation by thymocytes. Flow cytometry of thymocytes labeled with monoclonal antibodies revealed a decreased expression of the Thy-1 antigen in diabetic rats compared with control rats. In addition, a major deficiency of thymocytes expressing simultaneously the W3/25 and the Ox8 antigens was observed. These changes were restored towards normal by insulin as well as by IGF-I treatment. The antibody response to a T cell-dependent antigen (bovine serum albumin) was comparable in normal and diabetic rats. They conclude that IGF-I has important effects on the thymocyte number and the presence of CD4{sup +}/CD8{sup +} immature cells in the thymus of diabetic rats despite persisting hyperglycemia. However, helper T-cell function for antibody production appears to be preserved even in the severely diabetic state.

  18. Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of bone.

    Directory of Open Access Journals (Sweden)

    Grażyna E Sroga

    Full Text Available Despite our extensive knowledge of insulin-like growth factor 1 (IGF1 action on the growing skeleton, its role in skeletal homeostasis during aging and age-related development of certain diseases is still unclear. Advanced glycation end products (AGEs derived from glucose are implicated in osteoporosis and a number of diabetic complications. We hypothesized that because in humans and rodents IGF1 stimulates uptake of glucose (a glycation substrate from the bloodstream in a dose-dependent manner, the decline of IGF1 could be associated with the accumulation of glycation products and the decreasing resistance of bone to fracture. To test the aforementioned hypotheses, we used human tibial posterior cortex bone samples to perform biochemical (measurement of IGF1, fluorescent AGEs and pentosidine (PEN contents and mechanical tests (crack initiation and propagation using compact tension specimens. Our results for the first time show a significant, age-independent association between the levels of IGF1 and AGEs. Furthermore, AGEs (fAGEs, PEN predict propensity of bone to fracture (initiation and propagation independently of age in human cortical bone. Based on these results we propose a model of IGF1-based regulation of bone fracture. Because IGF1 level increases postnatally up to the juvenile developmental phase and decreases thereafter with aging, we propose that IGF1 may play a protective role in young skeleton and its age-related decline leads to bone fragility and an increased fracture risk. Our results may also have important implications for current understanding of osteoporosis- and diabetes-related bone fragility as well as in the development of new diagnostic tools to screen for fragile bones.

  19. Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Li, Zhiguo [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina (United States); Chao, Nelson J. [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Department of Pathology, Duke University Medical Center, Durham, North Carolina (United States); Department of Immunology, Duke University Medical Center, Durham, North Carolina (United States); Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Chen, Benny J., E-mail: chen0032@mc.duke.edu [Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina (United States); Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States)

    2013-03-15

    Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.

  20. Materno-foetal leptin and insulin-like growth factor in low birth weight neonates.

    Science.gov (United States)

    Elzein, A O M; Ali, A A; Hamdan, H Z; Elhassan, E M; Shrif, N E M A; Adam, I

    2016-01-01

    Low birth weight (LBW) is a health concern in developing countries. Leptin and insulin-like growth factor-I (IGF-I) are factors that influence LBW. A case-control study was conducted at Medani hospital, Sudan. Cases were women who had LBW deliveries ( 2,500 g) and controls were women with normal-weight babies ( 2.500 – 4,000 g). Sociodemographic and obstetrical characteristics were gathered from both groups and leptin and IGF-I levels were measured by ELISA. Cases and controls (45 in each arm) were matched in their basic data. The median (interquartile) of maternal leptin levels [9.9 (1.9 – 21.8) vs. 16.0 (9.6 – 20.8), ng/ml; P0.001] and IGF-I [1.6 (0.7 – 20.0) vs. 6.1 (4.3 – 7.1) ng/ml ; P 0.001] were significantly lower in cases than in controls. Likewise, cord serum leptin [5.8 (2.1 – 12.6) vs. 20.0 (5.1 – 37.8) ng/ml; P0.001] and cord serum IGF-I [1.7 (1.3 – 2.0) vs. 6.9 (5.9 – 7.4) ng/ml; P0.001] levels were significantly lower in cases than in controls. Significant positive correlation was found between birth weight and cord leptin ( r0.398), maternal ( r0.795) and cord ( r0.863) IGF-I levels. Maternal and cord leptin and IGF-I levels were significantly lower in LBW babies.

  1. Changes in Insulin-like Growth Factor-1 Level in Patients with Sepsis and Septic Shock

    Directory of Open Access Journals (Sweden)

    Sang Hoon Lee

    2016-11-01

    Full Text Available Background Despite many ongoing, prospective studies on the topic, sepsis still remains one of the main causes of death in hospital. The hormone insulin-like growth factor 1 (IGF-1 has a similar molecular structure to that of insulin. IGF-1 exerts anabolic effects and plays important roles in both normal physiology and pathologic processes. Previous studies have observed low serum IGF-1 level in patients with critical illnesses. Here, we evaluated changes in IGF-1 level based on survival of septic patients. Methods We evaluated 140 patients with sepsis and septic shock (21 with sepsis and 119 with septic shock admitted to the intensive care unit of a university-affiliated hospital in Korea. Serum IGF-1 level was measured on days 0, 1, 3, and 7. Patients with liver disease were excluded from this study. All data were analyzed using SPSS version 20 (SPSS Inc., Chicago, IL, USA. Results Patients with septic shock had significantly lower serum IGF-1 level on days 1 and 3 than patients without septic shock (p = 0.002 and p = 0.007, respectively. Generally, there was a negative relationship between IGF-1 and serum cortisol levels; however, this relationship was only significant on day 3 (p = 0.029. Furthermore, renin showed significantly negative correlation with IGF-1 on day 3 (p = 0.038. IGF-1 level did not show significant difference between survivors and non-survivors. Conclusions Our results showed that IGF-1 was associated with septic shock, and that the IGF-1 axis is severely disrupted in septic patients. Additionally, serum cortisol and renin levels were associated with IGF-1 level.

  2. Serum insulin-like growth factor-1 levels in patients with pseudoexfoliation syndrome and glaucoma.

    Science.gov (United States)

    Dogan, Aysun Sanal; Kabatas, Naciye; Erden, Gonul; Celikay, Osman; Arzuhal, Abdullah Ercan; Gurdal, Canan

    2017-04-01

    Insulin-like growth factor-1 (IGF-1) is altered in several neurodegenerative diseases, the association between serum IGF-1 levels and glaucoma has not been evaluated. This study was designed to evaluate whether serum IGF-1 levels are different in patients with Pseudoexfoliation (PEX) with or without glaucoma. The study was conducted with 110 participants aged 65 years or older who were divided into three groups: group 1, patients with PEX syndrome; group 2, patients with PEX glaucoma; and group 3, participants without PEX or glaucoma. All participants underwent full ophthalmological examination and a detailed medical history was recorded. Patients with known neurodegenerative diseases other than PEX glaucoma were excluded. Serum IGF-1 levels were measured by automated chemiluminescent assay. Groups 1, 2, and 3 included 35, 34, and 41 patients, respectively; there were no differences regarding age, gender, or systemic disease status. There were also no statistically significant differences between the groups in terms of IGF-1 levels, which were 91.7 ± 39.1, 101.1 ± 40.2, and 107.2 ± 43.8 ng/ml for groups 1, 2, and 3, respectively (p = 0.276). Serum IGF-1 levels were similar by gender, the presence of systemic disease, status of diabetes mellitus, and laterality of the PEX material. There was no correlation between the cup-to-disk ratios and IGF-1 levels (r = -0.214, p = 0.223). IGF-1 levels in the circulation did not differ in the presence of PEX syndrome with or without glaucoma. This may indicate that the neurodegenerative process is local rather than systemic.

  3. Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2010-07-01

    To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET).

  4. Neuroprotective Effect of Insulin-like Growth Factor-II on 1- Methyl-4 ...

    African Journals Online (AJOL)

    II) on 1-methyl-4-phenyl pyridinium (MPP)-induced oxidative damage in adult cortical neuronal cultures. ... development. However, in adults, there is a decrease in its synthesis, although IGF-II remains the most abundant insulin-like peptide in the adult brain, primarily expressed in ..... doses of IGF-II in aging rats, J. Transl.

  5. Changes in serum concentrations of growth hormone, insulin, insulin-like growth factor and insulin-like growth factor-binding proteins 1 and 3 and urinary growth hormone excretion during the menstrual cycle

    DEFF Research Database (Denmark)

    Juul, A; Scheike, Thomas Harder; Pedersen, A T

    1997-01-01

    Few studies exist on the physiological changes in the concentrations of growth hormone (GH), insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP) within the menstrual cycle, and some controversy remains. We therefore decided to study the impact of endogenous sex steroids on the GH......, with significantly higher values in the luteal phase compared to the proliferative phase (P changes in IGFBP-3 serum concentrations and no differences in IGFBP-3...... that returned to baseline at the day of the LH surge. Fasting insulin concentrations showed large fluctuations throughout the menstrual cycle without any distinct cyclic pattern. No cyclic changes in urinary GH excretion during menstrual cycle were detected. We conclude that, although IGF-I concentrations...

  6. Dietary protein during gestation affects maternal insulin-like growth factor, insulin-like growth factor binding protein, leptin concentrations, and fetal growth in heifers.

    Science.gov (United States)

    Sullivan, T M; Micke, G C; Perkins, N; Martin, G B; Wallace, C R; Gatford, K L; Owens, J A; Perry, V E A

    2009-10-01

    The influence of supplemental protein during gestation on maternal hormones and fetal growth was determined in composite beef heifers. At AI, 118 heifers were stratified by BW within each composite genotype (BeefX = 1/2 Senepol, 1/4 Brahman, 1/8 Charolais, 1/8 Red Angus and CBX = 1/2 Senepol, 1/4 Brahman, 1/4 Charolais) into 4 treatment groups: high high (HH = 1.4 kg CP/d for first and second trimesters of gestation), high low (HL = 1.4 kg of CP/d for first trimester and 0.4 kg of CP/d for second trimester), low high (lowH = 0.4 kg CP/d for first trimester and 1.4 kg of CP/d and for second trimester), or low low (LL = 0.4 kg CP/d for first and second trimesters). Maternal plasma IGF-I and -II, total IGFBP, and leptin concentrations were determined at 14 d before AI and at d 28, 82, 179, and 271 post-AI (mean gestation length 286 d), and leptin concentrations were also determined at calving. Increased dietary protein increased maternal plasma IGF-I (P < 0.001 on d 28, 82, and 179), IGF-II (P = 0.01 on d 82; P = 0.04 on d 271), and total IGFBP (P = 0.002 on d 82; P = 0.005 on d 179; P = 0.03 on d 271). Maternal plasma IGF-I at d 271 was negatively associated with calf crown-rump length at birth (P = 0.003). BeefX had greater birth weight calves (P = 0.01), greater IGF-II (P < 0.001), increased ratios of IGF-I:total IGFBP (P = 0.008) and IGF-II:total IGFBP (P < 0.001), and reduced total IGFBP compared with CBX (P = 0.02). Increased dietary protein during second trimester increased maternal plasma leptin at calving (P = 0.005). Maternal plasma leptin near term was positively associated with heifer BCS (P = 0.02) and with calf birth weight (P = 0.04), and at calving was positively associated with heifer age at AI (P = 0.02). These findings suggest that maternal dietary protein, age, and genotype influence plasma concentrations of metabolic hormones and fetal growth in Bos indicus-influenced heifers.

  7. Insulin and insulin-like growth factor-1 induce pronounced hypertrophy of skeletal myofibers in tissue culture

    Science.gov (United States)

    Vandenburgh, Herman H.; Karlisch, Patricia; Shansky, Janet

    1990-01-01

    Skeletal myofibers differentiated from primary avian myoblasts in tissue culture can be maintained in positive nitrogen balance in a serum-free medium for at least 6 to 7 days when embedded in a three dimensional collagen gel matrix. The myofibers are metabolically sensitive to physiological concentrations of insulin but these concentrations do not stimulate cell growth. Higher insulin concentrations stimulate both cell hyperplasia and myofiber hypertrophy. Cell growth results from a long term 42 percent increase in total protein synthesis and a 38 percent increase in protein degradation. Myofiber diameters increase by 71 to 98 percent after 6 to 7 days in insulin-containing medium. Insulin-like growth factor-1 but not insulin-like growth factor-2, at 250 ng/ml, is as effective as insulin in stimulating cell hyperplasia and myofiber hypertrophy. This model system provides a new method for studying the long-term anabolic effects of insulin and insulin-like growth factors on myofiber hypertrophy under defined tissue culture conditions.

  8. Knockout of insulin-like growth factor-1 receptor impairs distal lung morphogenesis.

    Directory of Open Access Journals (Sweden)

    Ralph Epaud

    Full Text Available BACKGROUND: Insulin-like growth factors (IGF-I and -II are pleiotropic regulators of somatic growth and development in vertebrate species. Endocrine and paracrine effects of both hormones are mediated by a common IGF type 1 receptor (IGF-1R. Lethal respiratory failure in neonatal IGF-1R knockout mice suggested a particular role for this receptor in pulmonary development, and we therefore investigated the consequences of IGF-1R inactivation in lung tissue. METHODS AND FINDINGS: We first generated compound heterozygous mutant mice harboring a hypomorphic (Igf1r(neo and a null (Igf1r(- allele. These IGF-1R(neo/- mice express only 22% of normal IGF-1R levels and are viable. In adult IGF-1R(neo/- mice, we assessed lung morphology and respiratory physiology and found normal histomorphometric characteristics and normal breathing response to hypercapnia. We then generated homozygous IGF-1R knockout mutants (IGF-1R(-/- and analyzed their lung development during late gestation using histomorphometric and immunohistochemical methods. IGF-1R(-/- embryos displayed severe lung hypoplasia and markedly underdeveloped diaphragms, leading to lethal neonatal respiratory distress. Importantly, IGF-1R(-/- lungs from late gestation embryos were four times smaller than control lungs and showed markedly thickened intersaccular mesenchyme, indicating strongly delayed lung maturation. Cell proliferation and apoptosis were significantly increased in IGF-1R(-/- lung tissue as compared with IGF-1R(+/+ controls. Immunohistochemistry using pro-SP-C, NKX2-1, CD31 and vWF as markers revealed a delay in cell differentiation and arrest in the canalicular stage of prenatal respiratory organ development in IGF-1R(-/- mutant mice. CONCLUSIONS/SIGNIFICANCE: We found that low levels of IGF-1R were sufficient to ensure normal lung development in mice. In contrast, complete absence of IGF-1R significantly delayed end-gestational lung maturation. Results indicate that IGF-1R plays

  9. Myostatin and insulin-like growth factor I: potential therapeutic biomarkers for pompe disease.

    Science.gov (United States)

    Chien, Yin-Hsiu; Han, Der-Sheng; Hwu, Wuh-Liang; Thurberg, Beth L; Yang, Wei-Shiung

    2013-01-01

    Myostatin and insulin-like growth factor 1 (IGF-1) are serum markers for muscle growth and regeneration. However, their value in the clinical monitoring of Pompe disease - a muscle glycogen storage disease - is not known. In order to evaluate their possible utility for disease monitoring, we assessed the levels of these serum markers in Pompe disease patients receiving enzyme replacement therapy (ERT). A case-control study that included 10 patients with Pompe disease and 10 gender- and age-matched non-Pompe disease control subjects was performed in a referral medical center. Average follow-up duration after ERT for Pompe disease patients was 11.7 months (range: 6-23 months). Measurements of serum myostatin, IGF-1, and creatine kinase levels were obtained, and examinations of muscle pathology were undertaken before and after ERT in the patient group. Compared with control subjects, Pompe disease patients prior to undergoing ERT had significantly lower serum IGF-1 levels (98.6 ng/ml vs. 307.9 ng/ml, p = 0.010) and lower myostatin levels that bordered on significance (1.38 ng/ml vs. 3.32 ng/ml, p = 0.075). After ERT, respective myostatin and IGF-1 levels in Pompe disease patients increased significantly by 129% (from 1.38 ng/ml to 3.16 ng/ml, p = 0.047) and 74% (from 98.6 ng/ml to 171.1 ng/ml, p = 0.013); these values fall within age-matched normal ranges. In contrast, myostatin and IGF-1 serum markers did not increase in age-matched controls. Follistatin, a control marker unrelated to muscle, increased in both Pompe disease patients and control subjects. At the same time, the percentage of muscle fibers containing intracytoplasmic vacuoles decreased from 80.0±26.4% to 31.6±45.3%. The increase in myostatin and IGF-1 levels in Pompe disease patients may reflect muscle regeneration after ERT. The role of these molecules as potential therapeutic biomarkers in Pompe disease and other neuromuscular diseases warrants further study.

  10. Production of functional human insulin-like growth factor binding proteins (IGFBPs) using recombinant expression in HEK293 cells

    DEFF Research Database (Denmark)

    Wanscher, Anne Sofie Molsted; Williamson, Michael; Ebersole, Tasja Wainani

    2015-01-01

    Insulin-like growth factor binding proteins (IGFBPs) display many functions in humans including regulation of the insulin-like growth factor (IGF) signaling pathway. The various roles of human IGFBPs make them attractive protein candidates in drug discovery. Structural and functional knowledge...... on human proteins with therapeutic relevance is needed to design and process the next generation of protein therapeutics. In order to conduct structural and functional investigations large quantities of recombinant proteins are needed. However, finding a suitable recombinant production system for proteins...... such as full-length human IGFBPs, still remains a challenge. Here we present a mammalian HEK293 expression method suitable for over-expression of secretory full-length human IGFBP-1 to -7. Protein purification of full-length human IGFBP-1, -2, -3 and -5 was conducted using a two-step chromatography procedure...

  11. INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR INHIBITOR, AMG-479, IN CETUXIMAB-REFRACTORY HEAD AND NECK SQUAMOUS CELL CARCINOMA

    Science.gov (United States)

    Pohlmann, Paula R.; Rothenberg, Mace L.; Burkey, Brian B.; Parker, Joel; Palka, Kevin; Aulino, Joseph; Puzanov, Igor; Murphy, Barbara

    2011-01-01

    Background Recurrent head and neck squamous cell carcinoma (HNSCC) remains a difficult cancer to treat. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents, cetuximab, and AMG-479 (monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]). Methods The clinical information was collected by a retrospective medical record review under an Institutional Review Board–approved protocol. From 4 tumors and 2 normal mucosal epithelia, global gene expression, and IGF-1R and dihydrofolate reductase (DHFR) protein levels were determined. Results Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with AMG-479. Decreased level of DHFR and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed. Conclusion This suggests that the combination of AMG- 479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC. PMID:20652976

  12. Prediction of the outcome of growth hormone provocative testing in short children by measurement of serum levels of insulin-like growth factor I and insulin-like growth factor binding protein 3

    DEFF Research Database (Denmark)

    Juul, A; Skakkebaek, N E

    1997-01-01

    Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) reflect the secretion of endogenous growth hormone (GH) in healthy children and exhibit little diurnal variation, which makes them potential candidates for screening of GH deficiency (GHD...... the positive predictive value and in 10- to 20-year-old children was 52.3% for IGF-I and 56.5% for IGFBP-3. Combination use of IGF-I and IGFBP-3 gave additional diagnostic information. We conclude that a subnormal IGF-I level, and especially a subnormal IGFBP-3 level, are highly predictive of a subnormal GH......). We evaluated serum IGF-I and IGFBP-3 levels in relation to the outcome of GH provocative testing in 203 children and adolescents (111 boys and 92 girls) in whom GHD was suspected. A total of 1030 children served as control subjects. In children less than 10 years of age, IGF-I levels were below...

  13. Prediction of the outcome of growth hormone provocative testing in short children by measurement of serum levels of insulin-like growth factor I and insulin-like growth factor binding protein 3

    DEFF Research Database (Denmark)

    Juul, A; Skakkebaek, N E

    1997-01-01

    Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) reflect the secretion of endogenous growth hormone (GH) in healthy children and exhibit little diurnal variation, which makes them potential candidates for screening of GH deficiency (GHD......). We evaluated serum IGF-I and IGFBP-3 levels in relation to the outcome of GH provocative testing in 203 children and adolescents (111 boys and 92 girls) in whom GHD was suspected. A total of 1030 children served as control subjects. In children less than 10 years of age, IGF-I levels were below...... the cutoff limit in 8 of 15 children with GHD (sensitivity 53.3%) and above the cutoff limit in 47 of 48 children with a normal GH response (specificity 97.9%). Similarly, IGFBP-3 levels were below the cutoff limit in 9 of 15 children with GHD (sensitivity 60%) and above the cutoff limit in 47 of 48 children...

  14. The insulin-like growth factors I and II stimulate proliferation of different types of Schwann cells

    DEFF Research Database (Denmark)

    Sondell, M; Svenningsen, Åsa Fex; Kanje, M

    1997-01-01

    A combination of immunocytochemistry for glial specific antigens and bromodeoxyuridine (BrdU) and teasing was used to identify proliferating cells in cultured rat sciatic nerve segments. The nerve segments were exposed to insulin, or the insulin-like growth factors IGF-I and IGF-II. Teasing in co......, truncated IGF-I promoted proliferation of Schwann cells of myelinated nerve fibres while insulin increased proliferation of both cell types....

  15. The effects of testosterone and insulin-like growth factor 1 on motor system form and function

    OpenAIRE

    Oki, Kentaro; Law, Timothy D.; Loucks, Anne B.; Clark, Brian C.

    2015-01-01

    In this perspective article, we review the effects of selected anabolic hormones on the motoric system and speculate on the role these hormones may have on influencing muscle and physical function via their impact on the nervous system. Both muscle strength and anabolic hormone levels decline around middle age into old age over a similar time period, and several animal and human studies indicate that exogenously increasing anabolic hormones (e.g., testosterone and insulin-like growth factor-1...

  16. Insulin-like growth factor 1 (IGF-1 enhances the protein expression of CFTR.

    Directory of Open Access Journals (Sweden)

    Ha Won Lee

    Full Text Available Low levels of insulin-like growth factor 1 (IGF-1 have been observed in the serum of cystic fibrosis (CF patients. However, the effects of low serum IGF-1 on the cystic fibrosis transmembrane conductance regulator (CFTR, whose defective function is the primary cause of cystic fibrosis, have not been studied. Here, we show in human cells that IGF-1 increases the steady-state levels of mature wildtype CFTR in a CFTR-associated ligand (CAL- and TC10-dependent manner; moreover, IGF-1 increases CFTR-mediated chloride transport. Using an acceptor photobleaching fluorescence resonance energy transfer (FRET assay, we have confirmed the binding of CAL and CFTR in the Golgi. We also show that CAL overexpression inhibits forskolin-induced increases in the cell-surface expression of CFTR. We found that IGF-1 activates TC10, and active TC10 alters the functional association between CAL and CFTR. Furthermore, IGF-1 and active TC10 can reverse the CAL-mediated reduction in the cell-surface expression of CFTR. IGF-1 does not increase the expression of ΔF508 CFTR, whose processing is arrested in the ER. This finding is consistent with our observation that IGF-1 alters the functional interaction of CAL and CFTR in the Golgi. However, when ΔF508 CFTR is rescued with low temperature or the corrector VRT-325 and proceeds to the Golgi, IGF-1 can increase the expression of the rescued ΔF508 CFTR. Our data support a model indicating that CAL-CFTR binding in the Golgi inhibits CFTR trafficking to the cell surface, leading CFTR to the degradation pathway instead. IGF-1-activated TC10 changes the interaction of CFTR and CAL, allowing CFTR to progress to the plasma membrane. These findings offer a potential strategy using a combinational treatment of IGF-1 and correctors to increase the post-Golgi expression of CFTR in cystic fibrosis patients bearing the ΔF508 mutation.

  17. Growth hormone and insulin-like growth factor-1 in acute myocardial infarction

    DEFF Research Database (Denmark)

    Friberg, L; Werner, S; Eggertsen, G

    2000-01-01

    Growth hormone therapy after myocardial infarction improves cardiac function and survival in animals. Beneficial effects in humans are reported from studies where patients with idiopathic dilated cardiomyopathy were treated with growth hormone. We have studied the role of the endogenous growth...... hormone system in myocardial infarction....

  18. Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.

    Science.gov (United States)

    Horne, Hisani N; Sherman, Mark E; Pfeiffer, Ruth M; Figueroa, Jonine D; Khodr, Zeina G; Falk, Roni T; Pollak, Michael; Patel, Deesha A; Palakal, Maya M; Linville, Laura; Papathomas, Daphne; Geller, Berta; Vacek, Pamela M; Weaver, Donald L; Chicoine, Rachael; Shepherd, John; Mahmoudzadeh, Amir Pasha; Wang, Jeff; Fan, Bo; Malkov, Serghei; Herschorn, Sally; Hewitt, Stephen M; Brinton, Louise A; Gierach, Gretchen L

    2016-02-18

    Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. These results suggest that elevated IGF levels may define a sub-group of

  19. Growth factors II: insuline-like growth binging proteins (GFBPs Factores de crecimiento II: factores insulinoides de crecimiento

    Directory of Open Access Journals (Sweden)

    Hilda Norha Jaramillo Londoño

    1996-03-01

    Full Text Available This review summarizes recent knowledge concerning Insulin.like growth factors I and II, with emphasis on their biochemical structure, concentrations, binding proteins, receptors, mechanisms of action, biological effects, and alterations of their concentrations in biological fluids. Se revisan los Factores Insulinoides de Crecimiento, también denominados ";Factores de Crecimiento Similares a la Insulina";, sobre los cuales se dispone de abundante información. Se sintetizan conocimientos recientes sobre dichos factores con énfasis en los siguientes aspectos: estructura bioquímica, concentraciones y sus cambios en los líquidos biológicos, proteínas fijadoras, receptores, mecanismos de acción y efectos biológicos.

  20. Immunohistochemical expression of Insulin-like growth factor-1, Transforming growth factor-beta1, and Vascular endothelial growth factor in parathyroid adenoma and hyperplasia

    OpenAIRE

    Hamide Sayar; Murat Sahin; Perihan Ozlem Dogan; Sefika Karabulut; Nurten Seringec; Ayten Oguz

    2014-01-01

    Background: Insulin-like growth factor (IGF), transforming growth factor-beta1 (TGF-β1), and vascular endothelial growth factor (VEGF) are commonly studied growth factors, but little data are available on the immunohistochemical expression of these factors in parathyroid lesions. Materials and Methods: Tissue specimens from 36 patients with primary hyperparathyroidism (P-HPT) (26 adenomas and 10 primary hyperplasias) were examined. Normal parathyroid tissue adjacent to the adenoma or area of ...

  1. Intrauterine Growth Retardation (IUGR) as a Novel Condition of Insulin-Like Growth Factor-1 (IGF-1) Deficiency.

    Science.gov (United States)

    Martín-Estal, I; de la Garza, R G; Castilla-Cortázar, I

    2016-01-01

    Insulin-like growth factor 1 (IGF-1) is an anabolic hormone with several biological activities, such as proliferation, mitochondrial protection, cell survival, tissue growth and development, anti-inflammatory, antioxidant, antifibrogenic and antiaging. This hormone plays an important role in embryological and postnatal states, being essential for normal foetal and placental growth and differentiation. During gestation, the placenta is one of the major sources of IGF-1, among other hormones. This intrauterine organ expresses IGF-1 receptors and IGF-1 binding proteins (IGFBPs), which control IGF-1 activities. Intrauterine growth restriction (IUGR) is the second most frequent cause of perinatal morbidity and mortality, defined as the inability to achieve the expected weight for gestational age. Different studies have revealed that IUGR infants have placental dysfunction and low circulating levels of insulin, IGF-1, IGF-2 and IGFBPs. Such data suggest that IGF-1 deficiency in gestational state may be one of the major causes of foetal growth retardation. The aim of this review is to study the epidemiology, physiopathology and possible causes of IUGR. Also, it intends to study the possible role of the placenta as an IGF-1 target organ. The purpose is to establish if IUGR could be considered as a novel condition of IGF-1 deficiency and if its treatment with low doses of IGF-1 could be a suitable therapeutic strategy.

  2. An insulin-like growth factor in Rhodnius prolixus is involved in post-feeding nutrient balance and growth.

    Directory of Open Access Journals (Sweden)

    Marina Schumacher Defferrari

    2016-12-01

    Full Text Available Growth of organisms is modulated by the availability of nutrients and energy, and is mostly regulated by insulin-like growth factors (IGFs through the insulin signaling system. In insects, IGFs produced by the fat body induce cell division during the molt cycle, regulate adult body size and have metabolic effects. Here we describe an IGF from the hematophagous hemipteran Rhodnius prolixus and show its activity in regulating growth and metabolism in the post-feeding period during the fifth, and last, nymphal instar. Rhopr-IGF transcript is present in a variety of tissues, with greatest expression in the fat body, the dorsal vessel and the CNS. We silenced the expression of the transcript using RNA interference, and at two weeks after feeding, insects with reduced Rhopr-IGF expression showed increased hemolymph lipid and carbohydrate levels when compared to controls, but no differences were observed in fat body lipid or carbohydrate content. In order to assess the role of Rhopr-IGF in post-feeding growth, double stranded IGF-injected insects were followed through ecdysis, and this treatment resulted in shorter adults, with shorter and narrower wings, when compared to controls. The results suggest that Rhopr-IGF modulates growth in R. prolixus most likely through altering the usage of nutrients that are available in the hemolymph.

  3. Insulin-Like Growth Factor (IGF-I and Insulin in Normal and Growth-Restricted Mother/Infant Pairs

    Directory of Open Access Journals (Sweden)

    Ariadne Malamitsi-Puchner

    2007-01-01

    Full Text Available Insulin-like growth factor (IGF-I and insulin are essential for fetal growth. We investigated perinatal changes of both factors in 40 mothers and their 20 appropriate-for-gestational-age (AGA and 20 intrauterine-growth-restricted (IUGR fetuses and neonates on day 1 (N1 and day 4 (N4 postpartum. Fetal and N1, but not N4, IGF-I levels were increased in AGA (P<.001 and P=.037, resp.. N1 insulin levels were lower in IUGR (P=.048. Maternal, fetal, and N1 IGF-I, and fetal insulin levels positively correlated with customized centiles (r=.374, P=.035, r=.608, P<.001, r=.485, P=.006, and r=.654, P=.021, resp.. Female infants presented elevated fetal and N4 IGF-I levels (P=.023 and P=.016, resp.. Positive correlations of maternal, fetal, and neonatal IGF-I levels, and fetal insulin levels with customized centiles underline implication of both hormones in fetal growth. IUGR infants present gradually increasing IGF-I levels. Higher IGF-I levels are documented in females.

  4. Effects of basic fibroblast growth factor and insulin-like growth factor on cultured cartilage cells from skate Raja porasa

    Science.gov (United States)

    Fan, Tingjun; Jin, Lingyun; Wang, Xiaofeng

    2003-12-01

    Effects of basic fibroblast growth factor (bFGF) and insulin-like growth factor II (IGF-II) on cartilage cells from proboscis of skate, Raja porasa Günther, were investigated in this study. The cartilage cells were cultured in 20% FBS-supplemented MEM medium at 24°C. Twelve hours after culture initiation, the cartilage cells were treated with bFGF and IGF-II at different concentration combinations. It was found that 20 ng/ml of bFGF or 80 ng/ml of IGF-II was enough to have obvious stimulating effect on the growth and division of skate cartilage cells. Test of bFGF and IGF-II together, revealed that 20 ng/ml of bFGF and 80 ng/ml of IGF-II together had the best stimulating effect on the growth and division of skate cartilage cells. The cartilage cells cultured could form a monolayer at day 7.

  5. Klotho and the Growth Hormone/Insulin-Like Growth Factor 1 Axis: Novel Insights into Complex Interactions.

    Science.gov (United States)

    Rubinek, T; Modan-Moses, D

    2016-01-01

    The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is pivotal for many metabolic functions, including proper development and growth of bones, skeletal muscles, and adipose tissue. Defects in the axis' activity during childhood result in growth abnormalities, while increased secretion of GH from the pituitary results in acromegaly. In order to keep narrow physiologic concentration, GH and IGF-1 secretion and activity are tightly regulated by hypothalamic, pituitary, endocrine, paracrine, and autocrine factors. Klotho was first discovered as an aging-suppressor gene. Mice that do not express klotho die prematurely with multiple symptoms of aging, several of them are also characteristic of decreased GH/IGF-1 axis activity. Klotho is highly expressed in the brain, the kidney, and parathyroid and pituitary glands, but can also serve as a circulating hormone by its shedding, forming soluble klotho that can be detected in blood, cerebrospinal fluid, and urine. Several lines of evidence suggest an association between klotho levels and activity of the GH/IGF-1 axis: the GH-secreting cells in the anterior pituitary of klotho-deficient mice are hypotrophic; klotho levels are altered in subjects with pathologies of the GH/IGF-1 axis; and accumulating data indicate that klotho is a direct regulator of GH secretion. Thus, klotho seems to be a new player in the intricate regulation of the GH/IGF-1 axis. © 2016 Elsevier Inc. All rights reserved.

  6. SUMO-modified insulin-like growth factor 1 receptor (IGF-1R) increases cell cycle progression and cell proliferation.

    Science.gov (United States)

    Lin, Yingbo; Liu, Hongyu; Waraky, Ahmed; Haglund, Felix; Agarwal, Prasoon; Jernberg-Wiklund, Helena; Warsito, Dudi; Larsson, Olle

    2017-10-01

    Increasing number of studies have shown nuclear localization of the insulin-like growth factor 1 receptor (nIGF-1R) in tumor cells and its links to adverse clinical outcome in various cancers. Any obvious cell physiological roles of nIGF-1R have, however, still not been disclosed. Previously, we reported that IGF-1R translocates to cell nucleus and modulates gene expression by binding to enhancers, provided that the receptor is SUMOylated. In this study, we constructed stable transfectants of wild type IGF1R (WT) and triple-SUMO-site-mutated IGF1R (TSM) using igf1r knockout mouse fibroblasts (R-). Cell clones (R-WT and R-TSM) expressing equal amounts of IGF-1R were selected for experiments. Phosphorylation of IGF-1R, Akt, and Erk upon IGF-1 stimulation was equal in R-WT and R-TSM. WT was confirmed to enter nuclei. TSM did also undergo nuclear translocation, although to a lesser extent. This may be explained by that TSM heterodimerizes with insulin receptor, which is known to translocate to cell nuclei. R-WT proliferated substantially faster than R-TSM, which did not differ significantly from the empty vector control. Upon IGF-1 stimulation G1-S-phase progression of R-WT increased from 12 to 38%, compared to 13 to 20% of R-TSM. The G1-S progression of R-WT correlated with increased expression of cyclin D1, A, and CDK2, as well as downregulation of p27. This suggests that SUMO-IGF-1R affects upstream mechanisms that control and coordinate expression of cell cycle regulators. Further studies to identify such SUMO-IGF-1R dependent mechanisms seem important. © 2017 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.

  7. Perspectives on concordant and discordant relations between insulin-like growth factor 1 (IGF1) and growth in fishes.

    Science.gov (United States)

    Beckman, Brian R

    2011-01-15

    Many physiological processes are modulated by the endocrine system, including growth. Insulin-like growth factor 1 is one of the primary hormones involved in growth regulation in vertebrates, including fishes. Current work on IGF1 in fishes is driven both by a desire to better understand mechanisms of growth as well as to develop a reliable index of growth rate. A review of studies relating IGF1 to growth broadly reveals positive and significant relations between IGF1 and growth; however, relations found in individual studies range from no correlation to highly significant correlations. Potential sources for this variation include both biological and methodological issues and range from differences in how growth is defined (changes in length or weight), the duration of growth assessed (weeks to months) and how growth is calculated (total change, rate, percent change); yet, these methodological concerns cannot account for all the variation found. A further review of the literature reveals a number of physiological conditions and environmental factors that might influence IGF1 level and the subsequent relation of that IGF1 level to growth rate. The term concordance is introduced to categorize factors that influence IGF1 and growth in a similar fashion, such that positive and significant relations between IGF1 and growth are maintained even though the factor stimulates changes in IGF1 level. Conversely, the term discordance is introduced to categorize factors that stimulate changes in the relations between IGF1 and growth, such that IGF1 is not an efficacious index of growth for both pre and post-stimulus fish combined. IGF1 and growth relations generally remain concordant after changes in nutrition (consumption rate or diet). Differences in IGF1 level of juvenile, maturing male and maturing female fish are common and IGF1-growth relations appear discordant between these groups. Acute changes in temperature and salinity induce discordant relations between IGF1 and

  8. Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

    Directory of Open Access Journals (Sweden)

    Ingrid van der Pluijm

    2007-01-01

    Full Text Available Cockayne syndrome (CS is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER. Here, complete inactivation of NER in Csb(m/m/Xpa(-/- mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m/Xpa(-/- mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1 somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m/Xpa(-/- and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

  9. Expression of the genes for insulin-like growth factors and their receptors in bone during skeletal growth

    Science.gov (United States)

    Bikle, D. D.; Harris, J.; Halloran, B. P.; Roberts, C. T.; Leroith, D.; Morey-Holton, E.

    1994-01-01

    Insulin-like growth factors (IGF) are important regulators of skeletal growth. To determine whether the capacity to produce and respond to these growth factors changes during skeletal development, we measured the protein and mRNA levels for IGF-I, IGF-II, and their receptors (IGF-IR and IGF-IIR, respectively) in the tibia and femur of rats before and up to 28 mo after birth. The mRNA levels remained high during fetal development but fell after birth, reaching a nadir by 3-6 wk. This fall was most pronounced for IGF-II and IGF-IIR mRNA and least pronounced for IGF-I mRNA. However, after 6 wk, both IGF-I and IGF-IR mRNA levels recovered toward the levels observed at birth. In the prenatal bones, the signals for the mRNAs of IGF-II and IGF-IIR were stronger than the signals for the mRNAs of IGF-I and IGF-IR, although the content of IGF-I was three- to fivefold greater than that of IGF-II. IGF-II levels fell postnatally, whereas the IGF-I content rose after birth such that the ratio IGF-I/IGF-II continued to increase with age. We conclude that, during development, rat bone changes its capacity to produce and respond to IGFs with a progressive trend toward the dominance of IGF-I.

  10. Regulation of REDD1 by Insulin-like Growth Factor-I in Skeletal Muscle and Myotubes

    OpenAIRE

    Frost, Robert A.; Huber, Danuta; Pruznak, Anne; Charles H Lang

    2009-01-01

    Insulin-like growth factor-I (IGF-I) is a major anabolic hormone for skeletal muscle and a potent stimulus for protein synthesis and translation initiation. Recent studies suggest that translation can be inhibited by over expression of the mammalian target of rapamycin (mTOR) repressor REDD1. The purpose of the present study was to determine whether IGF-I alters the expression of REDD1 and whether this is associated with a concomitant change in protein synthesis in vitro. Subcutaneous injecti...

  11. Differential changes in free and total insulin-like growth factor I after major, elective abdominal surgery

    DEFF Research Database (Denmark)

    Skjærbæk, Christian; Frystyk, Jan; Ørskov, Hans

    1998-01-01

    Major surgery is accompanied by extensive proteolysis of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3). Proteolysis of IGFBP-3 is generally believed to increase IGF bioavailability due to a diminished affinity of the IGFBP-3 fragments for IGFs. We have investigated 18 patients...... undergoing elective ileo-anal J-pouch surgery. Patients were randomized to treatment with GH (12 IU/day; n = 9) or placebo (n = 9) from 2 days before to 7 days after operation. Free IGF-I and IGF-II were measured by ultrafiltration of serum, and IGFBP-3 proteolytic activity was determined by a [125I...

  12. Urinary growth hormone (U-GH) excretion and serum insulin-like growth factor 1 (IGF-1) in patients with alcoholic cirrhosis

    DEFF Research Database (Denmark)

    Møller, S; Grønbaek, M; Main, K

    1993-01-01

    Basal serum growth hormone (GH) levels are elevated and insulin-like growth factor 1 (IGF-1) concentrations in serum are suppressed in patients with chronic liver disease. The aim of this study was to measure the urinary GH (U-GH) excretion and IGF-1 concentrations in patients with cirrhosis...... was significantly higher in patients than in the healthy controls (p encephalopathy (p

  13. Molecular Characterization and Expression Analysis of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-1 Genes in Qinghai-Tibet Plateau Bos grunniens and Lowland Bos taurus.

    Science.gov (United States)

    Chen, Ya-Bing; Fu, Mei; Lan, Dao-Liang; Li, Jian

    2015-01-01

    Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) play a pivotal role in regulating cellular hypoxic response. In this study, we cloned and characterized the genes encoding IGF-1 and IGFBP-1 to improve the current knowledge on their roles in highland Bos grunniens (Yak). We also compared their expression levels in the liver and kidney tissues between yaks and lowland cattle. We obtained full-length 465 bp IGF-1 and 792 bp IGFBP-1, encoding 154 amino acids (AA) IGF-1, and 263 AA IGFBP-1 protein, respectively using reverse transcriptase-polyerase chain reaction (RT-PCR) technology. Analysis of their corresponding amino acid sequences showed a high identity between B. grunniens and lowland mammals. Moreover, the two genes were proved to be widely distributed in the examined tissues through expression pattern analysis. Real-time PCR results revealed that IGF-1 expression was higher in the liver and kidney tissues in B. grunniens than in Bos taurus (ptaurus than B. grunniens, but it has a similar expression level in the kidneys of the two species. These results indicated that upregulated IGF-1 and downregulated IGFBP-1 are associated with hypoxia adaptive response in B. grunniens.

  14. Molecular Characterization and Expression Analysis of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-1 Genes in Qinghai-Tibet Plateau and Lowland

    Directory of Open Access Journals (Sweden)

    Ya-bing Chen

    2015-01-01

    Full Text Available Insulin-like growth factor-1 (IGF-1 and insulin-like growth factor binding protein-1 (IGFBP-1 play a pivotal role in regulating cellular hypoxic response. In this study, we cloned and characterized the genes encoding IGF-1 and IGFBP-1 to improve the current knowledge on their roles in highland Bos grunniens (Yak. We also compared their expression levels in the liver and kidney tissues between yaks and lowland cattle. We obtained full-length 465 bp IGF-1 and 792 bp IGFBP-1, encoding 154 amino acids (AA IGF-1, and 263 AA IGFBP-1 protein, respectively using reverse transcriptase-polyerase chain reaction (RT-PCR technology. Analysis of their corresponding amino acid sequences showed a high identity between B. grunniens and lowland mammals. Moreover, the two genes were proved to be widely distributed in the examined tissues through expression pattern analysis. Real-time PCR results revealed that IGF-1 expression was higher in the liver and kidney tissues in B. grunniens than in Bos taurus (p<0.05. The IGFBP-1 gene was expressed at a higher level in the liver (p<0.05 of B. taurus than B. grunniens, but it has a similar expression level in the kidneys of the two species. These results indicated that upregulated IGF-1 and downregulated IGFBP-1 are associated with hypoxia adaptive response in B. grunniens.

  15. Physical capacity influences the response of insulin-like growth factor and its binding proteins to training

    DEFF Research Database (Denmark)

    Rosendal, Lars; Langberg, Henning; Flyvbjerg, Allan

    2002-01-01

    The influence of initial training status on the response of circulating insulin-like growth factor (IGF) and its binding proteins (IGFBP) to prolonged physical training was studied in young men. It was hypothesized that highly standardized training would result in more extensive changes in the ci......The influence of initial training status on the response of circulating insulin-like growth factor (IGF) and its binding proteins (IGFBP) to prolonged physical training was studied in young men. It was hypothesized that highly standardized training would result in more extensive changes...... in the circulating IGF system in untrained subjects because of lower fitness level. Seven untrained (UT) and 12 well-trained (WT) individuals performed 11 wk of intense physical training (2-4 h daily). Fasting serum samples were analyzed for total and free IGF-I and -II, for IGFBP-1 to -4, as well as for IGFBP-3...... proteolysis. Eleven weeks of physical training resulted in decreased levels of total IGF-I, free IGF-I, and IGFBP-4 in both the UT and WT groups. In the UT group, IGFBP-2 increased, IGFBP-3 decreased [from 4,255 +/- 410 (baseline) to 3,896 +/- 465 (SD) microg/l (week 4); P

  16. Insulin-like growth factor 2 enhances regulatory T-cell functions and suppresses food allergy in an experimental model.

    Science.gov (United States)

    Yang, Gui; Geng, Xiao-Rui; Song, Jiang-Ping; Wu, Yingying; Yan, Hao; Zhan, Zhengke; Yang, Litao; He, Weiyi; Liu, Zhi-Qiang; Qiu, Shuqi; Liu, Zhigang; Yang, Ping-Chang

    2014-06-01

    The functions of regulatory T (Treg) cells are important in immunity, and the regulatory mechanisms of Treg cell activities are not fully understood yet. We sought to investigate the role of insulin-like growth factor (IGF) 2 in the upregulation of Treg cell function. The expression of insulin-like growth factor 2 receptor (IGF2R) on T cells was assessed by using flow cytometry. Treg cell functions were evaluated by assessing the suppressor effect on proliferation of other effector T (Teff) cells. The effect of IGF2 on regulating Treg cell functions were evaluated with a cell-culture model and a food allergy mouse model. Expression of IGF2R was observed in more than 90% of murine and human Treg cells but in less than 10% of effector CD4(+) T cells. Activation of IGF2R and T-cell receptor induced marked Treg cell proliferation and release of TGF-β from Treg cells, which enhanced Treg cell immune suppressor effects on other Teff cell activities and allergic inflammation in the intestine. Activation of IGF2R enhances Treg cell functions in suppressing other Teff cell activities and inhibiting allergic inflammation in the intestine. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  17. Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways.

    Directory of Open Access Journals (Sweden)

    Yujiro Hayashi

    Full Text Available Stem cell factor (mouse: Kitl, human: KITLG and insulin-like growth factor-1 (IGF1, acting via KIT and IGF1 receptor (IGF1R, respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST, the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC, the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2, a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i. GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes.

  18. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development

    DEFF Research Database (Denmark)

    Nielsen, J; Christiansen, J; Lykke-Andersen, J

    1999-01-01

    Insulin-like growth factor II (IGF-II) is a major fetal growth factor. The IGF-II gene generates multiple mRNAs with different 5' untranslated regions (5' UTRs) that are translated in a differential manner during development. We have identified a human family of three IGF-II mRNA-binding proteins...... and are homologous to the Xenopus Vera and chicken zipcode-binding proteins. IMP localizes to subcytoplasmic domains in a growth-dependent and cell-specific manner and causes a dose-dependent translational repression of IGF-II leader 3 -luciferase mRNA. Mouse IMPs are produced in a burst at embryonic day 12...

  19. Acromegaly with Normal Insulin-Like Growth Factor-1 Levels and Congestive Heart Failure as the First Clinical Manifestation

    Directory of Open Access Journals (Sweden)

    Hyae Min Lee

    2015-09-01

    Full Text Available The leading cause of morbidity and mortality in patients with acromegaly is cardiovascular complications. Myocardial exposure to excessive growth hormone can cause ventricular hypertrophy, hypertension, arrhythmia, and diastolic dysfunction. However, congestive heart failure as a result of systolic dysfunction is observed only rarely in patients with acromegaly. Most cases of acromegaly exhibit high levels of serum insulin-like growth factor-1 (IGF-1. Acromegaly with normal IGF-1 levels is rare and difficult to diagnose. Here, we report a rare case of an acromegalic patient whose first clinical manifestation was severe congestive heart failure, despite normal IGF-1 levels. We diagnosed acromegaly using a glucose-loading growth hormone suppression test. Cardiac function and myocardial hypertrophy improved 6 months after transsphenoidal resection of a pituitary adenoma.

  20. The stimulatory effect of growth hormone, prolactin, and placental lactogen on beta-cell proliferation is not mediated by insulin-like growth factor-I

    DEFF Research Database (Denmark)

    Billestrup, N; Nielsen, Jens Høiriis

    1991-01-01

    The effects of GH, PRL, and placental lactogen (PL) on the proliferation of pancreatic beta-cells in vitro were studied as well as the possible effect of insulin-like growth factor-I (IGF-I) in mediating this effect. Proliferating beta-cells were identified by staining with a monoclonal antibody ...

  1. Commercial assays available for insulin-like growth factor I and their use in diagnosing growth hormone deficiency.

    Science.gov (United States)

    Clemmons, D R

    2001-01-01

    Radioimmunoassays of insulin-like growth factor I (IGF-I) are commonly used for screening adults and children for growth hormone (GH) deficiency or excess. There are, however, many problems with such assays. Attempts to resolve these problems have focused on methods of separating IGF-I from its binding proteins, and on reducing inter- and intra-assay variability. In particular, the collection of sufficient high-quality normative data is a major difficulty in many laboratories. Clinical evaluation of assays is also problematic. IGF-I levels vary with age after puberty, and this is complicated by the maintenance of IGF-binding protein 3 levels by IGF-II. Generally, studies have shown that IGF-I is sensitive and specific for the diagnosis of acromegaly, but screening for GH deficiency (GHD) is less precise. The most commonly used commercial assays are immunoradiometric (IRMA) sandwich assays, using antibodies specific to IGF-I. IRMA assays are quick and accurate, and the two-site antibody reactivity produces a high degree of specificity. Additional techniques such as acid-ethanol extraction or saturation with IGF-II can improve reliability. More recently, the introduction of chemiluminescence has provided enhanced speed and sensitivity. The clinical use of these assays has provided a wealth of information regarding the diagnosis of GHD, and it may be possible to reduce the number of patients who require provocative GH testing. IGF-I assays are also of great use in monitoring GH replacement therapy. Despite the problems, IGF-I measurement is currently the best indirect method available for screening and monitoring patients with GHD. Copyright 2001 S. Karger AG, Basel

  2. Insulin-Like Growth Factor 1 and Related Compounds in the Treatment of Childhood-Onset Neurodevelopmental Disorders

    Directory of Open Access Journals (Sweden)

    Cyrus Vahdatpour

    2016-09-01

    Full Text Available Insulin-Like Growth Factor 1 (IGF-1 is a neurotrophic polypeptide with crucial roles to play in Central Nervous System (CNS growth, development and maturation. Following interrogation of the neurobiology underlying several neurodevelopmental disorders and Autism Spectrum Disorders (ASD, both recombinant IGF-1 (mecasermin and related derivatives, such as (1-3 IGF-1, have emerged as potential therapeutic approaches. Clinical pilot studies and early reports have supported the safety/preliminary efficacy of IGF-1 and related compounds in the treatment of Rett Syndrome, with evidence mounting for its use in Phelan McDermid Syndrome and Fragile X Syndrome. In broader ASD, clinical trials are ongoing. Here, we review the role of IGF-1 in the molecular etiologies of these conditions in addition to the accumulating evidence from early clinical studies highlighting the possibility of IGF-1 and related compounds as potential treatments for these childhood-onset neurodevelopmental disorders.

  3. Associations of serum insulin-like growth factor-I and insulin-like growth factor-binding protein 3 levels with biomarker-calibrated protein, dairy product and milk intake in the Women's Health Initiative.

    Science.gov (United States)

    Beasley, Jeannette M; Gunter, Marc J; LaCroix, Andrea Z; Prentice, Ross L; Neuhouser, Marian L; Tinker, Lesley F; Vitolins, Mara Z; Strickler, Howard D

    2014-03-14

    It is well established that protein-energy malnutrition decreases serum insulin-like growth factor (IGF)-I levels, and supplementation of 30 g of whey protein daily has been shown to increase serum IGF-I levels by 8 % after 2 years in a clinical trial. Cohort studies provide the opportunity to assess associations between dietary protein intake and IGF axis protein levels under more typical eating conditions. In the present study, we assessed the associations of circulating IGF axis protein levels (ELISA, Diagnostic Systems Laboratories) with total biomarker-calibrated protein intake, as well as with dairy product and milk intake, among postmenopausal women enrolled in the Women's Health Initiative (n 747). Analyses were carried out using multivariate linear regression models that adjusted for age, BMI, race/ethnicity, education, biomarker-calibrated energy intake, alcohol intake, smoking, physical activity and hormone therapy use. There was a positive association between milk intake and free IGF-I levels. A three-serving increase in milk intake per d (approximately 30 g of protein) was associated with an estimated average 18·6 % higher increase in free IGF-I levels (95 % CI 0·9, 39·3 %). However, total IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were not associated with milk consumption and nor were there associations between biomarker-calibrated protein intake, biomarker-calibrated energy intake, and free IGF-I, total IGF-I or IGFBP-3 levels. The findings of the present study carried out in postmenopausal women are consistent with clinical trial data suggesting a specific relationship between milk consumption and serum IGF-I levels, although in the present study this association was only statistically significant for free, but not total, IGF-I or IGFBP-3 levels.

  4. Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups.

    Science.gov (United States)

    Sveinsdóttir, Kristbjörg; Länsberg, John-Kalle; Sveinsdóttir, Snjólaug; Garwicz, Martin; Ohlsson, Lennart; Hellström, Ann; Smith, Lois; Gram, Magnus; Ley, David

    2017-10-04

    Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r2 = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased

  5. Cow milk consumption, insulin-like growth factor-I, and human biology: a life history approach.

    Science.gov (United States)

    Wiley, Andrea S

    2012-01-01

    To assess the life history consequences of cow milk consumption at different stages in early life (prenatal to adolescence), especially with regard to linear growth and age at menarche and the role of insulin-like growth factor I (IGF-I) in mediating a relationship among milk, growth and development, and long-term biological outcomes. United States National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 and review of existing literature. The literature tends to support milk's role in enhancing growth early in life (prior to age 5 years), but there is less support for this relationship during middle childhood. Milk has been associated with early menarche and with acceleration of linear growth in adolescence. NHANES data show a positive relationship between milk intake and linear growth in early childhood and adolescence, but not middle childhood, a period of relatively slow growth. IGF-I is a candidate bioactive molecule linking milk consumption to more rapid growth and development, although the mechanism by which it may exert such effects is unknown. Routine milk consumption is an evolutionarily novel dietary behavior that has the potential to alter human life history parameters, especially vis-à-vis linear growth, which in turn may have negative long-term biological consequences. Copyright © 2011 Wiley Periodicals, Inc.

  6. An investigation of fetal, postnatal and childhood growth with insulin-like growth factor I and binding protein 3 in adulthood.

    Science.gov (United States)

    Ben-Shlomo, Y; Holly, J; McCarthy, A; Savage, P; Davies, D; Gunnell, D; Davey Smith, G

    2003-09-01

    Weight at birth and adult height are positively associated with cancer risk. These patterns may be mediated by the insulin-like growth factor (IGF) axis. We have examined whether pre- and postnatal growth patterns have a long-term influence on adult IGF-I and IGFBP-3 levels. A follow-up study of a randomized controlled trial of milk supplementation in pregnancy and childhood. A total of 951 individuals took part in a study of diet and growth in South Wales between 1972 and 1974 followed up from birth until their mid-20s. Anthopometric measures at birth, postnatally up to 5 years of age and in adulthood, and serum measures of IGF-I and IGF-I to IGFBP-3 ratio at mean age of 25 years. A total of 63 subjects (70%) provided blood for analysis. We found no association between birth dimensions and adult IGF-I. Subjects who exhibited 'catch-down growth' had lower IGF-I levels (P-value for trend 0.02). Adult height was positively related to IGF-I, for every one standard deviation increase in adult height, IGF-I increased by 3.75 ng/dl (95% CI 0.46-7.08, P = 0.03). Adiposity was inversely associated with the IGF-I and IGF-I to IGFBP-3 ratio and positively associated with IGFBP-3. The strength of the associations increased with age. Downward centile crossing at any time in childhood was associated with lower IGF-I whilst the highest levels were observed in subjects who were tall throughout their early life course. Adult height remained a significant predictor of IGF-I even after adjustment for earlier growth. Our results indicate that IGF-I levels in early adulthood are associated with patterns of childhood growth as well as adult stature and adiposity. These associations suggest the IGFs may contribute to anthropometric associations with cancer risk.

  7. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Kythreotis, Prokopis; Kokkini, Ageliki; Avgeropoulou, Stavrina; Hadjioannou, Argyro; Anastasakou, Efgenia; Rasidakis, Antonis; Bakakos, Petros

    2009-04-05

    Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-alpha). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation. We measured serum leptin, IGF-I, TNF-alpha, interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema). Serum leptin and IGF-I were measured by radioimmunoassay and TNF-alpha, IL-1 beta, IL-6 and IL-8 were measured by ELISA. Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p leptin and TNF-alpha on Day 1 (r = 0.620, p leptin levels along with decreased IGF-I levels occurred during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.

  8. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Rasidakis Antonis

    2009-04-01

    Full Text Available Abstract Background Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α. Insulin-like growth factor I (IGF-I mediates the metabolic effects of growth hormone (GH. The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD. The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I levels and furthermore, whether these changes are related to systemic inflammation. Methods We measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β, interleukin 6 (IL-6 and interleukin 8 (IL-8 levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1 and two weeks later (Day 15. 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema. Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA. Results Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p Conclusion Inappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.

  9. Determination of free insulin-like growth factor-I in human serum: comparison of ultrafiltration and direct immunoradiometric assay

    DEFF Research Database (Denmark)

    Frystyk, J; Ivarsen, P; Støving, R K

    2001-01-01

    Two fundamentally different methods are currently used for the determination of free insulin-like growth factor-I (IGF-I): ultrafiltration by centrifugation (UF) and direct immunoradiometric assay (IRMA). The aim was to evaluate a commercial IRMA (DSL, Webster, TX, USA) and to compare it with UF....... In the IRMA it is recommended that samples be incubated for 2 h at 5;C. When comparing samples (n = 8) incubated for 1 and 2 h, levels increased by 27 +/- 5% (Psamples at 22;C instead of 5;C, levels increased by 192 +/- 32% (P....0001). Similarly, women with anorexia nervosa (n = 9) studied before and after weight gain showed significant changes in ultrafiltered free IGF-I only (Psample incubation and this may bias results. IRMA generally yielded higher levels...

  10. Effects of insulin-like growth factor 1 on pathologic processes in the cuprizone model of multiple sclerosis

    Science.gov (United States)

    Fedorishin, D.; Sorokina, I.; Tolstikova, T.; Akulov, A.; Glazacheva, V.; Nemirovich-Danchenko, N.; Khodanovich, M.; Yarnykh, V.

    2017-08-01

    The study aims to evaluate the effect of insulin-like growth factor 1 (IGF-1) on the demyelination and astrogliosis using the cuprizone murine model. Demyelination was induced in 14 adult male mice by 0.3% cuprizone in drinking water. Five animals from the cuprizone-treated group received subcutaneous injections of IGF-1. Seven animals were used as a control group. The extent of demyelination was evaluated as a decrease in the size of the corpus callosum on T2-weighted images that were received using an 11.7T animal MRI scanner. Brain sections were immunohistochemically stained for glial fibrillary acidic protein (GFAP), a marker of astrocytes. It was revealed that the cuprizone caused extensive demyelination and astroglyosis. IGF-1 treatment restored the size of the corpus callosum and the number of astrocytes in the corpus callosum and the anterior commissure to the control level.

  11. Intrathecal insulin-like growth factor 1 but not insulin enhances myelin repair in young and aged rats.

    Science.gov (United States)

    Hlavica, Martin; Delparente, Aro; Good, Andrin; Good, Nicolas; Plattner, Patricia S; Seyedsadr, Maryam S; Schwab, Martin E; Figlewicz, Dianne P; Ineichen, Benjamin V

    2017-05-01

    One main pathological hallmark of multiple sclerosis (MS) is demyelination. Novel therapies which enhance myelin repair are urgently needed. Insulin and insulin-like growth factor 1 (IGF-1) have strong functional relationships. Here, we addressed the potential capacity of IGF-1 and insulin to enhance remyelination in an animal demyelination model in vivo. We found that chronic intrathecal infusion of IGF-1 enhanced remyelination after lysolecithin-induced demyelination in the spinal cord of young and aged rats. Aged rats showed a weaker innate remyelination capacity and are therefore a good model for progressive MS which is defined by chronic demyelination. In contrast to IGF-1, Insulin had no effect on remyelination in either age group. Our findings highlight the potential use of IGF-1 as remyelinating therapy for MS, particularly the progressive stage in which chronic demyelination is the hallmark. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Dwarfism and impaired gut development in insulin-like growth factor II mRNA-binding protein 1-deficient mice

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Hammer, Niels A; Nielsen, Jacob

    2004-01-01

    and twisted colon crypts. Analysis of target mRNAs and global expression profiling at E12.5 indicated that Igf2 translation was downregulated, whereas the postnatal intestine showed reduced expression of transcripts encoding extracellular matrix components, such as galectin- 1, lumican, tenascin......Insulin-like growth factor II mRNA-binding protein 1 (IMP1) belongs to a family of RNA-binding proteins implicated in mRNA localization, turnover, and translational control. Mouse IMP1 is expressed during early development, and an increase in expression occurs around embryonic day 12.5 (E12....... Moreover, Imp1(-/-) mice exhibited high perinatal mortality, and only 50% were alive 3 days after birth. In contrast to most other organs, intestinal epithelial cells continue to express IMP1 postnatally, and Imp1(-/-) mice exhibited impaired development of the intestine, with small and misshapen villi...

  13. Dexamethasone effects on creatine kinase activity and insulin-like growth factor receptors in cultured muscle cells

    Science.gov (United States)

    Whitson, Peggy A.; Stuart, Charles A.; Huls, M. H.; Sams, Clarence F.; Cintron, Nitza M.

    1989-01-01

    The effect of dexamethasone on the activity of creatine kinase (CK) and the insulin-like growth factor I (IGF-I) binding were investigated using skeletal- and cardiac-muscle-derived cultured cell lines (mouse, C2C12; rat, L6 and H9c2). It was found that, in skeletal muscle cells, dexamethasone treatment during differentiation of skeletal-muscle cells caused dose-dependent increases in CK activity and increases in the degree of myotube formation, whereas cardiac cells (H9c2) exhibited very low CK activity during culture or dexamethasone treatment. Results for IGF-I binding were similar in all three cell lines. The IGF-I binding to dexamethasone-treated cells (50 nM for 24 hr on the day prior to confluence) resulted in an increased number of available binding sites, with no effect on the binding affinities.

  14. Increase in tendon protein synthesis in response to insulin-like growth factor-I is preserved in elderly men

    DEFF Research Database (Denmark)

    Nielsen, Rie Harboe; Holm, Lars; Malmgaard-Clausen, Nikolaj Mølkjær

    2014-01-01

    Insulin-like growth factor-I (IGF-I) is known to be an anabolic factor in tendon, and the systemic levels are reduced with aging. However, it is uncertain how tendon fibroblasts are involved in tendon aging and how aging cells respond to IGF-I. The purpose of this study was to investigate...... the in vivo IGF-I stimulation of tendon protein synthesis in elderly compared with young men. We injected IGF-I in the patellar tendons of young (n = 11, 20-30 yr of age) and old (n = 11, 66-75 yr of age) men, and the acute fractional synthesis rate (FSR) of tendon protein was measured with the stable isotope......, despite lower systemic IGF-I levels in the old group. This could indicate that the changed phenotype in aging tendon is not caused by decreased fibroblast function....

  15. Insulin and insulin-like growth factor-1 modulate the lipolytic action of growth hormone by altering signal pathway linkages.

    Science.gov (United States)

    Bergan-Roller, Heather E; Ickstadt, Alicia T; Kittilson, Jeffrey D; Sheridan, Mark A

    2017-07-01

    Growth hormone (GH) has many actions in vertebrates, including the regulation of two disparate metabolic processes: growth promotion (anabolic) and the mobilization of stored lipids (catabolic). Our previous studies showed that GH stimulated IGF-1 production in hepatocytes from fed rainbow trout, but in cells from fasted fish GH stimulated lipolysis. In this study, we used rainbow trout (Oncorhynchus mykiss) to elucidate regulation of the mechanisms that enable cells to alter their lipolytic responsiveness to GH. In the first experiment, cells were removed from either fed or fasted fish, conditioned in medium containing serum (10%) from either fed or fasted fish, then challenged with GH. GH stimulated the expression of hormone sensitive lipase (HSL), the primary lipolytic enzyme, in cells from fasted fish conditioned with "fasted serum" but not in cells from fasted fish conditioned in "fed serum." Pretreatment of cells from fed fish with "fasted serum" resulted in GH-stimulated HSL expression, whereas GH-stimulated HSL expression in cells from fasted fish was blocked by conditioning in "fed serum." The nature of the conditioning serum governed the signaling pathways activated by GH irrespective of the nutritional state of the animals from which the cells were removed. When hepatocytes were pretreated with "fed serum," GH activated JAK2, STAT5, Akt, and ERK pathways; when cells were pretreated with "fasted serum," GH activated PKC and ERK. In the second study, we examined the direct effects of insulin (INS) and insulin-like growth factor (IGF-1), two nutritionally-regulated hormones, on GH-stimulated lipolysis and signal transduction in isolated hepatocytes. GH only stimulated HSL mRNA expression in cells from fasted fish. Pretreatment with INS and/or IGF-1 abolished this lipolytic response to GH. INS and/or IGF-1 augmented GH activation of JAK2 and STAT5 in cells from fed and fasted fish. However, INS and/or IGF-1 eliminated the ability of GH to activate PKC and

  16. The insulin-like growth factor pathway is altered in Spinocerebellar ataxia type 1 and type 7

    Energy Technology Data Exchange (ETDEWEB)

    Gatchel, Jennifer R.; Watase, Kei; Thaller, Christina; Carson, James P.; Jafar-Nejad, Paymaan; Shaw, Chad A.; Zu, Tao; Orr, Harry T.; Zoghbi, Huda Yahya

    2008-01-29

    Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG trinucleotide repeats encoding a polyglutamine tract in the disease-causing proteins. There are nine of these disorders each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with corresponding degeneration of Purkinje cells. Given this common phenotype, we asked whether the two disorders share common molecular pathogenic events. To address this question we studied two genetically accurate mouse models of SCA1 and SCA7—Sca1154Q/2Q and Sca7266Q/5Q knock-in mice—that express the glutamine-expanded proteins from the respective endogenous loci. We found common transcriptional changes in early symptomatic mice, with downregulation of Insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust transcriptional changes that closely correlates with disease state. Interestingly, down-regulation of Igfbp5 occurred in granule neurons through a non-cell autonomous mechanism and was concomitant with activation of the Insulin-like growth factor I (Igf-I) pathway, and, in particular, the Igf-I receptor, expressed in part on Purkinje cells (PC). These data define a possible common pathogenic response in SCA1 and SCA7 and reveal the importance of neuron-neuron interactions in SCA1 and SCA7 pathogenesis. The sensitivity of Igfbp5 levels to disease state could render it and other components of its effector pathway useful as biomarkers in this class of diseases.

  17. Evidences for involvement of growth hormone and insulin-like growth factor in ovarian development of starry flounder (Platichthys stellatus).

    Science.gov (United States)

    Xu, Yongjiang; Wang, Bin; Liu, Xuezhou; Shi, Bao; Zang, Kun

    2017-04-01

    Although gonadotrophins are major regulators of ovarian function in teleosts and other vertebrates, accumulating evidence indicates that the growth hormone (GH)-insulin-like growth factor (IGF) axis also plays an important role in fish reproduction. As a first step to understand the physiological role of the GH-IGF system in the ovarian development of starry flounder (Platichthys stellatus), the expression profiles of GH and IGF messenger RNAs (mRNAs) and plasma GH, IGF-I, estradiol-17β (E2), and testosterone (T) levels during the ovarian development were investigated. The developmental stages of ovaries were divided into five stages (II, III, IV, V, and VI) by histological analysis. The hepatosomatic index (HSI) and gonadosomatic index (GSI) values increased and peaked at stage IV and stage V, respectively, and then declined at stage VI. Pituitary GH mRNA levels decreased sharply at stage III and raised to top level at stage VI. The hepatic IGF-I mRNA levels ascended to maximum value at stage V and then declined significantly at stage VI. However, the hepatic IGF-II mRNA levels remained stable and increased significantly at stage VI. In contrast, the ovarian IGF-I mRNA levels increased gradually and peaked at stage VI. The ovarian IGF-II mRNA levels were initially stable and increased significantly at stage V until the top level at stage VI. Consistent with the pituitary GH mRNA levels, plasma GH levels reduced sharply at stage III and remained depressed until stage V and then raised remarkably at stage VI. Plasma IGF-I level peaked at stage V and then declined to initial level. Plasma E2 level peaked at stage IV and then dramatically descended to the basal level. Plasma T level peaked at stage V and then declined significantly back to the basal level. Based on statistical analysis, significant positive correlations between hepatic IGF-I mRNA and GSI, ovarian IGF-II mRNA and hepatic IGF-II mRNA, ovarian IGF-I mRNA and ovarian IGF-II mRNA, and plasma IGF-I and

  18. Differential expression of insulin like growth factor I and other fibroblast mitogens in porcine colostrum and milk

    Energy Technology Data Exchange (ETDEWEB)

    Tan, T.J.; Simmen, R.C.M.; Simmen, F.A.

    1987-05-01

    Sow mammary secretions contain at least 3 distinct growth factor activities, distinguished by their size and relative abundance in colostrum or later milk. Gel filtration of colostrum in Sephadex G-200 columns, followed by acid-ethanol extraction and radioimmunoassay (RIA) for insulin like growth factor I (IGF-I) revealed high levels of this factor in the 150K and 50K MW regions, characteristic of IGF-I: binding protein complexes. Acid treatment of these fractions yielded free IGF-I peptide (7.5K). Parallel mitogen assays with a fibroblast cell line (AKR-2B) demonstrated a predominant peak of high MW activity (sow colostral growth factor-I, SCGF-I) eluting near the column void volume (MW > 150K). Treatment of SCGF-I with 1M acetic acid resulted in a size reduction of the mitogenic activity (MW < 10K), suggesting association of SCGF-I with a binding protein. The SCGF-I peptide was noncompetitive in IGF-I RIA, was distinct in MW from free IGF-I, and was not mitogenic for chick embryo fibroblasts. Sow milk contains less IGF-I and SCGF-I but does display a predominant peak of small MW (approx. 3K) AKR-2B activity. The changes in expression of these growth factors during lactation may reflect differing roles in lactogenesis and/or neonatal growth and development.

  19. Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

    Science.gov (United States)

    Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

    2013-09-15

    The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal muscle

    Science.gov (United States)

    Adams, Gregory R.

    2002-01-01

    Similar to bone, skeletal muscle responds and adapts to changes in loading state via mechanisms that appear to be intrinsic to the muscle. One of the mechanisms modulating skeletal muscle adaptation it thought to involve the autocrine and/or paracrine production of insulinlike growth factor-I. This brief review outlines components of the insulinlike growth factor-I system as it relates to skeletal muscle and provides the rationale for the theory that insulinlike growth factor-I is involved with muscle adaptation.

  1. Insulin-like growth factor-1 levels in children with Beta-thalassemia minor

    Directory of Open Access Journals (Sweden)

    Mehran Karimi

    2008-09-01

    Full Text Available Objective: Growth retardation in children with b-thalassemia major is multifactorial. Some etiologies described for this condition are hemochromatosis, disturbed growth hormone (GH / insulin growth factor-1 (IGF-1 axis, undernutrition and hypermetabolism. It has also been proven that growth retardation is present in b-thalassemia major children despite regular transfusion and chelation. Our aim was to evaluate the level of IGF-1 in b-thalassemia minor subjects and compare it with that in healthy children. Material and Methods: Fifty children aged 6 months to 15 years with b-thalassemia minor (32 males, 18 females and 50 age- and sex-matched normal healthy children were selected. Medical history was taken and complete physical examination was done in each case; IGF-1 level was checked in all cases. This study was done in Shiraz, southern Iran, during 2005.Results: IGF-1 levels were significantly lower in b-thalassemia minor children than normal children (P = 0.015. This result demonstrates that some etiologies of growth failure in b-thalassemia major other than those described to date can exist, which may be shared with b-thalassemia minor in feature or may be transformed by genes that are either expressed or not.Conclusion: We conclude that in addition to that observed in b-thalassemia major, IGF-1 level is also decreased in b-thalassemia minor, and these two may have similar etiologies.

  2. The effects of physical activity and fitness in Adolescence on cognition in adulthood and the role of insulin-like growth factor I .

    NARCIS (Netherlands)

    Ferro, D.A.; Deijen, J.B.; Koppes, L.L.; Mechelen, W. van; Twisk, J.W.; Drent, M.L.

    2016-01-01

    Background: Physical activity and fitness in adolescence may improve cognition in adulthood by increasing insulin-like growth factor I (IGF-I). Methods: As part of the Amsterdam Growth and Health Longitudinal Study, following subjects from age 13 to 42 years, physical activity and fitness of 303

  3. Plasma insulin-like growth factor I levels are higher in depressive and anxiety disorders, but lower in antidepressant medication users

    NARCIS (Netherlands)

    Bot, Mariska; Milaneschi, Yuri; Penninx, Brenda W J H; Drent, Madeleine L

    It has been postulated that many peripheral and (neuro)biological systems are involved in psychiatric disorders such as depression. Some studies found associations of depression and antidepressant treatment with insulin-like growth factor 1 (IGF-I) - a pleiotropic hormone affecting neuronal growth,

  4. Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Nielsen, Kaspar Renÿ; Kristensen, Lars Østergaard

    2009-01-01

    BACKGROUND AND OBJECTIVE: Measurements of Insulin-Like Growth Factor-I (IGF-I) play a pivotal role in the evaluation of the growth hormone-IGF-I axis. Due to assay variation IGF-I reference ranges are assay specific. We provide serum IGF-I reference ranges for adult men and women obtained...

  5. Insulin-like and fibroblast growth factors in spinal cords, nerve roots and skeletal muscle of human controls and patients with amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Kerkhoff, H.; Hassan, S. M.; Troost, D.; van Etten, R. W.; Veldman, H.; Jennekens, F. G.

    1994-01-01

    Insulin-like growth factors (IGF-I and IGF-II) and fibroblast growth factors [acidic FGF (aFGF) and basic FGF (bFGF)] are trophic for motor neurones in vitro and (in laboratory animals) in vivo. An immunohistochemical investigation was performed on the distribution of these factors in the

  6. Diagnostic utility of leptin and insulin-like growth factor binding ...

    African Journals Online (AJOL)

    Methods: Seventy five patients were divided equally into 3 groups as follows: healthy normal control (NC), non-diabetic hepatocellular carcinoma (HCC) and diabetic hepatocellular carcinoma (HCC-DM). Serum levels of leptin, insulin growth factor binding protein-2 (IGFBP-2) and alpha fetoprotein (AFP) were measured.

  7. Multiplex ready flow cytometric immunoassay for total insulin like growth factor 1 in serum of cattle

    NARCIS (Netherlands)

    Bremer, M.G.E.G.; Smits, N.G.E.; Haasnoot, W.; Nielen, M.W.F.

    2010-01-01

    The European Union has banned the use of recombinant bovine somatotropins (rbST, growth hormones) to increase milk yield in dairy cattle. As direct detection of rbST in serum is problematic, methods based on the detection of changes in multiple rbST-dependent biomarkers have high potential for

  8. Evaluation of insulin-like growth factor-I gene polymorphism in ...

    African Journals Online (AJOL)

    Tuoyo Aghomotsegin

    2016-11-30

    Nov 30, 2016 ... variations in IGF-I gene may be a potential molecular marker for growth traits in different Egyptian sheep and goat breeds. Key words: IGF-1, polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP), DNA sequencing, sheep, goat. INTRODUCTION. Molecular genetics techniques ...

  9. Single nucleotide polymorphism in Egyptian cattle insulin-like growth factor binding protein-3 gene

    Directory of Open Access Journals (Sweden)

    Othman E. Othman

    2014-12-01

    It is concluded that the IGFBP-3/HaeIII polymorphism may be utilized as a good marker for genetic differentiation between cattle animals for different body functions such as growth, metabolism, reproduction, immunity and energy balance. The nucleotide sequences of Egyptian cattle IGFBP-3 A and C alleles were submitted to GenBank with the accession numbers KF899893 and KF899894, respectively.

  10. Circulating insulin-like growth factor I levels in newborn premature and full-term infants followed longitudinally.

    Science.gov (United States)

    Lineham, J D; Smith, R M; Dahlenburg, G W; King, R A; Haslam, R R; Stuart, M C; Faull, L

    1986-02-01

    Longitudinal circulating levels of insulin-like growth factor I (IGF-I) were measured by radioimmunoassay after acid/ethanol extraction of serum or plasma in 44 appropriate-for-gestational age (AGA) premature infants, 7 small-for-gestational age (SGA) premature infants and 9 AGA full-term infants. The subjects were divided into cohorts with gestational age at birth 26-29 weeks, 30-33 weeks, 34-37 weeks and 38-42 weeks (full-term). The premature infants in this study exhibited diminished growth as compared with normal intrauterine growth. In all but the earliest premature infant cohort there was an immediate fall from the mean fetal IGF-I level, as reflected by the cord value, to a basal postnatal circulating level of IGF-I. The basal level of circulating IGF-I in premature infants was related only to gestational age. It increased slowly from 25 weeks gestation until four weeks after full-term equivalent and was independent of time of birth. Full-term infants were distinguished from early premature infants by the occurrence of a prominent postnatal surge in circulating IGF-I levels that was characterised by a significant (P less than 0.02) increase between day 1 and days 10-15. The SGA and AGA infants in the 34-37 week cohort showed similar profiles of circulating IGF-I with no significant difference in cord values between the two groups.

  11. Insulin like growth factor-1/insulin bypasses Pref-1/FA1-mediated inhibition of adipocyte differentiation

    DEFF Research Database (Denmark)

    Zhang, Hongbin; Nøhr, Jane; Jensen, Charlotte Harken

    2003-01-01

    Pref-1 is a highly glycosylated Delta-like transmembrane protein containing six epidermal growth factor-like repeats in the extracellular domain. Pref-1 is abundantly expressed in preadipocytes, but expression is down-regulated during adipocyte differentiation. Forced expression of Pref-1 in 3T3-L1...... cells was reported to inhibit adipocyte differentiation. Here we show that efficient and regulated processing of Pref-1 occurs in 3T3-L1 preadipocytes releasing most of the extracellular domain as a 50-kDa heterogeneous protein, previously isolated and characterized as FA1. Unexpectedly, we found...... that forced expression of the soluble form, FA1, or full-length Pref-1 did not inhibit adipocyte differentiation of 3T3-L1 cells when differentiation was induced by standard treatment with methylisobutylxanthine, dexamethasone, and high concentrations of insulin. However, forced expression of either form...

  12. Elevated insulin-like growth factor 2 expression may contribute to the hypermuscular phenotype of myostatin null mice.

    Science.gov (United States)

    Clark, Daniel L; Clark, Diana I; Hogan, Elizabeth K; Kroscher, Kellie A; Dilger, Anna C

    2015-10-01

    Myostatin (Mstn) inhibits while insulin-like growth factors 1 and 2 (Igf1 and Igf2) increase skeletal muscle growth. However, there is little known regarding Mstn regulation of Igf1 and Igf2 expression. Therefore, the objective of this study was to quantify the expression of IGF family members in skeletal muscle and liver throughout the growth phase of Mstn null (MN) mice. Further, differences between male and female mice were investigated. Male and female wild type (WT) and MN mice were euthanized at birth (0 d), 7 days (7 d), weaning (21 d), sexual maturity (42 d), and 70 d. For the neonatal periods, 0 d and 7 d, all muscles from the hind limbs were compiled for RNA extraction. At 21 d, 42 d, and 70 d, biceps femoris (BF), tibialis anterior, triceps brachii (TB), and gastrocnemius-soleus complex were collected. As expected, muscle weights were up to 90% greater in MN mice compared with WT mice at 21 d, 42 d and 70 d. However, Igf1 expression was reduced (P ≤ 0.04) at 7d and 21 d in MN mice compared to WT mice. Expression of Igf2 did not differ between genotypes at 0 d and 7d, but, at 21 d, 42 d and 70 d in BF and TB muscles, Igf2 expression was 1.9-2.9 fold greater (Pgrowth differences. In every case, when expression was different between sexes, female expression was increased despite increased growth in male mice. This study is the first to provide evidence that Mstn may negatively regulate Igf2 expression to control postnatal skeletal muscle growth, however differences in growth between male and female mice are not readily explained by changes in expression of Igf family members. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. The effects of testosterone and insulin-like growth factor 1 on motor system form and function.

    Science.gov (United States)

    Oki, Kentaro; Law, Timothy D; Loucks, Anne B; Clark, Brian C

    2015-04-01

    In this perspective article, we review the effects of selected anabolic hormones on the motoric system and speculate on the role these hormones may have on influencing muscle and physical function via their impact on the nervous system. Both muscle strength and anabolic hormone levels decline around middle age into old age over a similar time period, and several animal and human studies indicate that exogenously increasing anabolic hormones (e.g., testosterone and insulin-like growth factor-1 (IGF-1)) in aged subjects is positively associated with improved muscle strength. While most studies in humans have focused on the effects of anabolic hormones on muscle growth, few have considered the impact these hormones have on the motoric system. However, data from animals demonstrate that administering either testosterone or IGF-1 to cells of the central and peripheral motor system can increase cell excitability, attenuate atrophic changes, and improve regenerative capacity of motor neurons. While these studies do not directly indicate that changes in anabolic hormones contribute to reduced human performance in the elderly (e.g., muscle weakness and physical limitations), they do suggest that additional research is warranted along these lines. Published by Elsevier Inc.

  14. Displacement of insulin-like growth factors from their binding proteins as a potential treatment for stroke

    Science.gov (United States)

    Loddick, Sarah A.; Liu, Xin-Jun; Lu, Zi-Xian; Liu, Changlu; Behan, Dominic P.; Chalmers, Derek C.; Foster, Alan C.; Vale, Wylie W.; Ling, Nicholas; De Souza, Errol B.

    1998-01-01

    Insulin-like growth factors I and II (IGF-I and IGF-II) play an important role in normal growth and brain development and protect brain cells from several forms of injury. The effects of IGFs are mediated by type-I and type-II receptors and modulated by potentially six specific binding proteins that form high-affinity complexes with IGFs in blood and cerebrospinal fluid (CSF) and under most circumstances inactivate them. Because brain injury is commonly associated with increases in IGFs and their associated binding proteins, we hypothesized that displacement of this large “pool” of endogenous IGF from the binding proteins would elevate “free” IGF levels to elicit neuroprotective effects comparable to those produced by administration of exogenous IGF. A human IGF-I analog [(Leu24, 59, 60, Ala31)hIGF-I] with high affinity to IGF-binding proteins (Ki = 0.3–3.9 nM) and no biological activity at the IGF receptors (Ki = >10,000 nM) increased the levels of “free, bioavailable” IGF-I in the CSF. Intracerebroventricular administration of this analog up to 1h after an ischemic insult to the rat brain had a potent neuroprotective action comparable to IGF-I. This novel strategy for increasing “free” IGF levels in the brain may be useful for the treatment of stroke and other neurodegenerative diseases. PMID:9465113

  15. The Role of Insulin-Like Growth Factor 1 in the Progression of Age-Related Hearing Loss.

    Science.gov (United States)

    Rodríguez-de la Rosa, Lourdes; Lassaletta, Luis; Calvino, Miryam; Murillo-Cuesta, Silvia; Varela-Nieto, Isabel

    2017-01-01

    Aging is associated with impairment of sensorial functions and with the onset of neurodegenerative diseases. As pari passu circulating insulin-like growth factor 1 (IGF-1) bioavailability progressively decreases, we see a direct correlation with sensory impairment and cognitive performance in older humans. Age-related sensory loss is typically caused by the irreversible death of highly differentiated neurons and sensory receptor cells. Among sensory deficits, age-related hearing loss (ARHL), also named presbycusis, affects one third of the population over 65 years of age and is a major factor in the progression of cognitive problems in the elderly. The genetic and molecular bases of ARHL are largely unknown and only a few genes related to susceptibility to oxidative stress, excitotoxicity, and cell death have been identified. IGF-1 is known to be a neuroprotective agent that maintains cellular metabolism, activates growth, proliferation and differentiation, and limits cell death. Inborn IGF-1 deficiency leads to profound sensorineural hearing loss both in humans and mice. IGF-1 haploinsufficiency has also been shown to correlate with ARHL. There is not much information available on the effect of IGF-1 deficiency on other human sensory systems, but experimental models show a long-term impact on the retina. A secondary action of IGF-1 is the control of oxidative stress and inflammation, thus helping to resolve damage situations, acute or made chronic by aging. Here we will review the primary actions of IGF-1 in the auditory system and the underlying molecular mechanisms.

  16. The Role of Insulin-Like Growth Factor 1 in the Progression of Age-Related Hearing Loss

    Directory of Open Access Journals (Sweden)

    Lourdes Rodríguez-de la Rosa

    2017-12-01

    Full Text Available Aging is associated with impairment of sensorial functions and with the onset of neurodegenerative diseases. As pari passu circulating insulin-like growth factor 1 (IGF-1 bioavailability progressively decreases, we see a direct correlation with sensory impairment and cognitive performance in older humans. Age-related sensory loss is typically caused by the irreversible death of highly differentiated neurons and sensory receptor cells. Among sensory deficits, age-related hearing loss (ARHL, also named presbycusis, affects one third of the population over 65 years of age and is a major factor in the progression of cognitive problems in the elderly. The genetic and molecular bases of ARHL are largely unknown and only a few genes related to susceptibility to oxidative stress, excitotoxicity, and cell death have been identified. IGF-1 is known to be a neuroprotective agent that maintains cellular metabolism, activates growth, proliferation and differentiation, and limits cell death. Inborn IGF-1 deficiency leads to profound sensorineural hearing loss both in humans and mice. IGF-1 haploinsufficiency has also been shown to correlate with ARHL. There is not much information available on the effect of IGF-1 deficiency on other human sensory systems, but experimental models show a long-term impact on the retina. A secondary action of IGF-1 is the control of oxidative stress and inflammation, thus helping to resolve damage situations, acute or made chronic by aging. Here we will review the primary actions of IGF-1 in the auditory system and the underlying molecular mechanisms.

  17. Antepartal insulin-like growth factor concentrations indicating differences in the metabolic adaptive capacity of dairy cows

    Science.gov (United States)

    Holzhausen, Lars; Araujo, Marcelo Gil; Heppelmann, Maike; Sipka, Anja; Pfarrer, Chistiane; Schuberth, Hans-Joachim; Bollwein, Heinrich

    2014-01-01

    Cows with different Insulin-like Growth Factor-I (IGF-I) concentrations showed comparable expression levels of hepatic growth hormone receptor (GHR). Suppressor of cytokine signaling 2 (SOCS2), could be responsible for additional inhibition of the GHR signal cascade. The aims were to monitor cows with high or low antepartal IGF-I concentrations (IGF-Ihigh or IGF-Ilow), evaluate the interrelationships of endocrine endpoints, and measure hepatic SOCS2 expression. Dairy cows (n = 20) were selected (240 to 254 days after artificial insemination (AI)). Blood samples were drawn daily (day -17 until calving) and IGF-I, GH, insulin, thyroid hormones, estradiol, and progesterone concentrations were measured. Liver biopsies were taken (day 264 ± 1 after AI and postpartum) to measure mRNA expression (IGF-I, IGFBP-2, IGFBP-3, IGFBP-4, acid labile subunit (ALS), SOCS2, deiodinase1, GHR1A). IGF-I concentrations in the two groups were different (p 0.05). Thyroxine levels and ALS expression were higher in the IGF-Ihigh cows compared to IGF-Ilow cows. Estradiol concentration tended to be greater in the IGF-Ilow group (p = 0.06). It was hypothesized that low IGF-I levels are associated with enhanced SOCS2 expression although this could not be decisively confirmed by the present study. PMID:24962413

  18. Plasma insulin-like growth factor I as predictor of progression and all cause mortality in chronic heart failure

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Kistorp, Caroline; Raymond, Ilan

    2009-01-01

    , renal function and LVEF) IGF-I levels did not influence the overall mortality risk or the admission rate to hospital, hazard ratio (HR) (95% confidence intervals) 1.05 (0.75-1.47) (P=0.77) and 1.00 (0.80-1.26) (P=0.96), respectively per each SD increase in log IGF-I levels. CONCLUSIONS: IGF-I levels......OBJECTIVES: Insulin-like growth factor I (IGF-I) is an anabolic growth factor that seems to increase cardiac contractility. Reduced levels of IGF-I may be implicated in progression of CHF. The objective was to compare plasma IGF-I in CHF patients with healthy controls, and to examine...... the associations between baseline IGF-I levels, cardiac contractility and the prognosis as judged by all cause mortality and progression of CHF requiring admission to hospital. METHODS: A prospective study comprising 194 CHF outpatients, and 169 matched controls. All patients and controls underwent...

  19. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II

    Science.gov (United States)

    Pannu, Hariyadarshi; Tran-Fadulu, Van; Papke, Christina L.; Scherer, Steve; Liu, Yaozhong; Presley, Caroline; Guo, Dongchuan; Estrera, Anthony L.; Safi, Hazim J.; Brasier, Allan R.; Vick, G. Wesley; Marian, A.J.; Raman, C.S.; Buja, L. Maximilian; Milewicz, Dianna M.

    2010-01-01

    Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in ~20% of cases. Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11). On sequencing MYH11 in 93 families with TAAD alone and three families with TAAD/PDA, we identified novel mutations in two families with TAAD/PDA, but none in families with TAAD alone. Histopathological analysis of aortic sections from two individuals with MYH11 mutations revealed SMC disarray and focal hyperplasia of SMCs in the aortic media. SMC hyperplasia leading to significant lumen narrowing in some of the vessels of the adventitia was also observed. Insulin-like growth factor-1 (IGF-1) was upregulated in mutant aortas as well as explanted SMCs, but no increase in transforming growth factor-β expression or downstream targets was observed. Enhanced expression of angiotensin-converting enzyme and markers of Angiotensin II (Ang II) vascular inflammation (macrophage inflammatory protein-1α and β) were also found. These data suggest that MYH11 mutations are likely to be specific to the phenotype of TAAD/PDA and result in a distinct aortic and occlusive vascular pathology potentially driven by IGF-1 and Ang II. PMID:17666408

  20. Localization, characterization, and quantification of insulin-like growth factor-I-binding sites in the ewe ovary

    Energy Technology Data Exchange (ETDEWEB)

    Monget, P.; Monniaux, D.; Durand, P. (INRA, Station de Physiologie de la Reproduction, Nouzilly (France))

    1989-11-01

    To assess a potential role of insulin-like growth factor-I (IGF-I) in the ewe ovary, the presence of IGF-I receptors and IGF-I-binding proteins was studied by binding assays performed on granulosa cell suspensions, in follicular fluid, and on ovarian sections. On the ovarian sections, labeling was quantified after autoradiography by microphotometry. Competition studies with IGF-I and insulin allowed us to estimate the relative proportions of binding proteins and type I receptors in the different compartments of the ewe ovary. Our results clearly show that saturable, specific, and high affinity IGF-I receptors are present on the ovine granulosa cells. At equilibrium for both granulosa cell suspensions and frozen sections, the Kd value was close to 2 nM. IGF-I binding proteins were also present in follicular fluid and stroma, thecal, and granulosa cells. At equilibrium for follicular fluid, the Kd value was 0.91 +/- 0.27 nM (mean +/- SE). Moreover, on frozen sections, it was shown that atresia of small follicles (less than 2 mm) was accompanied by a decrease in the number of IGF-I receptors and an increase in the number of IGF-I-binding proteins on granulosa cells. By contrast, this phenomenon was not observed in large follicles. These data indicate that granulosa cells of ewe ovary possess type I receptors, and IGF-I-binding proteins may modulate IGF-I action in the process of follicular growth and atresia.

  1. Animal protein intakes during early life and adolescence differ in their relation to the growth hormone-insulin-like-growth-factor axis in young adulthood.

    Science.gov (United States)

    Joslowski, Gesa; Remer, Thomas; Assmann, Karen E; Krupp, Danika; Cheng, Guo; Garnett, Sarah P; Kroke, Anja; Wudy, Stefan A; Günther, Anke L B; Buyken, Anette E

    2013-07-01

    Recent studies provide evidence that insulin-like-growth-factor I (IGF-I) and its binding proteins (IGFBP) IGFBP-2 and IGFBP-3 are related to the risk of several common cancers. It remains to be clarified whether their concentrations can be programmed by protein intake from different sources during growth. This study addressed the hypothesis that animal protein intakes during infancy, mid-childhood, and adolescence differ in their relevance for the growth-hormone (GH)-IGF-I axis in young adulthood. Data from the Dortmund Nutritional and Anthropometric Longitudinally Designed Study participants with at least 2 plausible 3-d weighed dietary records during adolescence (age: girls, 9-14 y; boys, 10-15 y; n = 213), around the adiposity rebound (age 4-6 y; n = 179) or early life (age 0.5-2 y; n = 130), and one blood sample in young adulthood were included in the study. Mean serum concentrations of IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 were compared between tertiles of habitual animal protein intake using multivariable regression analysis. Habitually higher animal protein intakes in females during puberty were related to higher IGF-I (P-trend = 0.005) and IGFBP-3 (P-trend = 0.01) and lower IGFBP-2 (P-trend = 0.04), but not to IGFBP-1 in young adulthood. In turn, IGF-I concentrations in young adulthood were inversely related to animal protein intakes in early life among males only (P-trend = 0.03), but not to animal protein intake around adiposity rebound (P-trend > 0.5). Our data suggest that, among females, a habitually higher animal protein intake during puberty may precipitate an upregulation of the GH-IGF-I axis, which is still discernible in young adulthood. By contrast, among males, higher animal protein intakes in early life may exert a long-term programming of the GH-IGF-I axis.

  2. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor.

    Science.gov (United States)

    Rowinsky, Eric K; Youssoufian, Hagop; Tonra, James R; Solomon, Phillip; Burtrum, Douglas; Ludwig, Dale L

    2007-09-15

    Targeted monoclonal antibody therapy is an important strategy in cancer therapeutics. Among the most promising characteristics of therapeutic targets are those that modulate the growth and survival of malignant neoplasms and their sensitivity to anticancer therapies. The insulin-like growth factor-I receptor (IGF-IR) is overexpressed in many types of solid and hematopoietic malignancies, and has been implicated as a principal cause of heightened proliferative and survival signaling. IGF-IR has also been shown to confer resistance to cytotoxic, hormonal, and targeted therapies, suggesting that therapeutics targeting IGF-IR may be effective against a broad range of malignancies. IMC-A12 (ImClone Systems Incorporated), a fully human monoclonal IgG1 antibody that binds with high affinity to the IGF-IR, inhibits ligand-dependent receptor activation and downstream signaling. IMC-A12 also mediates robust internalization and degradation of the IGF-IR. In human tumor xenograft models, IGF-IR blockade by IMC-A12 results in rapid and profound growth inhibition of cancers of the breast, lung, colon, and pancreas, and many other neoplasms. Although promising single-agent activity has been observed, the most impressive effects of targeting the IGF-IR with IMC-A12 have been noted when this agent was combined with cytotoxic agents or other targeted therapeutics. The results with IMC-A12 to date suggest that it may be an effective therapeutic in a diverse array of oncologic indications.

  3. Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down-Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling.

    Directory of Open Access Journals (Sweden)

    Shasha Yang

    Full Text Available Growth factor receptor-bound protein 10 (Grb10 is an adaptor protein that can negatively regulate the insulin-like growth factor 1 receptor (IGF-1R. The IGF1-1R pathway is critical for cell growth and apoptosis and has been implicated in kidney diseases; however, it is still unknown whether Grb10 expression is up-regulated and plays a role in diabetic nephropathy. Catalpol, a major active ingredient of a traditional Chinese medicine, Rehmannia, has been reported to possess anti-inflammatory and anti-aging activities and then used to treat diabetes. Herein, we aimed to assess the therapeutic effect of catalpol on a mouse model diabetic nephropathy and the potential role of Grb10 in the pathogenesis of this diabetes-associated complication. Our results showed that catalpol treatment improved diabetes-associated impaired renal functions and ameliorated pathological changes in kidneys of diabetic mice. We also found that Grb10 expression was significantly elevated in kidneys of diabetic mice as compared with that in non-diabetic mice, while treatment with catalpol significantly abrogated the elevated Grb10 expression in diabetic kidneys. On the contrary, IGF-1 mRNA levels and IGF-1R phosphorylation were significantly higher in kidneys of catalpol-treated diabetic mice than those in non-treated diabetic mice. Our results suggest that elevated Grb10 expression may play an important role in the pathogenesis of diabetic nephropathy through suppressing IGF-1/IGF-1R signaling pathway, which might be a potential molecular target of catalpol for the treatment of this diabetic complication.

  4. Potential role of growth factors with particular focus on growth hormone and insulin-like growth factor-1 in the management of chronic kidney disease

    DEFF Research Database (Denmark)

    Feldt-Rasmussen, Bo; El Nahas, Meguid

    2009-01-01

    Prevention and treatment of chronic kidney disease (CKD) so far primarily has been based on early and aggressive treatment of hypertension. A number of other therapeutic approaches have the potential of being translated to the clinical area within the foreseeable future. In this review, we focus...... administration on the nutritional parameters of patients on renal replacement therapy. More recently, a larger randomized, double-blind, placebo-controlled, 26-week, proof-of-concept clinical study was conducted to investigate the effect of GH (Norditropin; Novo Nordisk, Bagsvaerd, Denmark) in adult chronic...... on growth factors and, in particular, on the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in the treatment of CKD and the management of its complications. Disturbances of the GH-IGF-1 axis in CKD have suggested therapeutic roles for both the inhibition, as well as the stimulation...

  5. Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients

    DEFF Research Database (Denmark)

    Laursen, Torben; Jørgensen, Jens Otto Lunde; Ørskov, Hans

    1993-01-01

    Abstract Animals studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent.......5 +/- 1.47 (octreotide) and 12.8 +/- 1.42 (placebo) (p = 0.83), and Tmax (h) was 6.1 +/- 0.97 (octreotide) and 5.2 +/- 0.65 (placebo) (p = 0.49). Growth hormone administration was associated with an increase in serum IGF-I (microgram/l), which was identical during the two studies, from 85.3 +/- 19...

  6. Insulin-like growth factor (IGF)-I binding to a cell membrane associated IGF binding protein-3 acid-labile subunit complex in human anterior pituitary gland

    NARCIS (Netherlands)

    Wilczak, N; Kuhl, N; Chesik, D; Geerts, A; Luiten, P; De Keyser, J

    The binding characteristics of [(125) I]insulin-like growth factor (IGF)-I were studied in human brain and pituitary gland. Competition binding studies with DES(1-3)IGF-I and R-3 -IGF-I, which display high affinity for the IGF-I receptor and low affinity for IGF binding proteins (IGFBPs), were

  7. Effects of insulin-like growth factor-I, insulin, and leucine on protein turnover and pathways that regulate ubiquitin ligase expression in rainbow trout primary myocytes

    Science.gov (United States)

    The effects of insulin-like growth factor-I (IGF-I), insulin, and leucine on protein turnover and pathways that regulate proteolytic gene expression and protein polyubiquitination were investigated in primary cultures of four day old rainbow trout myocytes. Supplementing media with 100 nM IGF-I inc...

  8. The Effect of Insulin and Insulin-Like Growth Factors on Hippocampus- and Amygdala-Dependent Long-Term Memory Formation

    Science.gov (United States)

    Stern, Sarah A.; Chen, Dillon Y.; Alberini, Cristina M.

    2014-01-01

    Recent work has reported that the insulin-like growth factor 2 (IGF2) promotes memory enhancement. Furthermore, impaired insulin or IGF1 functions have been suggested to play a role in the pathogenesis of neurodegeneration and cognitive impairments, hence implicating the insulin/IGF system as an important target for cognitive enhancement and/or…

  9. Peri/nuclear localization of intact insulin-like growth factor binding protein-2 and a distinct carboxyl-terminal IGFBP-2 fragment in vivo

    NARCIS (Netherlands)

    Hoeflich, A; Reisinger, R; Schuett, BS; Elmlinger, MW; Russo, VC; Vargas, GA; Jehle, PM; Lahm, H; Renner-Muller, [No Value; Wolf, E

    2004-01-01

    Insulin-like growth factor binding protein-2 (IGFBP-2) as one of the most important IGFBPs has never been assessed in the intracellular compartment in vivo. Since there is evidence for novel intracellular functions of distinct IGFBPs, we investigated the presence of IGFBP-2 inside the cell. In

  10. Characterization of O-glycosylated precursors of insulin-like growth factor II by matrix-assisted laser desorption/ionization mass spectrometry

    NARCIS (Netherlands)

    Jespersen, S.; Koedam, J.A.; Hoogerbrugge, C.M.; Tjaden, U.R.; Greef, J. van der; Brande, J.L. van den

    1996-01-01

    High molecular weight precursors of insulin-like growth factor II (IGF-II) were isolated from Cohn fraction IV of human plasma by ultrafiltration, affinity chromatography and reversed-phase high-performance liquid chromatography. Molecular weight determination by matrix-assisted laser

  11. Changes in the insulin-like growth factor-system may contribute to in vitro age-related impaired osteoblast functions

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Flyvbjerg, Allan; Rattan, Suresh

    2000-01-01

    Age-related bone loss is thought to be due to impaired osteoblast functions. Insulin-like growth factors (IGFs) have been shown to be important stimulators of bone formation and osteoblast activities in vitro and in vivo. We tested the hypothesis that in vitro osteoblast senescence is associated ...

  12. Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems

    NARCIS (Netherlands)

    J. Rijlaarsdam (Jolien); C.A.M. Cecil (Charlotte A.M.); E. Walton (Esther); Mesirow, M.S.C. (Maurissa S. C.); C.L. Relton (Caroline); T.R. Gaunt (Tom); W.L. McArdle (Wendy); Barker, E.D. (Edward D.)

    2017-01-01

    textabstractBackground: Conduct problems (CP) and attention deficit hyperactivity disorder (ADHD) are often comorbid and have each been linked to 'unhealthy diet'. Early-life diet also associates with DNA methylation of the insulin-like growth factor 2 gene (IGF2), involved in fetal and neural

  13. Cord blood level of insulin-like growth factor-1 and IGF binding protein-3 in monochorionic twins.

    Science.gov (United States)

    Teng, Ru-Jeng; Wu, Tzong-Jin; Hsieh, Fon-Jou

    2015-04-01

    Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are known to modulate fetal growth but their role in intrauterine growth of monochorionic twins (MCT) has not been studied. Cord venous blood was collected directly after birth. IGF-1 and IGFBP-3 in the cord venous blood were quantified by radioimmunoassay. Birth weights (BWs) were obtained electronically. Placentas were examined for chorionicity. Cord blood was collected in 37 pairs of MCT (15 pairs were males). BWs ranged from 564 to 3240 g, and gestational ages (GAs) were between 24 weeks and 39 weeks. There was a correlation between BW and cord venous blood IGFBP-3 concentration (r = 0.28, p = 0.015), but not between BW and cord venous blood IGF-1 level. There was no difference in IGF-1 between the heavier twins (30.8 ± 61.8 ng/mL) and lighter twins (33.2 ± 63.7 ng/mL), but a trend (p = 0.096) of higher IGFBP-3 level was demonstrated in heavier twins (3.14 ± 1.23 μg/mL) than in lighter twins (2.71 ± 1.19 μg/mL). The IGFBP-3 levels were higher (p = 0.042) in female twins (3.20 ± 1.33 μg/mL) than in male twins (2.64 ± 1.04 μg/mL). The IGF-1 level of the heavier twins correlated significantly to their lighter co-twin (r = 0.73, p < 0.001). Our data showed that cord venous blood IGF-1 level might be controlled mainly by genetic factors. IGFBP-3 might play an important role in fetal growth. Copyright © 2013. Published by Elsevier B.V.

  14. Insulin-like growth factor 1 synergizes with bone morphogenetic protein 7-mediated anabolism in bovine intervertebral disc cells.

    Science.gov (United States)

    Kim, Jae-Sung; Ellman, Michael B; An, Howard S; van Wijnen, Andre J; Borgia, Jeffrey A; Im, Hee-Jeong

    2010-12-01

    We undertook this study to assess the therapeutic benefits of intervertebral disc matrix repair and regeneration by evaluating the potential synergistic effect of insulin-like growth factor 1 (IGF-1) and bone morphogenetic protein 7 (BMP-7) on bovine spine discs and by elucidating the relevant molecular/cellular mechanisms. Bovine nucleus pulposus (NP) cells were treated with BMP-7 and IGF-1. The subsequent anabolic effects driven by NP cells were assessed for proteoglycan (PG) synthesis by (35) S-sulfate incorporation and for PG accumulation by dimethylmethylene blue assays. Matrix formation was visualized by particle exclusion assay. Key matrix components and transcription factors were analyzed by real-time reverse transcription-polymerase chain reaction to determine the signaling pathways by which IGF-1 suppresses noggin, a potent inhibitor of BMP-7. Western blotting and nuclear translocation experiments were performed to assess the activation of Smad proteins. Stimulation of bovine NP cells by both IGF-1 and BMP-7 greatly potentiated anabolism through complementary and synergistic mechanisms on matrix formation compared with treatment with either growth factor alone. The exogenously added decoy ligand, noggin, attenuated the anabolic effects of BMP-7, and noggin was substantially increased by BMP-7, suggesting a negative feedback regulatory mechanism. In contrast, IGF-1 significantly suppressed noggin expression via the phosphatidylinositol 3-kinase/Akt pathway and thus potentiated BMP-7 signaling in bovine NP cells. Upon combination treatment, IGF-1 activated Smad2, while BMP-7 activated Smad1/5/8 and Smad3, thus inducing all Smad signaling pathways and mimicking the effects of the combination of transforming growth factor β and BMP-7 Combination growth factor therapy using BMP-7 and IGF-1 may have considerable promise in the treatment of spine disc degeneration. Copyright © 2010 by the American College of Rheumatology.

  15. Insulin-like growth factor 1 regulation of proliferation and differentiation of Xenopus laevis myogenic cells in vitro.

    Science.gov (United States)

    Miyata, Sairi; Yada, Tomotaka; Ishikawa, Natsuko; Taheruzzaman, Kazi; Hara, Ryohei; Matsuzaki, Takashi; Nishikawa, Akio

    2017-03-01

    To understand the mechanism of muscle remodeling during Xenopus laevis metamorphosis, we examined the in vitro effect of insulin-like growth factor 1 (IGF-1) on growth and differentiation of three different-fate myogenic cell populations: tadpole tail, tadpole dorsal, and young adult leg muscle. IGF-1 promoted growth and differentiation of both tail and leg myogenic cells only under conditions where these cells could proliferate. Inhibition of cell proliferation by DNA synthesis inhibitor cytosine arabinoside completely canceled the IGF-1's cell differentiation promotion, suggesting the possibility that IGF-1's differentiation-promotion effect is an indirect effect via IGF-1's cell proliferation promotion. IGF-1 promoted differentiation dose dependently with maximum effect at 100-500 ng/ml. RT-PCR analysis revealed the upregulation (11-fold) of ifg1 mRNA expression in developing limbs, suggesting that IGF-1 plays a role in promoting muscle differentiation during limb development. The combined effect of triiodo-L-thyronine (T3) and IGF-1 was also examined. In adult leg cells, IGF-1 promoted growth and differentiation irrespective of the presence of T3. In larval tail cells, cell count was 76% lower in the presence of T3, and IGF-1 did not promote proliferation and differentiation in T3-containing medium. In larval dorsal cells, cell count was also lower in the presence of T3, but IGF-1 enhanced proliferation and differentiation in T3-containing medium. This result is likely due to the presence among dorsal cells of both adult and larval types (1:1). Thus, IGF-1 affects only adult-type myogenic cells in the presence of T3 and helps accelerate dorsal muscle remodeling during metamorphosis.

  16. The pregnancy-associated plasma protein A and insulin-like growth factor system in response to cigarette smoking.

    Science.gov (United States)

    Chelchowska, Magdalena; Maciejewski, Tomasz; Gajewska, Joanna; Ambroszkiewicz, Jadwiga; Laskowska-Klita, Teresa; Leibschang, Jerzy

    2012-11-01

    Maternal smoking during pregnancy is associated with a reduction in birth size but the mechanism by which this occurs still remains unclear. The purpose of this study was to evaluate the effect of tobacco smoking on concentrations of pregnancy-associated plasma protein A (PAPP-A), insulin-like growth factor I (IGF-I), II (IGF-II) and binding proteins BP-3 and BP-4 in pregnant women and correlations between these parameters. Sixty healthy pregnant women were divided into smoking and tobacco-abstinent group according to results of serum cotinine concentration. The current smokers were defined as those who had smoked five or more cigarettes per day during pregnancy. The mean serum concentrations of PAPP-A, IGF-I and IGF-II were significantly lower in smoking than in non-smoking pregnant women (p PAPP-A correlated positively with the IGF-II concentration in both studied group (non-smoking: r = 0.54; p PAPP-A and IGF-II may suggest function of this protein as a protease and regulator in the IGF system.

  17. Epigenetic dysregulation of Insulin-like growth factor (IGF)-related genes and adverse pregnancy outcomes: a systematic review.

    Science.gov (United States)

    Toure, Drissa M; Baccaglini, Lorena; Opoku, Samuel T; Barnes-Josiah, Debora; Cox, Roxanne; Hartman, Teresa; Klinkebiel, David

    2016-11-01

    Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) are leading causes of neonatal mortality and morbidity around the world. Epigenetic alterations of the human genome may be involved in the causal chain of adverse pregnancy outcomes. In this systematic review we investigated whether PTB, LBW and SGA are associated with epigenetic dysregulation of insulin-like growth factor-related genes (IGF). We searched MEDLINE and EMBASE for peer-reviewed articles about IGF and PTB, LBW and SGA published up to February 2015. Two independent reviewers selected original, controlled, human studies published in any language and graded them using the Newcastle-Ottawa Quality Assessment Scale. Disagreements were resolved by consensus with a third reviewer. Eighteen observational studies of low-to-moderate quality met the eligibility criteria out of 210 unique studies. There was substantial heterogeneity across studies. Most studies reported no, limited or borderline association between epigenetic changes (methylation or imprinting) of IGF-related genes and LBW or SGA. There were no IGF-related epigenetic studies of PTB. Overall, evidence of an association between epigenetic abnormalities of IGF-related genes and LBW or SGA was weak and inconsistent. Methodological concerns limited results validity.

  18. Deficiency in type 1 insulin-like growth factor receptor in mice protects against oxygen-induced lung injury

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    Flejou Jean-François

    2005-04-01

    Full Text Available Abstract Background Cellular responses to aging and oxidative stress are regulated by type 1 insulin-like growth factor receptor (IGF-1R. Oxidant injury, which is implicated in the pathophysiology of a number of respiratory diseases, acutely upregulates IGF-1R expression in the lung. This led us to suspect that reduction of IGF-1R levels in lung tissue could prevent deleterious effects of oxygen exposure. Methods Since IGF-1R null mutant mice die at birth from respiratory failure, we generated compound heterozygous mice harboring a hypomorphic (Igf-1rneo and a knockout (Igf-1r- receptor allele. These IGF-1Rneo/- mice, strongly deficient in IGF-1R, were subjected to hyperoxia and analyzed for survival time, ventilatory control, pulmonary histopathology, morphometry, lung edema and vascular permeability. Results Strikingly, after 72 h of exposure to 90% O2, IGF-1Rneo/- mice had a significantly better survival rate during recovery than IGF-1R+/+ mice (77% versus 53%, P neo/- mice which developed conspicuously less edema and vascular extravasation than controls. Also, hyperoxia-induced abnormal pattern of breathing which precipitated respiratory failure was elicited less frequently in the IGF-1Rneo/- mice. Conclusion Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.

  19. Insulin-Like Growth Factor Binding Protein 1 Could Improve Glucose Regulation and Insulin Sensitivity Through Its RGD Domain.

    Science.gov (United States)

    Haywood, Natalie J; Cordell, Paul A; Tang, Kar Yeun; Makova, Natallia; Yuldasheva, Nadira Y; Imrie, Helen; Viswambharan, Hema; Bruns, Alexander F; Cubbon, Richard M; Kearney, Mark T; Wheatcroft, Stephen B

    2017-02-01

    Low circulating levels of insulin-like growth factor binding protein 1 (IGFBP-1) are associated with insulin resistance and predict the development of type 2 diabetes. IGFBP-1 can affect cellular functions independently of IGF binding through an Arg-Gly-Asp (RGD) integrin-binding motif. Whether causal mechanisms underlie the favorable association of high IGFBP-1 levels with insulin sensitivity and whether these could be exploited therapeutically remain unexplored. We used recombinant IGFBP-1 and a synthetic RGD-containing hexapeptide in complementary in vitro signaling assays and in vivo metabolic profiling in obese mice to investigate the effects of IGFBP-1 and its RGD domain on insulin sensitivity, insulin secretion, and whole-body glucose regulation. The RGD integrin-binding domain of IGFBP-1, through integrin engagement, focal adhesion kinase, and integrin-linked kinase, enhanced insulin sensitivity and insulin secretion in C2C12 myotubes and INS-1 832/13 pancreatic β-cells. Both acute administration and chronic infusion of an RGD synthetic peptide to obese C57BL/6 mice improved glucose clearance and insulin sensitivity. These favorable effects on metabolic homeostasis suggest that the RGD integrin-binding domain of IGFBP-1 may be a promising candidate for therapeutic development in the field of insulin resistance. © 2017 by the American Diabetes Association.

  20. Effect of KiFAY on Performance, Insulin-like Growth Factor-1, and Thyroid Hormones in Broilers

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    Amit Kini

    2016-10-01

    Full Text Available A comparative study was performed to investigate the efficacy of KiFAY as a feed additive on performance parameters, thyroid, and pancreatic hormone levels in broilers. Ninety birds (Vencobb 400 were randomly divided into three groups viz., Control (no DL-methionine supplementation, Treatment1 (containing added DL-methionine and Treatment 2 (containing KiFAY and without DL-methionine supplementation. The performance parameters (weekly body weight, body weight gain, feed intake, and feed consumption ratio were recorded and calculated during the whole study of 4 weeks. Analyses of insulin and insulin-like growth factor (IGF 1, triiodothyronine (T3, thyroxine (T4 and thyroid stimulating hormone (TSH were performed at the end of the study. The results show that birds on supplementation of KiFAY performed significantly (p<0.001 better than other treatments. The weekly body weight, body weight gain, feed in-take and feed consumption ratio improved in KiFAY treated birds. The study found an increase in insulin and IGF1 levels (p<0.001 in KiFAY compared with the other treatments. Serum T3, T4, and TSH levels in the Treatment 2 were higher than other treatments (p<0.001. The KiFAY supplementation was able to improve performance with associated responses at a hormonal level in broilers.

  1. Adeno-associated viral-mediated insulin-like growth factor delivery protects motor neurons in vitro.

    Science.gov (United States)

    Vincent, Andrea M; Feldman, Eva L; Song, Debbie K; Jung, Verena; Schild, Andreas; Zhang, Wei; Imperiale, Michael J; Boulis, Nicholas M

    2004-01-01

    Recent work has demonstrated that adeno-associated viral (AAV) vector-mediated delivery of the insulin-like growth factor (IGF-I) gene through retrograde axonal transport can prolong survival and delay disease onset in the superoxide dismutase mutant mouse model of motor neuron (MN) disease. The present experiment examines IGF-I gene transfer in vitro. Adenoviral and AAV vectors for IGF-I infect neurons triggering expression and secretion of biologically active IGF-I. AAV-mediated IGF-I expression in SH-SY5Y neurons protects both cells expressing the transgene, and bystanders without transgene expression from glutamate-induced apoptosis. Similarly, AAV-mediated IGF-I delivery in primary E15 MN culture provides a titer-dependent neuroprotection from glutamate-induced DNA fragmentation. Both infected and noninfected neurons are equally protected. These observations argue that vector-mediated IGF-I gene transfer induces secretion of active IGF-I that acts through direct effects on spinal cord MNs. This mechanism may explain the therapeutic effects observed in vivo despite relatively low affinity AAV spinal cord uptake.

  2. Intracellular protein delivery activity of peptides derived from insulin-like growth factor binding proteins 3 and 5.

    Science.gov (United States)

    Goda, Natsuko; Tenno, Takeshi; Inomata, Kosuke; Shirakawa, Masahiro; Tanaka, Toshiki; Hiroaki, Hidekazu

    2008-08-01

    Insulin-like growth factor binding proteins (IGFBPs) have various IGF-independent cellular activities, including receptor-independent cellular uptake followed by transcriptional regulation, although mechanisms of cellular entry remain unclear. Herein, we focused on their receptor-independent cellular entry mechanism in terms of protein transduction domain (PTD) activity, which is an emerging technique useful for clinical applications. The peptides of 18 amino acid residues derived from IGFBP-3 and IGFBP-5, which involve heparin-binding regions, mediated cellular delivery of an exogenous protein into NIH3T3 and HeLa cells. Relative protein delivery activities of IGFBP-3/5-derived peptides were approximately 20-150% compared to that of the HIV-Tat peptide, a potent PTD. Heparin inhibited the uptake of the fusion proteins with IGFBP-3 and IGFBP-5, indicating that the delivery pathway is heparin-dependent endocytosis, similar to that of HIV-Tat. The delivery of GST fused to HIV-Tat was competed by either IGFBP-3 or IGFBP-5-derived synthetic peptides. Therefore, the entry pathways of the three PTDs are shared. Our data has shown a new approach for designing protein delivery systems using IGFBP-3/5 derived peptides based on the molecular mechanisms of IGF-independent activities of IGFBPs.

  3. Increased insulin-like growth factor-1 levels in cerebrospinal fluid of advanced subacute sclerosing panencephalitis patients.

    Science.gov (United States)

    Yılmaz, Deniz; Yüksel, Deniz; Gökkurt, Didem; Oguz, Hava; Anlar, Banu

    2016-07-01

    Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal disease. Brain histopathology in certain SSPE patients shows, neurofibrillary tangles composed of abnormally phosphorylated, microtubule-associated protein tau (PHF-tau). Because the, phosphorylation of tau is inhibited by insulin and insulin-like growth factor-1 (IGF-1), we investigated cerebrospinal fluid (CSF) insulin and IGF-1 levels in SSPE patients. In this study CSF IGF-1 and insulin levels of 45 SSPE and 25 age-matched control patients were investigated. CSF IGF-1 levels were significantly higher in SSPE patients at stage 4, compared to other stages (p 0.05). CSF insulin and IGF-1 levels were both positively correlated with serum measles IgG. The correlation between CSF insulin and IGF-1 levels and serum measles virus IgG titer may be the result of, insulin activating IGF-1 receptors, and consequently, IGF-1 stimulating, plasma cells and enhancing IgG production. Increased IGF-1 may also, inhibit the phosphorylation of tau. Further studies examining the, correlation between IGF-1, insulin, tau, and PHF-tau levels in the same, patients may clarify any possible pathogenetic relation between these, pathways. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  4. A dose titration of triamcinolone acetonide on insulin-like growth factor-1 and interleukin-1-conditioned equine cartilage explants.

    Science.gov (United States)

    Sandler, E A; Frisbie, D D; McIlwraith, C W

    2004-01-01

    Previous in vitro pilot studies have defined a potentially beneficial effect of insulin-like growth factor-1 (IGF-1) and triamcinolone acetonide (TA) on interleukin-1 (IL-1)-conditioned equine cartilage. Furthermore, an optimal dose for IGF-1 treatment alone has been documented previously using the same test system as in the current project. To perform a dose titration of TA on IL-1-conditioned equine articular cartilage explants in the presence of an optimised IGF-1 dose, in order to optimise a triamcinolone concentration for use in combination with IGF-1 for future investigations. Cartilage explants were harvested from the distal femur of a normal horse. The effect of a clinically relevant TA dose range was evaluated in the presence of IL-1 and IGF-1 through measurement of proteoglycan (PG) matrix metabolism (synthesis and degradation). TA and IGF-1 in combination inhibited the IL-1-induced release of PG matrix components (glycosaminoglycan or GAG) from the articular cartilage, as well as producing a significant increase in GAG synthesis. This experiment provided proof of principle that a combination treatment appears to be able to combat the IL-1-induced matrix depletion, while enhancing anabolic metabolism within the articular cartilage. The use of IGF-1 in conjunction with TA in vivo has the potential to provide beneficial anabolic effects not seen with TA alone.

  5. MSC attenuate diabetes-induced functional impairment in adipocytes via secretion of insulin-like growth factor-1.

    Science.gov (United States)

    Gao, Dongyun; Xie, Jiangfan; Zhang, Junhua; Feng, Changjiang; Yao, Bin; Ma, Kui; Li, Jiwei; Wu, Xu; Huang, Sha; Fu, Xiaobing

    2014-09-12

    The function of subcutaneous adipocytes in promoting wound healing is significantly suppressed in diabetic wounds. Recent studies have demonstrated the ability of mesenchymal stem cell (MSC) to ameliorate impaired diabetic wound healing. We hypothesized that MSC function may involve subcutaneous adipocytes. The abnormal function of subcutaneous adipocytes from STZ induced diabetic mice including glucose uptake and free fatty acid (FFA) secretion level were assessed. Then these cells were co-cultured with MSC via a transwell system to observe the changes of metabolic index and glucose transporter four (GLUT4) as well as phosphoinositide 3-kinase/protein kinase (PI3K/AKT) signaling pathway expression. The results of metabolic index suggest that MSC obviously attenuated the diabetes-induced functional impairment. Both mRNA and protein expression analyses showed that PI3K/AKT insulin signaling pathway and GLUT4 expression were up-regulated. These changes were substantially associated with a increased level of insulin-like growth factor-1 (IGF-1) secretion from MSC. These findings suggest that MSC could attenuate abnormal function of diabetic adipocytes by IGF-1secretion, which was more or less associated with the beneficial effects of MSC on improving diabetic wound healing. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Role of the Insulin-Like Growth Factor Type 1 Receptor in the Pathogenesis of Diabetic Encephalopathy

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    Duo Zhang

    2015-01-01

    Full Text Available Defective cognitive function is common in patients with diabetes, suggesting that insulin normally exerts anabolic actions in neuron, namely, diabetic encephalopathy. However, because insulin can cross-activate the insulin-like growth factor type 1 receptor (IGF-1R, which also functions in most of tissues, such as muscle and bone, it has been difficult to establish the direct (IGF-1-independent actions of insulin in the pathogenesis of diabetic encephalopathy. To overcome this problem, we examined insulin signaling and action in primary PC-12 cells engineered for conditional disruption of the IGF-1 receptor (ΔIGF-1R. The results showed that the lower glucose metabolism and high expression of IGF-1R occurred in the brain of the DE rat model. The results also showed the defect of IGF-1R could significantly improve the ability of glucose consumption and enhance sensitivity to insulin-induced IR and Akt phosphorylation in PC12 cells. And meanwhile, IGF-1R allele gene knockout (IGF-1Rneo mice treated with HFD/STZ had better cognitive abilities than those of wild mice. Those results indicate that insulin exerts direct anabolic actions in neuron-like cells by activation of its cognate receptor and prove that IGF-1R plays an important role in the pathogenesis of diabetic encephalopathy.

  7. High plasma insulin-like growth factor-II and low lipid content in transgenic mice: measurements of lipid metabolism.

    Science.gov (United States)

    Da Costa, T H; Williamson, D H; Ward, A; Bates, P; Fisher, R; Richardson, L; Hill, D J; Robinson, I C; Graham, C F

    1994-12-01

    Transgenic mice were made by introducing extra copies of the mouse insulin-like growth factor-II (IGF-II) gene driven by the bovine keratin 10 promoter (BKVI). The adult plasma IGF-II levels were elevated at least three times in one line. In this line, there was a lower lipid content of both brown and white adipose depots at 2-4 months of age, and 40% less fat in the carcass at 7-9 months. The low lipid phenotype was not detected in the carcass at 2 weeks after birth. The lean characteristic was attributed to circulating IGF-II because the transgene was not expressed in fat. At 2-4 months of age, the transgenes oxidized more oral lipid, and less of this lipid was incorporated into the whole body and the epididymal fat. In contrast, the interscapular brown adipose tissue maintained lipid incorporation and lipoprotein lipase activity despite its reduced size. The altered activity of the brown adipose tissue may account for the gradual onset and persistence of the lean feature of the transgenic mice. There were no substantial changes in lipogenesis which could account for the low fat content. The plasma levels of IGF-I, insulin, glycerol, non-esterified fatty acids, triacylglycerols and glucose were not greatly changed and the pituitary GH content was within the normal range.

  8. Differential cellular synthesis of insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 within human liver.

    Science.gov (United States)

    Arany, E; Afford, S; Strain, A J; Winwood, P J; Arthur, M J; Hill, D J

    1994-12-01

    The two major insulin-like growth factor-binding protein (IGFBP) species in the human circulation, IGFBP-1 and IGFBP-3, are synthesized in large amounts by liver. To determine which hepatic cell populations in human liver were responsible for the synthesis and release of these IGFBPs, we 1) performed in situ hybridization with specific complementary RNA (RNA) probes for human IGFBP-1 or-3 or performed immunohistochemical analysis to reveal the sites of messenger RNA (mRNA) presence and peptide translation, respectively, in sections of normal liver derived from organ donors; and 2) examined the release of IGFBP species by Western ligand and immunoblots of medium conditioned by isolated cultures of hepatocytes, lipocytes, and Kupffer cells. In situ hybridization showed that IGFBP-1 mRNA was distributed widely among the parenchymal cell population, which also showed immunohistochemical staining for IGFBP-1 peptide. Conversely, IGFBP-3 mRNA and immunoreactive peptide were mainly localized to Kupffer cells, which were positively identified by immunoreactivity with antiserum against the glycoprotein marker, CD68. Isolated hepatocytes released two species of IGFBP of 28 and 30-32 kilodaltons, which were recognized immunologically as IGFBP-1. Isolated Kupffer cells released only a 43- to 46-kilodalton IGFBP immunologically recognized as IGFBP-3. Lipocyte cultures released no detectable IGFBP species. The results suggest that IGFBP-1 and IGFBP-3 are derived from separate cell populations in human liver.

  9. Insulin-like growth factor-1 receptor in mature osteoblasts is required for periosteal bone formation induced by reloading

    Science.gov (United States)

    Kubota, Takuo; Elalieh, Hashem Z.; Saless, Neema; Fong, Chak; Wang, Yongmei; Babey, Muriel; Cheng, Zhiqiang; Bikle, Daniel D.

    2013-11-01

    Skeletal loading and unloading has a pronounced impact on bone remodeling, a process also regulated by insulin-like growth factor-1 (IGF-1) signaling. Skeletal unloading leads to resistance to the anabolic effect of IGF-1, while reloading after unloading restores responsiveness to IGF-1. However, a direct study of the importance of IGF-1 signaling in the skeletal response to mechanical loading remains to be tested. In this study, we assessed the skeletal response of osteoblast-specific Igf-1 receptor deficient (Igf-1r-/-) mice to unloading and reloading. The mice were hindlimb unloaded for 14 days and then reloaded for 16 days. Igf-1r-/- mice displayed smaller cortical bone and diminished periosteal and endosteal bone formation at baseline. Periosteal and endosteal bone formation decreased with unloading in Igf-1r+/+ mice. However, the recovery of periosteal bone formation with reloading was completely inhibited in Igf-1r-/- mice, although reloading-induced endosteal bone formation was not hampered. These changes in bone formation resulted in the abolishment of the expected increase in total cross-sectional area with reloading in Igf-1r-/- mice compared to the control mice. These results suggest that the Igf-1r in mature osteoblasts has a critical role in periosteal bone formation in the skeletal response to mechanical loading.

  10. The effects of spaceflight and Insulin-like Growth Factor-1 on the T-cell and macrophage populations

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    Pecaut, M.J.; Simske, S.J. [BioServe Space Technologies Engineering Center Campus Box 429 University of Colorado Boulder, Colorado80309 (United States); Fleshner, M. [Laboratory of Behavioral Neuroscience Department of Psychology Campus Box 345 University of Colorado Boulder, Colorado80309 (United States); Zimmerman, R. [Chiron Corporation, 4560 Horton St., Emeryville, California94025 (United States)

    1997-01-01

    Twelve Sprague-Dawley rats were flown aboard the Space Shuttle Endeavor (STS-77) to study the effects of microgravity-induced stress on the immunoskeletal system. Sixteen rats were used as simultaneous vivarium ground controls during the ten day mission. Osmotic pumps, half of which contained Insulin-like Growth Factor-1 (IGF-1, provided by Chiron), were surgically implanted (subcutaneous) into the rats prior to launch in an attempt to counter any stress effects. On the day of landing, the rats were sacrificed and dissected. Splenocytes and thymocytes were labeled with antibodies against CD4, CD8, CD11b, and TCR for flow cytometry. The percentage of splenic cytotoxic/suppressor (TCR+/CD8+) T-cells increased significantly (by 118{percent}) in spaceflight. There were also decreases in splenic helper (TCR+/CD4+) T-cells and (CD11b+) macrophages (by 33{percent} and 38{percent}, respectively). Together, these results suggest the stress of spaceflight could cause a significant decrease in the ability of rats to mount an immune response. The effects of IGF-1 on cell population distributions were negligible for both flight and vivarium ground controls. However, there were significant differences in spleen and thymus masses suggesting that while IGF-1 did not effect population distributions, the drug may have caused an increase in population size. {copyright} {ital 1997 American Institute of Physics.}

  11. Airway epithelial cell-derived insulin-like growth factor-1 triggers skewed CD8(+) T cell polarization.

    Science.gov (United States)

    Zou, Jian-Yong; Huang, Shao-hong; Li, Yun; Chen, Hui-guo; Rong, Jian; Ye, Sheng

    2014-10-01

    Skewed CD8(+) T cell responses are important in airway inflammation. This study investigates the role of the airway epithelial cell-derived insulin-like growth factor 1 (IGF1) in contributing to CD8(+) T cell polarization. Expression of IGF1 in the airway epithelial cell line, RPMI2650 cells, was assessed by quantitative real time RT-PCR and Western blotting. The role of IGF1 in regulating CD8(+) T cell activation was observed by coculture of mite allergen-primed RPMI2650 cells and naïve CD8(+) T cells. CD8(+) T cell polarization was assessed by the carboxyfluorescein succinimidyl ester-dilution assay and the determination of cytotoxic cytokine levels in the culture medium. Exposure to mite allergen, Der p1, increased the expression of IGF1 by RPMI2650 cells. The epithelial cell-derived IGF1 prevented the activation-induced cell death by inducing the p53 gene hypermethylation. Mite allergen-primed RPMI2650 cells induced an antigen-specific CD8(+) T cell polarization. We conclude that mite allergens induce airway epithelial cell line, RPMI2650 cells, to produce IGF1; the latter contributes to antigen-specific CD8(+) T cell polarization. © 2014 International Federation for Cell Biology.

  12. Serum Insulin-like Growth Factor I Quantitation by Mass Spectrometry: Insights for Protein Quantitation with this Technology.

    Science.gov (United States)

    Kam, Richard Kin Ting; Ho, Chung Shun; Chan, Michael Ho Ming

    2016-12-01

    Liquid chromatography mass spectrometry (LC-MS) is a widely used technique in the clinical laboratory, especially for small molecule quantitation in biological specimens, for example, steroid hormones and therapeutic drugs. Analysis of circulating macromolecules, including proteins and peptides, is largely dominated by traditional enzymatic, spectrophotometric, or immunological assays in clinical laboratories. However, these methodologies are known to be subjected to interfering substances, for example heterophilic antibodies, as well as subjected to non-specificity issues. In recent years, there has been a growing interest in using LC-MS platforms for protein analysis in the clinical setting, due to the superior specificity compared to immunoassay, and the possibility of simultaneous quantitation of multiple proteins. Different analytical approaches are possible using LC-MS-based methodology, including accurate mass measurement of intact molecules, protein digestion followed by detection of proteolytic peptides, and in combination with immunoaffinity purification. Proteins with different complexity, isoforms, variants, or chemical alteration can be simultaneously analysed by LC-MS, either by targeted or non-targeted approaches. While the LC-MS platform offers a more specific determination of proteins, there remain issues of LC-MS assay harmonization, correlation with current existing platforms, and the potential impact in making clinical decision. In this review, the clinical utility, historical aspect, and challenges in using LC-MS for protein analysis in the clinical setting will be discussed, using insulin-like growth factor (IGF) as an example.

  13. Effects of insulin-like growth factor-1 on the relaxation responses of the cavernous smooth muscle from aged rats.

    Science.gov (United States)

    Xu, Zhan-Ping; Wang, Huai-Peng; Liu, Jiu-Min; Zheng, Xiang-Guang; Wu, Dan; Pu, Xiao-Yong

    2015-06-01

    The aim of this study was determine whether intracavernosal injection (ICI) of insulin-like growth factor-1 (IGF-1) protein can improve corpus cavernosal smooth muscle relaxation in aging rats. Ten young (4-month-old) and 30 old (24-month-old) Sprague-Dawley male rats were enrolled in the study. The old rats were divided into three groups: vehicle-only (n = 10), IGF-1 1 µg/kg (n = 10) and IGF-1 10 µg/kg treatment groups (n = 10). After 4 weeks of single IGF-1 injection treatment, strips of corporal tissue were precontracted with phenylephrine, and dose-response curves were generated to evaluate endothelial-dependent [acetylcholine (ACh)], endothelial-independent [sodium nitroprusside (SNP)] and electrical field stimulation (EFS) vasoreactivity. The changes in percentage of cavernosal smooth muscle and the concentration of nitric oxide (NO) in penile tissue were also evaluated. After IGF-1 treatment, the vasoreactivity was significantly improved in both the 1 µg/kg and the 10 µg/kg treatment groups compared with the vehicle-only group at 4 weeks in response to ACh, SNP and EFS (all p corpus cavernosum of the aging rat.

  14. Antioxidant effects of insulin-like growth factor-I (IGF-I in rats with advanced liver cirrhosis

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    Puche Juan

    2005-03-01

    Full Text Available Abstract Background The exogenous administration of Insulin-like Growth Factor-I (IGF-I induces hepatoprotective and antifibrogenic actions in experimental liver cirrhosis. To better understand the possible pathways behind the beneficial effect of IGF-I, the aim of this work was to investigate severe parameters involved in oxidative damage in hepatic tissue from cirrhotic animals treated with IGF-I (2 μg. 100 g-1. day-1. Iron and copper play an important role in oxidative mechanisms, producing the deleterious hydroxyl radical (*OH that peroxides lipid membranes and damages DNA. Myeloperoxidase (MPO and nitric oxide (NO are known sources of free radicals and induce reduction of ferritin-Fe3+ into free Fe2+, contributing to oxidative damage. Methods Liver cirrhosis was induced by CCl4 inhalation in Wistar male rats for 30 weeks. Healthy controls were studied in parallel (n = 10. Fe and Cu were assessed by atomic absoption spectrometry and iron content was also evaluated by Perls' staining. MPO was measured by ELISA and transferrin and ferritin by immunoturbidimetry. iNOS expression was studied by immuno-histochemistry. Results Liver cirrhosis was histologically proven and ascites was observed in all cirrhotic rats. Compared to controls untreated cirrhotic rats showed increased hepatic levels of iron, ferritin, transferrin (p Conclusion the hepatoprotective and antifibrogenic effects of IGF-I in cirrhosis are associated with a diminution of the hepatic contents of several factors all of them involved in oxidative damage.

  15. Detection of anti-sense transcripts of the insulin-like growth factor-2 gene in Wilms' tumor.

    Science.gov (United States)

    Baccarini, P.; Fiorentino, M.; D'Errico, A.; Mancini, A. M.; Grigioni, W. F.

    1993-01-01

    The expression of the insulin-like growth factor-2 (IGF-2) gene was studied by means of both in situ hybridization and immunohistochemistry in eight cases of Wilms' tumor with different histological features. An anti-sense cRNA IGF-2 probe revealed the presence of abundant IGF-2 mRNAs in all eight tumors examined, localized in the most undifferentiated tumoral cells (blastemal cells); none of the tumors showed immunoreactivity for the anti-IGF-2 antibody. Using a sense cRNA IGF-2 probe, we also detected anti-sense transcripts of the IGF-2 gene in five of eight tumors. These transcripts were exclusively localized in the cells expressing the IGF-2 mRNAs. Although the function of these anti-sense transcripts is unknown, we think that their presence could explain the lack of IGF-2 peptides in Wilms' tumors despite increased expression of IGF-2 mRNAs. Images Figure 1 Figure 2 Figure 3 PMID:8256846

  16. Adult and near-adult height in patients with severe insulin-like growth factor-I deficiency after long-term therapy with recombinant human insulin-like growth factor-I.

    Science.gov (United States)

    Backeljauw, Philippe F; Kuntze, Joyce; Frane, James; Calikoglu, Ali S; Chernausek, Steven D

    2013-01-01

    Treatment with recombinant human insulin-like growth factor-I (IGF-I) stimulates linear growth in children with severe IGF-I deficiency (IGFD). To evaluate the efficacy and safety of treatment with IGF-I in patients with severe IGFD treated until adult or near-adult height. Twenty-one children with severe IGFD were treated until adult or near-adult height under a predominantly open-label design. All patients were naive to IGF-I. Recombinant human IGF-I was administered subcutaneously in doses between 60 and 120 µg/kg twice daily. Nine patients received additional therapy with gonadotropin- releasing hormone (GnRH) analog for a mean period of 2.9 ± 1.8 years. Mean duration of treatment was 10.0 years. Mean height velocity increased from 3.1 cm/year prior to treatment to 7.4 cm/year during the first year of treatment. Height velocities during the subsequent years were lower, but remained above baseline for up to 12 years. Cumulative mean Δ height SD score at (near) adult height was +2. The observed mean gain in height was 13.4 cm more than had been expected without treatment. The adult height achieved by the patients also treated with GnRH analog was not different from those who received IGF-I therapy alone. There were no new safety signals identified in these patients, a subset of those previously reported. Long-term therapy with IGF-I improves adult height of patients with severe IGFD. Most patients did not bring their heights into the normal adult range. Copyright © 2013 S. Karger AG, Basel.

  17. AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells.

    Science.gov (United States)

    Beltran, Pedro J; Mitchell, Petia; Chung, Young-A; Cajulis, Elaina; Lu, John; Belmontes, Brian; Ho, Joanne; Tsai, Mei Mei; Zhu, Min; Vonderfecht, Steven; Baserga, Renato; Kendall, Richard; Radinsky, Robert; Calzone, Frank J

    2009-05-01

    Pancreatic carcinoma is a leading cause of cancer deaths, and recent clinical trials of a number of oncology therapeutics have not substantially improved clinical outcomes. We have evaluated the therapeutic potential of AMG 479, a fully human monoclonal antibody against insulin-like growth factor (IGF) type I receptor (IGF-IR), in two IGF-IR-expressing pancreatic carcinoma cell lines, BxPC-3 and MiaPaCa2, which also differentially express insulin receptor (INSR). AMG 479 bound to IGF-IR (K(D) 0.33 nmol/L) and blocked IGF-I and IGF-II binding (IC(50) AMG 479 completely inhibited ligand-induced (IGF-I, IGF-II, and insulin) activation of IGF-IR homodimers and IGF-IR/INSR hybrids (but not INSR homodimers) leading to reduced cellular viability in serum-deprived cultures. AMG 479 inhibited >80% of basal IGF-IR activity in BxPC-3 and MiaPaCa2 xenografts and prevented IGF-IR and IGF-IR/INSR hybrid activation following challenge with supraphysiologic concentrations of IGF-I. As a single agent, AMG 479 inhibited (∼ 80%) the growth of pancreatic carcinoma xenografts, and long-term treatment was associated with reduced IGF-IR signaling activity and expression. Efficacy seemed to be the result of two distinct biological effects: proapoptotic in BxPC-3 and antimitogenic in MiaPaCa2. The combination of AMG 479 with gemcitabine resulted in additive inhibitory activity both in vitro and in vivo. These results indicate that AMG 479 is a clinical candidate, both as a single agent and in combination with gemcitabine, for the treatment of patients with pancreatic carcinoma

  18. Elevated Serum Insulin-Like Growth Factor 1 Levels in Patients with Neurological Remission after Traumatic Spinal Cord Injury.

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    Arash Moghaddam

    Full Text Available After traumatic spinal cord injury, an acute phase triggered by trauma is followed by a subacute phase involving inflammatory processes. We previously demonstrated that peripheral serum cytokine expression changes depend on neurological outcome after spinal cord injury. In a subsequent intermediate phase, repair and remodeling takes place under the mediation of growth factors such as Insulin-like Growth Factor 1 (IGF-1. IGF-1 is a promising growth factor which is thought to act as a neuroprotective agent. Since previous findings were taken from animal studies, our aim was to investigate this hypothesis in humans based on peripheral blood serum. Forty-five patients after traumatic spinal cord injury were investigated over a period of three months after trauma. Blood samples were taken according to a fixed schema and IGF-1 levels were determined. Clinical data including AIS scores at admission to the hospital and at discharge were collected and compared with IGF-1 levels. In our study, we could observe distinct patterns in the expression of IGF-1 in peripheral blood serum after traumatic spinal cord injury regardless of the degree of plegia. All patients showed a marked increase of levels seven days after injury. IGF-1 serum levels were significantly different from initial measurements at four and nine hours and seven and 14 days after injury, as well as one, two and three months after injury. We did not detect a significant correlation between fracture and the IGF-1 serum level nor between the quantity of operations performed after trauma and the IGF-1 serum level. Patients with clinically documented neurological remission showed consistently higher IGF-1 levels than patients without neurological remission. This data could be the base for the establishment of animal models for further and much needed research in the field of spinal cord injury.

  19. Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury.

    Science.gov (United States)

    Feeney, Claire; Sharp, David J; Hellyer, Peter J; Jolly, Amy E; Cole, James H; Scott, Gregory; Baxter, David; Jilka, Sagar; Ross, Ewan; Ham, Timothy E; Jenkins, Peter O; Li, Lucia M; Gorgoraptis, Nikos; Midwinter, Mark; Goldstone, Anthony P

    2017-07-01

    Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43. © 2017 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

  20. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression.

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    Pouladi, Mahmoud A; Xie, Yuanyun; Skotte, Niels Henning; Ehrnhoefer, Dagmar E; Graham, Rona K; Kim, Jeong Eun; Bissada, Nagat; Yang, X William; Paganetti, Paolo; Friedlander, Robert M; Leavitt, Blair R; Hayden, Michael R

    2010-04-15

    Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing a truncated N-terminal htt fragment (shortstop), indicating that FL htt is required for the modulation of IGF-1 expression. Treatment with 17beta-estradiol (17beta-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17beta-ED, but not placebo, reduces plasma IGF-1 levels and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128 and littermate WT mice. We demonstrate that the levels of FL htt influence IGF-1 expression in striatal tissues. Our data identify a novel function for FL htt in influencing IGF-1 expression.

  1. Hepatic insulin-like growth-factor binding protein (igfbp) responses tofood restriction in Atlantic salmon smolts

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    Breves, Jason P.; Phipps-Costin, Silas K.; Fujimoto, Chelsea K.; Einarsdottir, Ingibjörg E.; Regish, Amy M.; Björnsson, Björn Thrandur; McCormick, Stephen

    2016-01-01

    The growth hormone (Gh)/insulin-like growth-factor (Igf) system plays a central role in the regulation of growth in fishes. However, the roles of Igf binding proteins (Igfbps) in coordinating responses to food availability are unresolved, especially in anadromous fishes preparing for seaward migration. We assayed plasma Gh, Igf1, thyroid hormones and cortisol along with igfbp mRNA levels in fasted and fed Atlantic salmon ( Salmo salar ). Fish were fasted for 3 or 10 days near the peak of smoltification (late April to early May). Fasting reduced plasma glucose by 3 days and condition factor by 10 days. Plasma Gh, cortisol, and thyroxine (T 4 ) were not altered in response to fasting, whereas Igf1 and 3,5,3′-triiodo- l -thyronine (T 3 ) were slightly higher and lower than controls, respectively. Hepatic igfbp1b1 , - 1b2 , - 2a , - 2b1 and - 2b2 mRNA levels were not responsive to fasting, but there were marked increases in igfbp1a1 following 3 and 10 days of fasting. Fasting did not alter hepatic igf1or igf2 ; however, muscle igf1 was diminished by 10 days of fasting. There were no signs that fasting compromised branchial ionoregulatory functions, as indicated by unchanged Na + /K + -ATPase activity and ion pump/transporter mRNA levels. We conclude that dynamic hepatic igfbp1a1 and muscle igf1 expression participate in the modulation of Gh/Igf signaling in smolts undergoing catabolism.

  2. Insulin-like growth factor-independent insulin-like growth factor binding protein 3 promotes cell migration and lymph node metastasis of oral squamous cell carcinoma cells by requirement of integrin β1.

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    Yen, Yi-Chen; Hsiao, Jenn-Ren; Jiang, Shih Sheng; Chang, Jeffrey S; Wang, Ssu-Han; Shen, Ying-Ying; Chen, Chung-Hsing; Chang, I-Shou; Chang, Jang-Yang; Chen, Ya-Wen

    2015-12-08

    Frequent metastasis to the cervical lymph nodes leads to poor survival of patients with oral squamous cell carcinoma (OSCC). To understand the underlying mechanisms of lymph node metastasis, two sublines were successfully isolated from cervical lymph nodes of nude mice through in vivo selection, and identified as originating from poorly metastatic parental cells. These two sublines specifically metastasized to cervical lymph nodes in 83% of mice, whereas OEC-M1 cells did not metastasize after injection into the oral cavity. After gene expression analysis, we identified insulin-like growth factor binding protein 3 (IGFBP3) as one of the significantly up-regulated genes in the sublines in comparison with their parental cells. Consistently, meta-analysis of the public microarray datasets and IGFBP3 immunohistochemical analysis revealed increased both levels of IGFBP3 mRNA and protein in human OSCC tissues when compared to normal oral or adjacent nontumorous tissues. Interestingly, the up-regulated IGFBP3 mRNA expression was significantly associated with OSCC patients with lymph node metastasis. IGFBP3 knockdown in the sublines impaired and ectopic IGFBP3 expression in the parental cells promoted migration, transendothelial migration and lymph node metastasis of orthotopic transplantation. Additionally, ectopic expression of IGFBP3 with an IGF-binding defect sustained the IGFBP3-enhanced biological functions. Results indicated that IGFBP3 regulates metastasis-related functions of OSCC cells through an IGF-independent mechanism. Furthermore, exogenous IGFBP3 was sufficient to induce cell motility and extracellular signal-regulated kinase (ERK) activation. The silencing of integrin β1 was able to impair exogenous IGFBP3-mediated migration and ERK phosphorylation, suggesting a critical role of integrin β1 in IGFBP3-enchanced functions.

  3. INSULIN LIKE GROWTH FACTOR 1 POSSIBLE DEPENDENCE IN PATIENTS WITH METABOLIC SYNDROME OF NODULAR PATHOLOGY OF THE THYROID GLAND.

    Science.gov (United States)

    Rekvava, M; Dundua, T; Kobulia, M; Javashvili, L; Giorgadze, E

    2017-09-01

    Metabolic syndrome and nodular pathology of the thyroid gland is a widespread problem nowadays. Recently there has been a notable coincidence between metabolic syndrome and nodular pathology of thyroid gland. Hence, it is interesting to reveal the connection between these two diseases. It is possible that insulin-like growth factor system (IGF), namely IGF 1 is connecting link between metabolic syndrome and nodular pathology of thyroid gland, because IGF1 stimulates growth and proliferation of cells in the body. We have investigated18-82 years of age 71 patients. group 1 n27- subjects with thyroid nodular disease, and metabolic syndrome, group 2 n31- subjects with thyroid nodular disease and without metabolic syndrome. group 3 n13 - subjects with metabolic syndrome and no thyroid pathology. In all groups were assessed thyroid structural data, defined parameters of carbohydrate metabolism, thyroid function and blood concentration of IGF1. In patients with hyperinsulinemia IGF 1 was noted in normal or reduced concentration. In I group IGF1 was normal in 70,4% (n=19), decreased in 29,6% (n=8), In II group was normal in 77,4 % (n=24), decreased in 22,6% (n=7) and in III group was normal in 76,9% (n=10), decreased in 23,1% (n=3). Increase of IGF 1 in patients with thyroid nodular disease patients was not noted. Statistically significant connection between IGF1 and thyroid nodules was not revealed. For the further investigation of this connection we plan to measure IGF1 in the thyroid histological samples in the future studies.

  4. The effect of subcutaneous Insulin-like Growth Factor-1 (IGF-1 injection on rabbit auricular cartilage autograft viability

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    Guclu Kaan Beriat

    2012-11-01

    Full Text Available Insulin-like Growth Factor-1 (IGF-1 is one of the significant substances affecting the growth and development of cartilage tissue in the body. The aim of this study is to evaluate the possible histopathological effects of local IGF-1 injection on the viability of rabbit auricular cartilage autografts.To this end, the single-piece and sliced cartilage tissues obtained from 20 albino rabbits’ auricula were implanted in the subcutaneous pockets created on the back skins of the experimental animals. Every two weeks IGF-1 (10 mg/ml injections were performed on the autograft implants of one group and normal saline (0.9% injections were performed on the other group. Experimental animals were sacrificed at the end of the third month. A total of 34 tissue samples obtained after dissection were evaluated and scored histopathologically according to their cartilage viability, environmental reaction, and regenerative activities.The intergroup evaluation carried out for the single-piece and sliced cartilage grafts revealed that there was statistically more cartilage viability and less foreign-body reaction in the IGF-1 group than the normal saline group (p<0.05.While there was a statistically significant difference between the groups for single-piece grafts regarding regenerative activity (p<0.05, there was no significant difference for sliced grafts. The IGF-1 group, however, showed more activity.The results we obtained point out to the fact that IGF-1 increases the tissue viability of the implanted auricular autograft and it suppresses immune modulation effect.

  5. Determination of insulin-like growth factor-I reference values using an immunoradiometric assay in a Brazilian adult population.

    Science.gov (United States)

    Leite, Denise B; Meirelles, Ricardo M R; Mandarim-De-Lacerda, Carlos A; Matos, Haroldo J; Santos-Filho, Sebastião D; Bernardo-Filho, Mario

    2012-01-01

    Serum levels of total insulin-like growth factor I (IGF-I) reflect endogenous growth hormone (GH) secretion in healthy adults, which makes it a good diagnostic marker for screening of GH-related disorders. Studies also have supported a possible relation between IGF-I levels and the risk and prognostic for some malignancies, besides a relation between IGF-I levels and mortality. As the determination of the IGF-I normal values for local populations is strongly desired, the aim of this investigation was to determine reference values for IGF-I using an immunoradiometric assay (IRMA) in an adult Brazilian population of Rio de Janeiro city, since there is no other study using this methodology in Brazilian population, and that this method is widely used in Brazil and worldwide. The study included samples of blood taken from 484 healthy subjects (251 men and 233 women) aged 18-70. The subjects agreed with this study, approved by the Ethical Committee of the Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti, Rio de Janeiro, Brazil. The samples were analyzed using a Diagnostic System Laboratories kit. For data analysis, age- and sex-specific figures were fitted after transformation of IGF-I values. In adulthood, a slow age-dependent decrease was found. There was no significant difference in IGF-I values between men and women. This study established age-specific IGF-I reference values, for a healthy Brazilian adult population, determined by a widely IGF-I, IRMA used currently in Brazil.

  6. Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2.

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    Say Viengchareun

    2008-02-01

    Full Text Available The lactogenic hormones prolactin (PRL and placental lactogens (PL play central roles in reproduction and mammary development. Their actions are mediated via binding to PRL receptor (PRLR, highly expressed in brown adipose tissue (BAT, yet their impact on adipocyte function and metabolism remains unclear.PRLR knockout (KO newborn mice were phenotypically characterized in terms of thermoregulation and their BAT differentiation assayed for gene expression studies. Derived brown preadipocyte cell lines were established to evaluate the molecular mechanisms involved in PRL signaling on BAT function. Here, we report that newborn mice lacking PRLR have hypotrophic BAT depots that express low levels of adipocyte nuclear receptor PPARgamma2, its coactivator PGC-1alpha, uncoupling protein 1 (UCP1 and the beta3 adrenoceptor, reducing mouse viability during cold challenge. Immortalized PRLR KO preadipocytes fail to undergo differentiation into mature adipocytes, a defect reversed by reintroduction of PRLR. That the effects of the lactogens in BAT are at least partly mediated by Insulin-like Growth Factor-2 (IGF-2 is supported by: i a striking reduction in BAT IGF-2 expression in PRLR KO mice and in PRLR-deficient preadipocytes; ii induction of cellular IGF-2 expression by PRL through JAK2/STAT5 pathway activation; and iii reversal of defective differentiation in PRLR KO cells by exogenous IGF-2.Our findings demonstrate that the lactogens act in concert with IGF-2 to control brown adipocyte differentiation and growth. Given the prominent role of brown adipose tissue during the perinatal period, our results identified prolactin receptor signaling as a major player and a potential therapeutic target in protecting newborn mammals against hypothermia.

  7. Insulin-like growth factor-1 gene delivery may enhance the proliferation of human corpus cavernosal smooth muscle cells.

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    Kim, Minkyung; Hwang, Eu Chang; Park, In-Kyu; Park, Kwangsung

    2010-08-01

    To investigate the effects of IGF-1 gene transfer in human corpus cavernosal smooth muscle cells (HCCSMCs) ex vivo. Insulin-like growth factor-1 (IGF-1) promotes the proliferation of penile cavernous smooth muscle cells in the rats. A plasmid expressing human IGF-1 was constructed by subcloning hIGF-1 into pcDNA3.1 vector. HCCSMCs were harvested from 3 impotent patients and cultured in vitro. The cultured smooth muscle cells were identified by immunofluorescent staining. RNA was extracted from HCCSMCs, and the gene expression of IGF-1 was determined by reverse transcription-polymerase chain reaction. Cell growth was examined by use of a novel cell proliferation assay based on the bioreduction of the fluorescent dye Alamar blue. The subcloned product was transfected into HCCSMCs. Western blotting and immunoassay were performed 2 days after transfection to evaluate the transfection efficiency. Endogenous IGF-1 mRNA expression was detected by reverse transcription-polymerase chain reaction analysis of total RNA extracted from cultured HCCSMCs. Increased proliferation of HCCSMCs in vitro was observed with exogenous treatment with IGF-1 (100 ng/mL) in a dose-dependent manner. Exogenous IGF-1 gene transfer to cultured HCCSMCs enhanced IGF-1 protein expression compared with the control, and the expression level peaked at 4 days after transfection and decreased slowly thereafter. Secretion of IGF-1 from transfected HCCSMCs induced cellular proliferation. IGF-1 gene transfer into HCCSMCs enhanced cellular proliferation, which was mediated by secretion of IGF-1. Our results suggest that IGF-1 gene therapy may be applied to corpus cavernosum regeneration. Copyright 2010 Elsevier Inc. All rights reserved.

  8. Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors

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    Campbell Craig I

    2011-11-01

    Full Text Available Abstract Background Targeted therapies are becoming an essential part of breast cancer treatment and agents targeting the type I insulin-like growth factor receptor (IGF-IR are currently being investigated in clinical trials. One of the limitations of targeted therapies is the development of resistant variants and these variants typically present with unique gene expression patterns and characteristics compared to the original tumor. Results MTB-IGFIR transgenic mice, with inducible overexpression of the IGF-IR were used to model mammary tumors that develop resistance to IGF-IR targeting agents. IGF-IR independent mammary tumors, previously shown to possess characteristics associated with EMT, were found to express elevated levels of PDGFRα and PDGFRβ. Furthermore, these receptors were shown to be inversely expressed with the IGF-IR in this model. Using cell lines derived from IGF-IR-independent mammary tumors (from MTB-IGFIR mice, it was demonstrated that PDGFRα and to a lesser extent PDGFRβ was important for cell migration and invasion as RNAi knockdown of PDGFRα alone or PDGFRα and PDGFRβ in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFRα and PDGFRβ resulted in a modest increase in cell proliferation and a decrease in apoptosis. Conclusion During IGF-IR independence, PDGFRs are upregulated and function to enhance tumor cell motility. These results demonstrate a novel interaction between the IGF-IR and PDGFRs and highlight an important, therapeutically relevant pathway, for tumor cell migration and invasion.

  9. Insulin, insulin-like growth factor–1, insulin receptor, and insulin-like growth factor–1 receptor expression in the chick eye and their regulation with imposed myopic or hyperopic defocus

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    Penha, Alexandra Marcha; Schaeffel, Frank

    2011-01-01

    Purpose Insulin stimulates eye growth in chicks and this effect is greatly enhanced if the retinal image is degraded by the defocus of either sign. However, it is unclear whether the insulin receptor (IR) is expressed at all in the chicken retina in animals 1–2 weeks post-hatching. We have investigated IR expression and whether IR transcript abundance varies in the fundal layers. To elucidate the possible role of insulin and insulin-like growth factor (IGF)-1 signaling in eye growth regulation, mRNA (mRNA) levels were measured for insulin, IGF-1, IR, and IGF-1 receptor (IGF-1R) during imposed negative or positive defocus. Methods Chicks were treated binocularly with positive or negative spectacle lenses for 4 or 24 h, or they remained untreated (n=6, for each treatment group). Northern blot analyses were performed to screen for transcription variants in the different fundal layers of untreated animals. Real-time PCR was used to quantify IR, IGF-1R, IGF-1, and insulin mRNA levels in the different fundal layers of the chick eye in the three treatment groups. Results IR mRNA was found in all the studied tissues, although there is evidence of tissue-specific transcript variations. Three major transcripts were detected for IR. The brain, retina, and choroid showed the longest transcript (4.3 kb), which was not present in the liver. Nevertheless, the liver and brain showed a second transcript (2.6 kb) not present in the retina and choroid. A short transcript (1.3 kb) was the predominant form in the liver and choroid, and it seems to be present in the retinal pigment epithelium (RPE) and sclera as well. In the retina, no significant gene expression changes were found when defocus was imposed. Interestingly, in the RPE, both IR and IGF-1R were already downregulated after short periods (4 h) of positive lens wear. In contrast, IR and IGF-1R were upregulated in the choroid and fibrous sclera during treatment with negative, but not positive, lenses. Conclusions Differences

  10. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A

    OpenAIRE

    Lawrence, James B.; Oxvig, Claus; Overgaard, Michael T.; Sottrup-Jensen, Lars; Gleich, Gerald J.; Hays, Lara G.; Yates, John R.; Conover, Cheryl A.

    1999-01-01

    Proteolytic cleavage of the six known insulin-like growth factor binding proteins (IGFBPs) is a powerful means of rapid structure and function modification of these important growth-regulatory proteins. Intact IGFBP-4 is a potent inhibitor of IGF action in vitro, and cleavage of IGFBP-4 has been shown to abolish its ability to inhibit IGF stimulatory effects in a variety of systems, suggesting that IGFBP-4 proteolysis acts as a positive regulator of IGF bioavailability. Here we report the iso...

  11. Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype.

    Science.gov (United States)

    Tarantini, Stefano; Valcarcel-Ares, Noa M; Yabluchanskiy, Andriy; Springo, Zsolt; Fulop, Gabor A; Ashpole, Nicole; Gautam, Tripti; Giles, Cory B; Wren, Jonathan D; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2017-06-01

    Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver-specific knockdown of IGF-1 (Igf1 f/f  + TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment. In IGF-1-deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress-mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension-induced cerebrovascular oxidative stress and MMP activation were increased in IGF-1-deficient mice. We found that IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF-1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF-1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high-risk elderly patients. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  12. Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients

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    Buckley Michael T

    2008-11-01

    Full Text Available Abstract Background Different Insulin-like Growth Factor Binding Proteins (IGFBPs have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression. Methods The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56 prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients. Results Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01 A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 μg/ml vs. 3.4 μg/ml, respectively, p = 0.09. However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients. Conclusion Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients.

  13. Insulin-like growth factor I signaling for brain recovery and exercise ability in brain ischemic rats.

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    Chang, Heng-Chih; Yang, Yea-Ru; Wang, Paulus S; Kuo, Chia-Hua; Wang, Ray-Yau

    2011-12-01

    Exercise increases neuron survival and plasticity in the adult brain by enhancing the uptake of insulin-like growth factor I (IGF-I). Exercise also reduces the infarct volume in the ischemic brain and improves motor function after such a brain insult. However, the underlying mechanisms are not fully known. The purpose of this study was to investigate the involvement of IGF-I signaling in neuroprotection after exercise. Rats were assigned to one of four groups: middle cerebral artery occlusion (MCAO) without exercise training (MC), MCAO with exercise training (ME), MCAO with IGF-I receptor inhibitor and without exercise training (MAg), and MCAO with IGF-I receptor inhibitor and exercise training (MEAg). Rats in the ME and MEAg groups underwent treadmill training for 14 d, and rats in the MC and MAg groups served as controls. After the final intervention, rats were sacrificed under anesthesia, and samples were collected from the affected motor cortex, striatum, and plasma. IGF-I and p-Akt levels in the affected motor cortex and the striatum of the ME group were significantly higher than those in the MC group, with significant decreases in infarct volume and improvements in motor function. However, IGF-I receptor inhibitor eliminated these effects and decreased the exercise ability. The brain IGF-I signaling strongly correlated with exercise ability. Exercise-enhanced IGF-I entrance into ischemic brain and IGF-I signaling was related to exercise-mediated neuroprotection. IGF-1 signaling also affected the ability to exercise after brain ischemia.

  14. Light stimuli control neuronal migration by altering of insulin-like growth factor 1 (IGF-1) signaling.

    Science.gov (United States)

    Li, Ying; Komuro, Yutaro; Fahrion, Jennifer K; Hu, Taofang; Ohno, Nobuhiko; Fenner, Kathleen B; Wooton, Jessica; Raoult, Emilie; Galas, Ludovic; Vaudry, David; Komuro, Hitoshi

    2012-02-14

    The role of genetic inheritance in brain development has been well characterized, but little is known about the contributions of natural environmental stimuli, such as the effect of light-dark cycles, to brain development. In this study, we determined the role of light stimuli in neuronal cell migration to elucidate how environmental factors regulate brain development. We show that in early postnatal mouse cerebella, granule cell migration accelerates during light cycles and decelerates during dark cycles. Furthermore, cerebellar levels of insulin-like growth factor 1 (IGF-1) are high during light cycles and low during dark cycles. There are causal relationships between light-dark cycles, speed of granule cell migration, and cerebellar IGF-1 levels. First, changes in light-dark cycles result in corresponding changes in the fluctuations of both speed of granule cell migration and cerebellar IGF-1 levels. Second, in vitro studies indicate that exogenous IGF-1 accelerates the migration of isolated granule cells through the activation of IGF-1 receptors. Third, in vivo studies reveal that inhibiting the IGF-1 receptors decelerates granule cell migration during light cycles (high IGF-1 levels) but does not alter migration during dark cycles (low IGF-1 levels). In contrast, stimulating the IGF-1 receptors accelerates granule cell migration during dark cycles (low IGF-1 levels) but does not alter migration during light cycles (high IGF-1 levels). These results suggest that during early postnatal development light stimuli control granule cell migration by altering the activity of IGF-1 receptors through modification of cerebellar IGF-1 levels.

  15. Relationship among insulin-like growth factor-I, blood metabolites and postpartum ovarian function in dairy cows.

    Science.gov (United States)

    Zulu, Victor Chisha; Sawamukai, Yutaka; Nakada, Ken; Kida, Katsuya; Moriyoshi, Masaharu

    2002-10-01

    The relationship among nutritional status, systemic insulin-like growth factor-I (IGF-I) and ovarian function early postpartum were investigated. A total of 27 Holstein-Friesian cows, 10 that cycled normally within 20 days postpartum, 5 diagnosed with follicular cysts, 8 with persistent corpus luteum (CL) after the first ovulation postpartum and 4 with inactive ovaries were used for the study. Blood samples were collected 1-3 times per week, for 60 days pre- and postpartum, for IGF-I, progesterone, estradiol, free fatty acids (FFA), blood urea nitrogen (BUN), and aspartate aminotransferase (AST) determination. Inactive ovary and cystic cows had a higher body condition score before calving and lost more condition than normal or persistent CL cows. Immediately postpartum, IGF-I levels were higher and rose sharply in cows that cycled normally than in cystic, inactive ovary or persistent CL cows. At calving and early postpartum, FFA was higher in inactive ovary and cystic than in normal and persistent CL cows. There was a significant strong positive relationship between IGF-I and BUN, and strong negative relationships between IGF-I and FFA and AST in all groups. There was a positive relationship between serum IGF-I and estradiol in normal cystic and inactive ovary cows. This study found that overconditioned cows during the dry period or at calving, lost more body condition postpartum. These cows also had a deeper and longer period of negative energy balance (NEB), poor liver function and low circulating IGF-I concentrations early postpartum. Such cows were likely to have poor reproductive function as seen in development of cystic ovaries, persistent CL and inactive ovary. Changes in serum IGF-I early postpartum may help predict both nutritional and reproductive status in dairy cattle.

  16. Insulin-like growth factor 1 receptor and response to anti-IGF1R antibody therapy in osteosarcoma.

    Directory of Open Access Journals (Sweden)

    Yu Cao

    Full Text Available Survival outcomes for patients with osteosarcoma (OS have remained stagnant over the past three decades. Insulin-like growth factor 1 receptor (IGF1R is over-expressed in a number of malignancies, and anti-IGF1R antibodies have and are currently being studied in clinical trials. Understanding the molecular aberrations which result in increased tumor response to anti-IGF1R therapy could allow for the selection of patients most likely to benefit from IGF1R targeted therapy.IGF1R mRNA expression was assessed by RT PCR in OS patient primary tumors, cell lines, and xenograft tumors. IGF1R copy number was assessed by 3 approaches: PCR, FISH, and dot blot analysis. Exons 1-20 of IGF1R were sequenced in xenograft tumors and 87 primary OS tumors, and surface expression of IGF1R was assessed by flow cytometry. Levels of mRNA and protein expression, copy number, and mutation status were compared with tumor response to anti-IGF1R antibody therapy in 4 OS xenograft models.IGF1R mRNA is expressed in OS. Primary patient samples and xenograft samples had higher mRNA expression and copy number compared with corresponding cell lines. IGF1R mRNA expression, cell surface expression, copy number, and mutation status were not associated with tumor responsiveness to anti-IGF1R antibody therapy.IGF1R is expressed in OS, however, no clear molecular markers predict response to IGF1R antibody-mediated therapy. Additional pre-clinical studies assessing potential predictive biomarkers and investigating targetable molecular pathways critical to the proliferation of OS cells are needed.

  17. Insulin-like growth factor-I gene therapy reverses morphologic changes and reduces hyperprolactinemia in experimental rat prolactinomas

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    Bracamonte Maria I

    2008-01-01

    Full Text Available Abstract Background The implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors. Up to now, suicide gene therapy has been the main experimental approach explored to treat experimental pituitary tumors. In the present study we assessed the effectiveness of insulin-like growth factor I (IGF-I gene therapy for the treatment of estrogen-induced prolactinomas in rats. Results Female Sprague Dawley rats were subcutaneously implanted with silastic capsules filled with 17-β estradiol (E2 in order to induce pituitary prolactinomas. Blood samples were taken at regular intervals in order to measure serum prolactin (PRL. As expected, serum PRL increased progressively and 23 days after implanting the E2 capsules (Experimental day 0, circulating PRL had undergone a 3–4 fold increase. On Experimental day 0 part of the E2-implanted animals received a bilateral intrapituitary injection of either an adenoviral vector expressing the gene for rat IGF-I (RAd-IGFI, or a vector (RAd-GFP expressing the gene for green fluorescent protein (GFP. Seven days post vector injection all animals were sacrificed and their pituitaries morphometrically analyzed to evaluate changes in the lactotroph population. RAd-IGFI but not RAd-GFP, induced a significant fall in serum PRL. Furthermore, RAd-IGFI but not RAd-GFP significantly reversed the increase in lactotroph size (CS and volume density (VD induced by E2 treatment. Conclusion We conclude that IGF-I gene therapy constitutes a potentially useful intervention for the treatment of prolactinomas and that bioactive peptide gene delivery may open novel therapeutic avenues for the treatment of pituitary tumors.

  18. Modelling of the disulphide-swapped isomer of human insulin-like growth factor-1: implications for receptor binding.

    Science.gov (United States)

    Gill, R; Verma, C; Wallach, B; Ursø, B; Pitts, J; Wollmer, A; De Meyts, P; Wood, S

    1999-04-01

    Insulin-like growth factor-1 (IGF-1) is a serum protein which unexpectedly folds to yield two stable tertiary structures with different disulphide connectivities; native IGF-1 [18-61,6-48,47-52] and IGF-1 swap [18-61,6-47, 48-52]. Here we demonstrate in detail the biological properties of recombinant human native IGF-1 and IGF-1 swap secreted from Saccharomyces cerevisiae. IGF-1 swap had a approximately 30 fold loss in affinity for the IGF-1 receptor overexpressed on BHK cells compared with native IGF-1. The parallel increase in dose required to induce negative cooperativity together with the parallel loss in mitogenicity in NIH 3T3 cells implies that disruption of the IGF-1 receptor binding interaction rather than restriction of a post-binding conformational change is responsible for the reduction in biological activity of IGF-1 swap. Interestingly, the affinity of IGF-1 swap for the insulin receptor was approximately 200 fold lower than that of native IGF-1 indicating that the binding surface complementary to the insulin receptor (or the ability to attain it) is disturbed to a greater extent than that to the IGF-1 receptor. A 1.0 ns high-temperature molecular dynamics study of the local energy landscape of IGF-1 swap resulted in uncoiling of the first A-region alpha-helix and a rearrangement in the relative orientation of the A- and B-regions. The model of IGF-1 swap is structurally homologous to the NMR structure of insulin swap and CD spectra consistent with the model are presented. However, in the model of IGF-1 swap the C-region has filled the space where the first A-region alpha-helix has uncoiled and this may be hindering interaction of Val44 with the second insulin receptor binding pocket.

  19. Insulin-like Growth Factor 1 Mediates Adrenal Development Dysfunction in Offspring Rats Induced by Prenatal Food Restriction.

    Science.gov (United States)

    He, Zheng; Lv, Feng; Ding, Yufeng; Zhu, Chunyan; Huang, Hegui; Zhang, Li; Guo, Yu; Wang, Hui

    2017-12-01

    Our previous study demonstrated that prenatal food restriction (PFR) could induce the dysfunction of the hypothalamic-pituitary-adrenal axis and glucocorticoid-related glucose and lipid metabolic alterations in adult offspring rats. To investigate the intrauterine programming mechanism of adrenal dysfunction in the PFR offspring rats. From gestational days (GDs) 11-20, pregnant Wistar rats were fed a restricted diet (50% of the daily food intake of control rats, 60 g/kg·d). Some were executed at GD20, while the others survived to full-term delivery; all pups were fed a high-fat diet (HFD) after weaning. The serum corticosterone concentration, expression level of adrenal steroidal synthetase, and insulin-like growth factor 1 (IGF1) signaling pathway were tested. We confirmed that the fetal body weight of the PFR group was lower than that of the control group, and the mRNA expression of adrenal steroidogenic acute regulatory protein, cytochrome P450 cholesterol side chain cleavage, 3β-hydroxysteroid dehydrogenase, and steroid 11β-hydroxylase (P450c11) were decreased in the PFR fetal rats. The maternal and fetal serum corticosterone levels were significantly increased in the PFR groups. Furthermore, the expression of the adrenal IGF1 signaling pathway (including IGF1, IGF1R, and Akt1) was suppressed. However, after a post-weaning HFD, the body weight gain rates and serum corticosterone levels were elevated, and the expression of adrenal steroid 21-hydroxylase and P450c11, as well as the IGF1 signaling pathway, were significantly increased in the PFR group. These results showed that a higher level of circulation corticosterone by PFR in utero inhibited adrenal IGF1 signaling and steroidogenesis, whereas post-weaning HFD induced adrenal steroidogenesis by an enhanced IGF1 signaling. Copyright © 2017.

  20. Insulin-like growth factor binding protein-3 affects osteogenic efficacy on dental implants in rat mandible

    Energy Technology Data Exchange (ETDEWEB)

    Bhattarai, Govinda; Lee, Young-Hee [Department of Oral Biochemistry, Institute of Oral Bioscience, School of Dentistry, Chonbuk National University, Jeonju (Korea, Republic of); Lee, Min-Ho [Department of Dental Materials, Institute of Oral Bioscience, School of Dentistry, Chonbuk National University, Jeonju (Korea, Republic of); Park, Il-Song [Division of Advanced Materials Engineering, Research Center for Advanced Materials, Development and Institute of Biodegradable Materials, Chonbuk National University, Jeonju 561-756 (Korea, Republic of); Yi, Ho-Keun, E-mail: yihokn@chonbuk.ac.kr [Department of Oral Biochemistry, Institute of Oral Bioscience, School of Dentistry, Chonbuk National University, Jeonju (Korea, Republic of)

    2015-10-01

    Insulin like growth factor binding protein-3 (IGFBP-3) in bone cells and its utilization in dental implants have not been well studied. The aim of this study was to determine the osteogenic efficacy of chitosan gold nanoparticles (Ch-GNPs) conjugated with IGFBP-3 coated titanium (Ti) implants. Ch-GNPs were conjugated with IGFBP-3 plasmid DNA through a coacervation process. Conjugation was cast over Ti surfaces, and cells were seeded on coated surfaces. For in vitro analysis the expression of different proteins was analyzed by immunoblotting. For in vivo analysis, Ch-GNP/IGFBP-3 coated implants were installed in rat mandibles. Four weeks post-implantation, mandibles were examined by microcomputed tomography (μCT), immunohistochemistry, hematoxylin & eosin and tartrate resistance acid phosphatase staining. In vitro overexpressed Ch-GNP/IGFBP-3 coated Ti surfaces was associated with activation of extracellular signal related kinase (ERK), inhibition of the stress activated protein c-Jun N-terminal kinase (JNK) and enhanced bone morphogenetic protein (BMP)-2 and 7 compared to control. Further, in vivo, Ch-GNP/IGFBP-3 coated implants were associated with inhibition of implant induced osteoclastogenesis molecules, receptor activator of nuclear factor kappa-B ligand (RANKL) and enhanced expression of osteogenic molecules including BMP2/7 and osteopontin (OPN). The μCT analysis demonstrated that IGFBP-3 increased the volume of newly formed bone surrounding the implants compared to control (n = 5; p < 0.05). These results support the view that IGFBP-3 overexpression diminishes osteoclastogenesis and enhances osteogenesis of Ti implants, and can serve as a potent molecule for the development of good implantation. - Highlights: • Chitosan gold nanoparticles were conjugated with IGFBP-3 and coated onto surface of the titanium implants for gene delivery to bone. • Implants were inserted in rat mandible for 4 weeks. • Parameters studied: histopathology and radiology.

  1. Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.

    Science.gov (United States)

    Okoreeh, Andre K; Bake, Shameena; Sohrabji, Farida

    2017-07-01

    Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for poststroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10-12 month old), acyclic female rats were injected with recombinant adeno-associated virus serotype 5 (AAV5) packaged with the coding sequence of the human (h)IGF-1 gene downstream of an astrocyte-specific promoter glial fibrillary acidic protein (GFAP) (AAV5-GFP-hIGF-1) into the striatum and cortex. The AAV5-control consisted of an identical shuttle vector construct without the hIGF-1 gene (AAV5-GFAP-control). Six to eight weeks later, animals underwent transient (90 min) middle cerebral artery occlusion via intraluminal suture. While infarct volume was not altered, AAV5-GFAP-hIGF-1 treatment significantly improved blood pressure and neurological score in the early acute phase of stroke (2 days) and sensory-motor performance at both the early and late (5 days) acute phase of stroke. AAV5-GFAP-hIGF-1 treatment also reduced circulating serum levels of GFAP, a biomarker for blood brain barrier permeability. Flow cytometry analysis of immune cells in the brain at 24 hr poststroke showed that AAV5-GFAP-hIGF-1 altered the type of immune cells trafficked to the ischemic hemisphere, promoting an anti-inflammatory profile. Collectively, these studies show that targeted enhancement of IGF-1 in astrocytes of middle-aged females improves stroke-induced behavioral impairment and neuroinflammation. © 2017 Wiley Periodicals, Inc.

  2. Effects of green tea polyphenols, insulin-like growth factor I and glucose on developmental competence of bovine oocytes

    Directory of Open Access Journals (Sweden)

    Zhengguang Wang

    2012-12-01

    Full Text Available The present study examined the effects of green tea polyphenols (GTP, insulin-like growth factor-I (IGF-I and glucose on oocyte in vitro maturation, subsequent embryo development and blastocyst quality in bovine. Cumulus-oocyte complexes (COC were aspirated from the ovaries and cultured in synthetic oviduct fluid supplemented with MEM amino acids (SOFaa media supplemented with one of the following supplements: GTP (0, 10, 15 and 20 µM, IGF-I (0, 50, 100 and 150 ng/mL or glucose (0, 1.5, 5.6 and 20 mM for 24 h. The results showed that oocytes cultured in media supplemented with 15 µM GTP, 100 ng/mL IGF-I and 5.6 mM glucose, in separate experiments, have higher cleavage and blastocyst rates compared with oocytes cultured in media without or with other concentration of GTP, IGF-I and glucose. Then these three substances with the concentration above were added together into SOFaa media and constituted a modified medium (Modified SOFaa. The COC were cultured in control SOFaa media and modified SOFaa media, respectively. The results showed that modified SOFaa media increased the intracellular glutathione concentration of matured oocytes, blastocyst rates and total cell numbers and cell numbers of inner cell mass per blastocyst compared with the control. Supplementing of GTP, IGF-I and glucose synchronously to maturation media can increase the intracellular GSH concentration of oocytes after in vitro maturation, and improve the embryo development and blastocyst quality in bovine.

  3. Insulin-like growth factor-1 inhibits adult supraoptic neurons via complementary modulation of mechanoreceptors and glycine receptors.

    Science.gov (United States)

    Ster, Jeanne; Colomer, Claude; Monzo, Cécile; Duvoid-Guillou, Anne; Moos, Françoise; Alonso, Gérard; Hussy, Nicolas

    2005-03-02

    In the CNS, insulin-like growth factor-1 (IGF-1) is mainly known for its trophic effect both during development and in adulthood. Here, we show than in adult rat supraoptic nucleus (SON), IGF-1 receptor immunoreactivity is present in neurons, whereas IGF-1 immunoreactivity is found principally in astrocytes and more moderately in neurons. In vivo application of IGF-1 within the SON acutely inhibits the activity of both vasopressin and oxytocin neurons, the two populations of SON neuroendocrine cells. Recordings of acutely isolated SON neurons showed that this inhibition occurs through two rapid and reversible mechanisms, both involving the neuronal IGF-1 receptor but different intracellular messengers. IGF-1 inhibits Gd3+-sensitive and osmosensitive mechanoreceptor cation current via phosphatidylinositol-3 (PI3) kinase activation. IGF-1 also potentiates taurine-activated glycine receptor (GlyR) Cl- currents by increasing the agonist sensitivity through a extremely rapid (within a second) PI3 kinase-independent mechanism. Both mechanoreceptor channels and GlyR, which form the excitatory and inhibitory components of SON neuron osmosensitivity, are active at rest, and their respective inhibition and potentiation will both be inhibitory, leading to strong decrease in neuronal activity. It will be of interest to determine whether IGF-1 is released by neurons, thus participating in an inhibitory autocontrol, or astrocytes, then joining the growing family of glia-to-neuron transmitters that modulate neuronal and synaptic activity. Through the opposite and complementary acute regulation of mechanoreceptors and GlyR, IGF-1 appears as a new important neuromodulator in the adult CNS, participating in the complex integration of neural messages that regulates the level of neuronal excitability.

  4. Insulin-like growth factor-1 and cardiotrophin 1 increase strength and mass of extraocular muscle in juvenile chicken.

    Science.gov (United States)

    Li, Tian; Wiggins, Larisa M; von Bartheld, Christopher S

    2010-05-01

    Insulin-like growth factor 1 (IGF1) and cardiotrophin 1 (CT1) are known to increase the strength of extraocular muscles in adult and embryonic animals, but no information is available for the early postnatal period, when strabismus treatment in humans is most urgent. Here the authors sought to determine whether these trophic factors strengthen juvenile maturing extraocular muscles and gain insight into mechanisms of force increase. After two injections of IGF1, CT1, or both with different dosages in posthatch chickens, the authors quantified five parameters of the superior oblique extraocular muscle at 2 weeks of age: contractile force, muscle mass, total myofiber area, myofiber diameter, and number of proliferating satellite cells labeled by bromodeoxyuridine. Treatment with IGF1, CT1, and combination of IGF1 and CT1 significantly increased contractile force by 14% to 22%. CT1 and combination treatment significantly increased muscle mass by 10% to 24%. IGF1/CT1 combination treatment did not have additive effects on strengthening muscles, compared with single-drug treatments. Myofiber area increased significantly with IGF1 and CT1 treatment in proximal, but not distal, parts of the muscle and this was due to increased fiber numbers or length (IGF1) or increased diameters of global layer myofibers (CT1). Trophic factors increased the number of proliferating (bromodeoxyuridine-labeled) satellite cells in proximal and middle segments of muscles. Exogenous IGF1 and CT1 strengthen extraocular muscles during maturation. They predominantly remodel the proximal segment of juvenile extraocular muscles. This information about muscle plasticity may aid the design of pharmacologic treatment of strabismus in children during the "critical period" of oculomotor maturation.

  5. Effects of prior exercise on the action of insulin-like growth factor I in skeletal muscle

    Science.gov (United States)

    Henriksen, E. J.; Louters, L. L.; Stump, C. S.; Tipton, C. M.

    1992-01-01

    Prior exercise increases insulin sensitivity for glucose and system A neutral amino acid transport activities in skeletal muscle. Insulin-like growth factor I (IGF-I) also activates these transport processes in resting muscle. It is not known, however, whether prior exercise increases IGF-I action in muscle. Therefore we determined the effect of a single exhausting bout of swim exercise on IGF-I-stimulated glucose transport activity [assessed by 2-deoxy-D-glucose (2-DG) uptake] and system A activity [assessed by alpha-(methylamino)isobutyric acid (MeAIB) uptake] in the isolated rat epitrochlearis muscle. When measured 3.5 h after exercise, the responses to a submaximal concentration (0.2 nM), but not a maximal concentration (13.3 nM), of insulin for activation of 2-DG uptake and MeAIB uptake were enhanced. In contrast, prior exercise increased markedly both the submaximal (5 nM) and maximal (20 nM) responses to IGF-I for activation of 2-DG uptake, whereas only the submaximal response to IGF-I (3 nM) for MeAIB uptake was enhanced after exercise. We conclude that 1) prior exercise significantly enhances the response to a submaximal concentration of IGF-I for activation of the glucose transport and system A neutral amino acid transport systems in skeletal muscle and 2) the enhanced maximal response for IGF-I action after exercise is restricted to the signaling pathway for activation of the glucose transport system.

  6. Repeated Insulin-like Growth Factor 1 (IGF1 treatment in a patient with Rett Syndrome: a single case study

    Directory of Open Access Journals (Sweden)

    Giorgio ePini

    2014-06-01

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that has no cure. Patients show regression of acquired skills, motor and speech impairment, cardio-respiratory distress, microcephaly and stereotyped hand movements. The majority of RTT patients display mutations in the gene that codes for the Methyl-CpG binding protein 2 (MeCP2, which is involved in the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function are good candidates for ameliorating the symptoms of RTT. In particular, Insulin-like growth Factor 1 (IGF1 and its active peptide (1-3IGF1 cross the Blood Brain Barrier, and therefore are ideal treatments for RTT Indeed, both (1-3IGF1 and IGF1 treatment significantly ameliorates RTT symptoms in a mouse model of the disease In a previous study we established that IGF1 is safe and well tolerated on Rett patients. In this open label clinical case study, we assess the safety and tolerability of IGF1 administration in two cycles of the treatment. Before and after each cycle we monitored the clinical and blood parameters, autonomic function and social and cognitive abilities, and we found that IGF1 was well tolerated each time and did not induce any side effect, nor it interfered with the other treatments that the patient was undergoing. We noticed a moderate improvement in the cognitive, social and autonomic abilities of the patient after each cycle but the benefits were not retained between the two cycles, consistent with the preclinical observation that treatments for RTT should be administered through life. We find that repeated IGF1 treatment is safe and well tolerated in Rett patients but observed effects are not retained between cycles. These results have applications to other pathologies considering that IGF1 has been shown to be effective in other disorders of the autism spectrum.

  7. Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A*

    Science.gov (United States)

    Morcavallo, Alaide; Genua, Marco; Palummo, Angela; Kletvikova, Emilia; Jiracek, Jiri; Brzozowski, Andrzej M.; Iozzo, Renato V.; Belfiore, Antonino; Morrione, Andrea

    2012-01-01

    The insulin receptor isoform A (IR-A) binds both insulin and insulin-like growth factor (IGF)-II, although the affinity for IGF-II is 3–10-fold lower than insulin depending on a cell and tissue context. Notably, in mouse embryonic fibroblasts lacking the IGF-IR and expressing solely the IR-A (R−/IR-A), IGF-II is a more potent mitogen than insulin. As receptor endocytosis and degradation provide spatial and temporal regulation of signaling events, we hypothesized that insulin and IGF-II could affect IR-A biological responses by differentially regulating IR-A trafficking. Using R−/IR-A cells, we discovered that insulin evoked significant IR-A internalization, a process modestly affected by IGF-II. However, the differential internalization was not due to IR-A ubiquitination. Notably, prolonged stimulation of R−/IR-A cells with insulin, but not with IGF-II, targeted the receptor to a degradative pathway. Similarly, the docking protein insulin receptor substrate 1 (IRS-1) was down-regulated after prolonged insulin but not IGF-II exposure. Similar results were also obtained in experiments using [NMeTyrB26]-insulin, an insulin analog with IR-A binding affinity similar to IGF-II. Finally, we discovered that IR-A was internalized through clathrin-dependent and -independent pathways, which differentially regulated the activation of downstream effectors. Collectively, our results suggest that a lower affinity of IGF-II for the IR-A promotes lower IR-A phosphorylation and activation of early downstream effectors vis à vis insulin but may protect IR-A and IRS-1 from down-regulation thereby evoking sustained and robust mitogenic stimuli. PMID:22318726

  8. Serum insulin-like growth factor-1 levels in females and males in different cervical vertebral maturation stages

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    Shreya Gupta

    2015-04-01

    Full Text Available OBJECTIVE: The aim of this cross sectional study was to assess serum insulin-like growth factor-1 (IGF-1 levels in female and male subjects at various cervical vertebral maturation (CVM stages. MATERIAL AND METHODS: The study sample consisted of 60 subjects, 30 females and 30 males, in the age range of 8-23 years. For all subjects, serum IGF-1 level was estimated from blood samples by means of chemiluminescence immunoassay (CLIA. CVM was assessed on lateral cephalograms using the method described by Baccetti. Serum IGF-1 level and cervical staging data of 30 female subjects were included and taken from records of a previous study. Data were analyzed by Kruska-Wallis and Mann Whitney test. Bonferroni correction was carried out and alpha value was set at 0.003. RESULTS: Peak value of serum IGF-1 was observed in cervical stages CS3 in females and CS4 in males. Differences between males and females were observed in mean values of IGF-1 at stages CS3, 4 and 5. The highest mean IGF-1 levels in males was observed in CS4 followed by CS5 and third highest in CS3; whereas in females the highest mean IGF-1 levelswas observed in CS3 followed by CS4 and third highest in CS5. Trends of IGF-1 in relation to the cervical stages also differed between males and females. The greatest mean serum IGF-1 value for both sexes was comparable, for females (397 ng/ml values were slightly higher than in males (394.8 ng/ml. CONCLUSIONS: Males and females showed differences in IGF-1 trends and levels at different cervical stages.

  9. Increased Cerebrospinal Fluid Level of Insulin-like Growth Factor-II in Male Patients with Alzheimer's Disease.

    Science.gov (United States)

    Åberg, Daniel; Johansson, Per; Isgaard, Jörgen; Wallin, Anders; Johansson, Jan-Ove; Andreasson, Ulf; Blennow, Kaj; Zetterberg, Henrik; Åberg, N David; Svensson, Johan

    2015-01-01

    Insulin-like growth factor-II (IGF-II) is important for brain development. Although IGF-II is abundant also in adult life, little is known of the role of IGF-II in Alzheimer's disease (AD). This was a cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), or other dementias (n = 15). IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 were analyzed in serum and cerebrospinal fluid (CSF). Levels of IGF-II, IGFBP-1, and IGFBP-2 were similar in all groups in the total study population. Gender-specific analyses showed that in men (n = 40), CSF IGF-II level was higher in AD compared to SMCI and controls (p <  0.01 and p <  0.05, respectively). Furthermore, CSF IGFBP-2 level was increased in AD men versus SMCI men (p <  0.01) and tended to be increased versus control men (p = 0.09). There were no between-group differences in women (n = 40). In the total study population (n = 80) as well as in men (n = 40), CSF levels of IGF-II and IGFBP-2 correlated positively with CSF levels of the AD biomarkers total-tau and phosphorylated tau protein. In men, but not women, in the early stages of AD, CSF IGF-II level was elevated, and CSF IGFBP-2 level tended to be increased, compared to healthy controls.

  10. Importin α-importin β complex mediated nuclear translocation of insulin-like growth factor binding protein-5.

    Science.gov (United States)

    Sun, Min; Long, Juan; Yi, Yuxin; Xia, Wei

    2017-10-28

    Insulin-like growth factor-binding protein (IGFBP)-5 is a secreted protein that binds to IGFs and modulates IGF actions, as well as regulates cell proliferation, migration, and apoptosis independent of IGF. Proper cellular localization is critical for the effective function of most signaling molecules. In previous studies, we have shown that the nuclear IGFBP-5 comes from ER-cytosol retro-translocation. In this study, we further investigated the pathway mediating IGFBP-5 nuclear import after it retro-translocation. Importin-α5 was identified as an IGFBP-5-interacting protein with a yeast two-hybrid system, and its interaction with IGFBP-5 was further confirmed by GST pull down and co-immunoprecipitation. Binding affinity of IGFBP-5 and importins were determined by surface plasmon resonance (IGFBP-5/importin-β: K D =2.44e-7, IGFBP-5/importin-α5: K D =3.4e-7). Blocking the importin-α5/importin-β nuclear import pathway using SiRNA or dominant negative impotin-β dramatically inhibited IGFBP-5-EGFP nuclear import, though importin-α5 overexpress does not affect IGFBP-5 nuclear import. Furthermore, nuclear IGFBP-5 was quantified using luciferase report assay. When deleted the IGFBP-5 nuclear localization sequence (NLS), IGFBP-5 ΔNLS loss the ability to translocate into the nucleus and accumulation of IGFBP-5 ΔNLS was visualized in the cytosol. Altogether, our findings provide a substantially evidence showed that the IGFBP-5 nuclear import is mediated by importin-α/importin-β complex, and NLS is critical domain in IGFBP-5 nuclear translocation.

  11. Insulin-Like Growth Factor Axis and Gestational Diabetes Mellitus: A Longitudinal Study in a Multiracial Cohort.

    Science.gov (United States)

    Zhu, Yeyi; Mendola, Pauline; Albert, Paul S; Bao, Wei; Hinkle, Stefanie N; Tsai, Michael Y; Zhang, Cuilin

    2016-11-01

    The insulin-like growth factor (IGF) axis may be implicated in glucose homeostasis, but its longitudinal profile across gestation in relation to the development of gestational diabetes mellitus (GDM) is largely unknown. We prospectively investigated IGF axis biomarkers in early-to-midpregnancy in relation to subsequent GDM risk in a case-control study of 107 case subjects with GDM and 214 control subjects without GDM, with blood sample collection at gestational weeks 10-14, 15-26, 23-31, and 33-39. Conditional logistic regression was used, adjusting for major risk factors including prepregnancy BMI. Plasma IGF-I and IGF binding protein 3 (IGFBP-3) concentrations and molar ratio of IGF-I to IGFBP-3 increased, whereas IGFBP-2 decreased throughout pregnancy. At gestational weeks 10-14, both IGF-I and IGF-I/IGFBP-3 were positively associated with GDM risk; adjusted odds ratio (OR) comparing the highest versus lowest quartile (ORQ4-Q1) was 2.93 (95% CI 1.18, 7.30) for IGF-I and 3.31 (1.10, 9.98) for IGF-I/IGFBP-3. In contrast, higher IGFBP-2 levels were related to a substantially lower risk of GDM (ORQ4-Q1 0.04 [0.01, 0.06]). Similar results were observed at gestational weeks 15-26. In sum, the IGF axis, IGFBP-2 in particular, may be implicated in the pathogenesis of GDM, with significant associations and incremental predictive value detected as early as gestational weeks 10-14, ∼10-18 weeks earlier before GDM is typically screened for. © 2016 by the American Diabetes Association.

  12. Genome-wide interactions between FSH and insulin-like growth factors in the regulation of human granulosa cell differentiation.

    Science.gov (United States)

    Stocco, Carlos; Baumgarten, Sarah C; Armouti, Marah; Fierro, Michelle A; Winston, Nicola J; Scoccia, Bert; Zamah, A Musa

    2017-04-01

    Is the genome-wide response of human cumulus cells to FSH and insulin-like growth factors (IGFs) comparable to the response observed in undifferentiated granulosa cells (GCs)? FSH actions in human cumulus cells mimic those observed in preantral undifferentiated GCs from laboratory animals, and approximately half of the regulated genes are dependent on the simultaneous activation of the IGF1 receptor (IGF1R). Animal studies have shown that FSH and the IGFs system are required for follicle growth and maturation. In humans, IGF levels in the follicular fluid correlate with patients' responses to IVF protocols. The main targets of FSH and IGFs in the ovary are the GCs; however, the genomic mechanisms involved in the response of GCs to these hormones are unknown. Human cumulus cells isolated from IVF patients were cultured for 48 h in serum-free media in the presence of vehicle, FSH, IGF1R inhibitor or their combination. Discarded cumulus cells were donated to research by reproductive-aged women undergoing IVF due to non-ovarian etiologies of infertility at a university-affiliated clinic. The effect of FSH and/or IGF1R inhibition on cumulus cell function was evaluated using Affymetrix microarrays, quantitative PCR, western blot, promoter assays and hormone level measurements. The findings demonstrate that human cumulus cells from IVF patients respond to FSH with the expression of genes known to be markers of the preantral to preovulatory differentiation of GCs. These results also demonstrate that ~50% of FSH-regulated genes require IGF1R activity and suggest that several aspects of follicle growth are coordinately regulated by FSH and IGFs in humans. This novel approach will allow for future mechanistic and molecular studies on the regulation of human follicle maturation. Data set can be accessed at Gene Expression Omnibus number GSE86427. Experiments were performed using primary human cumulus cells. This may not represent the response of intact follicles

  13. Insulin-like growth factor-I improves mucosal structure and function in transplanted rat small intestine.

    Science.gov (United States)

    Zhang, W; Frankel, W L; Adamson, W T; Roth, J A; Mantell, M P; Bain, A; Ziegler, T R; Smith, R J; Rombeau, J L

    1995-03-15

    The transplanted small intestine develops significant mucosal atrophy, impaired nutrient and water absorption, and increased bacterial translocation to mesenteric lymph nodes in rats maintained on elemental diets or total parenteral nutrition. This study determined the effects of administration of an peptide growth factor (insulin-like growth factor-I[IGF-I]) on the mucosal structure and barrier function of rat small bowel isografts. Thirty-six adult Lewis rats underwent either resection of the distal 60% of the small bowel and proximal colon followed by a 40-cm orthotopic jejunal isograft or proximal small bowel transection and distal small bowel resection to leave an analogous length of small intestine in control animals. All rats received an isocaloric, isonitrogenous, polymeric diet (200 kcal/kg/day, 2 gN/kg/day) by gastrostomy and were infused with either IGF-I (2.4 mg/kg/day) or vehicle by osmotic pumps subcutaneously. After 10 days of treatment, jejunal crypt cell production, mucosal morphometric indices, glucose and water absorption, body weight, and bacterial translocation to mesenteric lymph nodes (MLN) were measured. Jejunal mRNA content for IGF-I, IGF-I receptor, and IGF-binding proteins 3 and 4 (IGFBP-3,4) were determined by Northern blotting. Crypt cell production, villus height, crypt depth, and villus surface area were significantly increased in control and transplanted jejunum of rats infused with IGF-I when compared to animals given vehicle alone. Additionally, jejunal glucose absorption and water absorption were significantly improved in both IGF-I groups when compared with their respective vehicle controls. IGF-I infusion increased body weight in transplanted and control animals and markedly reduced bacterial translocation to MLN after small bowel transplantation. Jejunal levels of IGF-I mRNA were significantly increased in transplanted animals when compared to transected controls. IGF-I treatment significantly increased IGFBP-3 tissue m

  14. Insulin-like growth factors act synergistically with basic fibroblast growth factor and nerve growth factor to promote chromaffin cell proliferation

    DEFF Research Database (Denmark)

    Frödin, M; Gammeltoft, S

    1994-01-01

    We have investigated the effects of insulin-like growth factors (IGFs), basic fibroblast growth factor (bFGF), and nerve growth factor (NGF) on DNA synthesis in cultured chromaffin cells from fetal, neonatal, and adult rats by using 5-bromo-2'-deoxyuridine (BrdUrd) pulse labeling for 24 or 48 h...... and immunocytochemical staining of cell nuclei. After 6 days in culture in the absence of growth factors, nuclear BrdUrd incorporation was detected in 30% of fetal chromaffin cells, 1.5% of neonatal cells, and 0.1% of adult cells. Addition of 10 nM IGF-I or IGF-II increased the fraction of BrdUrd-labeled nuclei to 50...... and 10- to 20-fold in adult chromaffin cells compared with the effect of each growth factor alone. In contrast, the action of bFGF and NGF added together in the absence of IGFs was not synergistic or additive. IGF-II acted also as a survival factor on neonatal chromaffin cells and the cell survival...

  15. Systemic treatment with Epidermal Growth Factor (EGF)but not Insulin like Growth Factor (IGF-I) decrease the involution of the Prostate in Castrated Rats

    DEFF Research Database (Denmark)

    Tørring, Niels; Lars, Vinter-Jensen; Sørensen, Flemming Brandt

    2000-01-01

    Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated...... Wistar rats were treated with growth factors (EGF 35 microg/rat per day; IGF-I 350 microg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme...... proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration...

  16. Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Sørensen, Flemming Brandt

    2000-01-01

    Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated...... Wistar rats were treated with growth factors (EGF 35 microg/rat per day; IGF-I 350 microg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme...... proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration...

  17. Insulin-like growth factors and related proteins in plasma and cerebrospinal fluids of HIV-positive individuals.

    Science.gov (United States)

    Suh, Hyeon-Sook; Lo, Yungtai; Choi, Namjong; Letendre, Scott; Lee, Sunhee C

    2015-04-15

    Clinically significant dysregulation of the insulin-like growth factor (IGF) family proteins occurs in HIV-infected individuals, but the details including whether the deficiencies in IGFs contribute to CNS dysfunction are unknown. We measured the levels of IGF1, IGF2, IGFBP1, IGFBP2, and IGF2 receptor (IGF2R) in matching plasma and cerebrospinal fluid (CSF) samples of 107 HIV+ individuals from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and analyzed their associations with demographic and disease characteristics, as well as levels of several soluble inflammatory mediators (TNFα, IL-6, IL-10, IL-17, IP-10, MCP-1, and progranulin). We also determined whether IGF1 or IGF2 deficiency is associated with HIV-associated neurocognitive disorder (HAND) and whether the levels of soluble IGF2R (an IGF scavenging receptor, which we also have found to be a cofactor for HIV infection in vitro) correlate with HIV viral load (VL). There was a positive correlation between the levels of IGF-binding proteins (IGFBPs) and those of inflammatory mediators: between plasma IGFBP1 and IL-17 (β coefficient 0.28, P = 0.009), plasma IGFBP2 and IL-6 (β coefficient 0.209, P = 0.021), CSF IGFBP1 and TNFα (β coefficient 0.394, P protein expression/availability in the setting of HIV infection. However, there was no significant association between HAND and the reduced levels of plasma IGF1, IGF2, or CSF IGF1, suggesting a limited power of our study. Interestingly, plasma IGF1 was significantly reduced in subjects on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) compared to protease inhibitor-based therapy (174.1 ± 59.8 vs. 202.8 ± 47.3 ng/ml, P = 0.008), suggesting a scenario in which ART regimen-related toxicity can contribute to HAND. Plasma IGF2R levels were positively correlated with plasma VL (β coefficient 0.37, P = 0.021) and inversely correlated with current CD4+ T cell counts (β coefficient -0.04, P = 0.021), supporting our

  18. Circulating levels of insulin-like growth factor-I (IGF-I correlate with disease status in leprosy

    Directory of Open Access Journals (Sweden)

    Rodrigues Luciana

    2011-12-01

    Full Text Available Abstract Background Caused by Mycobacterium leprae (ML, leprosy presents a strong immune-inflammatory component, whose status dictates both the clinical form of the disease and the occurrence of reactional episodes. Evidence has shown that, during the immune-inflammatory response to infection, the growth hormone/insulin-like growth factor-I (GH/IGF-I plays a prominent regulatory role. However, in leprosy, little, if anything, is known about the interaction between the immune and neuroendocrine systems. Methods In the present retrospective study, we measured the serum levels of IGF-I and IGBP-3, its major binding protein. These measurements were taken at diagnosis in nonreactional borderline tuberculoid (NR BT, borderline lepromatous (NR BL, and lepromatous (NR LL leprosy patients in addition to healthy controls (HC. LL and BL patients who developed reaction during the course of the disease were also included in the study. The serum levels of IGF-I, IGFBP-3 and tumor necrosis factor-alpha (TNF-α were evaluated at diagnosis and during development of reversal (RR or erythema nodosum leprosum (ENL reaction by the solid phase, enzyme-labeled, chemiluminescent-immunometric method. Results The circulating IGF-I/IGFBP-3 levels showed significant differences according to disease status and occurrence of reactional episodes. At the time of leprosy diagnosis, significantly lower levels of circulating IGF-I/IGFBP-3 were found in NR BL and NR LL patients in contrast to NR BT patients and HCs. However, after treatment, serum IGF-I levels in BL/LL patients returned to normal. Notably, the levels of circulating IGF-I at diagnosis were low in 75% of patients who did not undergo ENL during treatment (NR LL patients in opposition to the normal levels observed in those who suffered ENL during treatment (R LL patients. Nonetheless, during ENL episodes, the levels observed in RLL sera tended to decrease, attaining similar levels to those found in NR LL patients

  19. Insulin-like growth factor I prevents the development of sensitivity to kainate neurotoxicity in cerebellar granule cells.

    Science.gov (United States)

    Leski, M L; Valentine, S L; Baer, J D; Coyle, J T

    2000-10-01

    This study reports that insulin-like growth factor I (IGF-I) prevents cerebellar granule cells from developing sensitivity to kainate neurotoxicity. Sensitivity to kainate neurotoxicity normally develops 5-6 days after switching cultures to a serum-free medium containing 25 mM K(+). Addition of either IGF-I or insulin to the serum-free medium at the time of the switch prevented the development of sensitivity to kainate, whereas brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, and nerve growth factor did not. The dose-response curves indicated IGF-I was more potent than insulin, favoring the assignment of the former as the physiological protective agent. The phosphatidylinositol 3-kinase (PI 3-K) inhibitors wortmannin (10-100 nM) and LY 294002 (0.3-1 microM) abolished the protection afforded by IGF-I. The p70 S6 kinase (p70(S6k)) inhibitor rapamycin (5-50 nM:) also abolished the protection afforded by IGF-I. The activities of both enzymes decreased in cultures switched to serum-free medium but increased when IGF-I was included; wortmannin (100 nM) lowered the activity of PI 3-K from 2 to 5 days after medium switch, whereas rapamycin (50 nM) prevented the increase observed for p70(S6k) activity over the same interval. The mitogen-activated protein kinase kinase inhibitor U 0126 and the mitogen-activated protein kinase inhibitor SB 203580 did not abolish IGF-I protection. Kainate neurotoxicity was not prevented by Joro spider toxin; therefore, the development of kainate neurotoxicity could not be explained by the formation of calcium-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors. These results indicate that IGF-I functions through a signal transduction pathway involving PI 3-K and p70(S6k) to prevent the development of sensitivity to kainate neurotoxicity in cerebellar granule cells.

  20. The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2012-02-01

    AIMS: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational age at delivery. METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a London University teaching hospital. Maternal IGF-1, IGF-2 and IGFBP-3 were measured in maternal blood at booking and analyzed with respect to gestational age at delivery. RESULTS: There was no significant association between maternal IGF-1 or IGF-2 and preterm birth (PTB). A significant reduction in mean IGFBP-3 levels was noted with delivery <32 completed weeks (P=0.02). CONCLUSION: Maternal mean IGFBP-3 levels are significantly reduced in cases complicated by delivery <32 completed weeks.

  1. Upregulation of insulin-like growth factor binding protein 3 in astrocytes of transgenic mice that express Borna disease virus phosphoprotein.

    Science.gov (United States)

    Honda, Tomoyuki; Fujino, Kan; Okuzaki, Daisuke; Ohtaki, Naohiro; Matsumoto, Yusuke; Horie, Masayuki; Daito, Takuji; Itoh, Masayuki; Tomonaga, Keizo

    2011-05-01

    In a previous study, we demonstrated that transgenic mice that express Borna disease virus (BDV) phosphoprotein (P) in astrocytes show striking neurobehavioral abnormalities resembling those in BDV-infected animals. To understand the molecular disturbances induced by the expression of P in astrocytes, we performed microarray analysis with cultured astroglial cells transiently expressing P. We showed that expression of insulin-like growth factor binding protein 3 mRNA increases not only in P-expressing cultured cells but also in astrocytes from the cerebella of P transgenic mice (P-Tg). Furthermore, we demonstrated that insulin-like growth factor signaling is disturbed in the P-Tg cerebellum, a factor that might be involved in the increased vulnerability of Purkinje cell neurons in the brain.

  2. Insulin-Like Growth Factor II mRNA-Binding Protein 3 Expression Correlates with Poor Prognosis in Acral Lentiginous Melanoma.

    Directory of Open Access Journals (Sweden)

    Yi-Shuan Sheen

    Full Text Available Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3 is an RNA-binding protein expressed in multiple cancers, including melanomas. However, the expression of IMP-3 has not been investigated in acral lentiginous melanoma (ALM. This study sought to elucidate its prognostic value in ALMs. IMP-3 expression was studied in 93 patients diagnosed with ALM via immunohistochemistry. Univariate and multivariate analyses for survival were performed, according to clinical and histologic parameters, using the Cox proportional hazard model. Survival curves were graphed using the Kaplan-Meier method. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%. IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals (P = 0.002, 0.006, 0.008 and 0.012, respectively. Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression (P = 0.048. IMP-3 (hazard ratio 3.67, 95% confidence intervals 1.35-9.97, P = 0.011 was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.

  3. New advances in understanding thyroid-associated ophthalmopathy and the potential role for insulin-like growth factor-I receptor [version 1; referees: 2 approved

    OpenAIRE

    Terry J Smith

    2018-01-01

    Thyroid-associated ophthalmopathy (TAO), a localized periocular manifestation of the autoimmune syndrome known as Graves’ disease, remains incompletely understood. Discussions of its pathogenesis are generally focused on the thyrotropin receptor, the proposed role for which is supported by substantial evidence. Considerations of any involvement of the insulin-like growth factor-I receptor (IGF-IR) in the disease are frequently contentious. In this brief, topically focused review, I have attem...

  4. Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II.

    OpenAIRE

    Rosenthal, S.M.; Brunetti, A; Brown, E J; Mamula, P W; Goldfine, I. D.

    1991-01-01

    Muscle is an important target tissue for insulin-like growth factor (IGF) action. The presence of specific, high affinity IGF receptors, as well as the expression of IGF peptides and binding proteins by muscle suggest that a significant component of IGF action in this tissue is mediated through autocrine and/or paracrine mechanisms. To explore autocrine/paracrine action of IGFs in muscle, we studied the regulation of the IGF-I receptor and the expression of IGF peptides during differentiation...

  5. Effects of exposure to artificial long days on milk yield, maternal insulin-like growth factor 1 levels and kid growth rate in subtropical goats.

    Science.gov (United States)

    Hernández, Horacio; Flores, José Alfredo; Delgadillo, José Alberto; Fernández, Ilda G; Flores, Manuel de Jesús; Mejía, Ángel; Elizundia, José Manuel; Bedos, Marie; Ponce, José Luis; Ramírez, Sergio

    2016-04-01

    This study was designed to determine whether any relationship exists between exposure to artificial long days, milk yield, maternal plasma insulin-like growth factor 1 (IGF-1) levels, and kid growth rate in goats. One group of lactating goats was maintained under naturally decreasing day length (control group; n = 19), while in another one, they were kept under artificial long days (LD group; n = 19). Milk yield was higher in goats from the LD group than that in the control group (P goats from the LD group than the levels in the control group and were positively correlated with the total milk yields per goat at days 43 and 57 of lactation (r = 0.77 and r = 0.84, respectively; P goats to artificial long days increases milk yield, plasma IGF-1 maternal levels and the growth rate of the kids. © 2015 Japanese Society of Animal Science.

  6. The role of growth hormone in growth, lipid homeostasis, energy utilization and partitioning in rainbow trout: interactions with leptin, ghrelin and insulin-like growth factor I.

    Science.gov (United States)

    Kling, Peter; Jönsson, Elisabeth; Nilsen, Tom Ole; Einarsdottir, Ingibjörg Eir; Rønnestad, Ivar; Stefansson, Sigurd O; Björnsson, Björn Thrandur

    2012-01-01

    The growth-promoting effects of in vivo growth hormone (GH) treatment were studied in relation to size and lipid content of energy stores including liver, mesentery, white muscle and belly flap in rainbow trout. In order to elucidate endocrine interactions and links to regulation of growth, adiposity and energy metabolism, plasma levels of GH, insulin-like growth factor I (IGF-I), leptin (Lep) and ghrelin, were assessed and correlated to growth and energy status. In addition tissue-specific expression of lepa1 mRNA was examined. Juvenile rainbow trout were implanted with sustained-release bovine GH implants and terminally sub-sampled at 1, 3 and 6 weeks. GH increased specific growth rate, reduced condition factor (CF) and increased feed conversion efficiency resulting in a redistribution of energy stores. Thus, GH decreased mesenteric (MSI) and liver somatic index (LSI). Lipid content of the belly flap increased following GH-treatment while liver and muscle lipid content decreased. Independent of GH substantial growth was accompanied by an increase in muscle lipids and a decrease in belly flap lipids. The data suggest that the belly flap may function as an energy buffering tissue during episodes of feeding and lean growth. Liver and muscle lipids were positively correlated to body weight, indicating a size-dependent change in adiposity. Hepatic lepa1 mRNA positively correlated to MSI and CF and its expression decreased following GH treatment, coinciding with decreased hepatic lipid content. Plasma Lep was positively correlated to MSI and belly flap lipid content, suggesting that Lep may communicate energy status. In summary, the observed GH tissue-specific effects on lipid metabolism in rainbow trout highlight the complex physiology of the energy reserves and their endocrine control. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Insulin-like growth factor-I receptor signal transduction and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway.

    Science.gov (United States)

    Himpe, Eddy; Kooijman, Ron

    2009-01-01

    The insulin-like growth factor IGF-I is an important fetal and postnatal growth factor, which is also involved in tissue homeostasis via regulation of proliferation, differentiation, and cell survival. To understand the role of IGF-I in the pathophysiology of a variety of disorders, including growth disorders, cancer, and neurodegenerative diseases, a detailed knowledge of IGF-I signal transduction is required. This knowledge may also contribute to the development of new therapies directed at the IGF-I receptor or other signaling molecules. In this review, we will address IGF-I receptor signaling through the JAK/STAT pathway in IGF-I signaling and the role of cytokine-induced inhibitors of signaling (CIS) and suppressors of cytokine signaling (SOCS). It appears that, in addition to the canonical IGF-I signaling pathways through extracellular-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K)-Akt, IGF-I also signals through the JAK/STAT pathway. Activation of this pathway may lead to induction of SOCS molecules, well-known feedback inhibitors of the JAK/STAT pathway, which also suppress of IGF-I-induced JAK/STAT signaling. Furthermore, other IGF-I-induced signaling pathways may also be modulated by SOCS. It is conceivable that the effect of these classical inhibitors of cytokine signaling directly affect IGF-I receptor signaling, because they are able to associate to the intracellular part of the IGF-I receptor. These observations indicate that CIS and SOCS molecules are key to cross-talk between IGF-I receptor signaling and signaling through receptors belonging to the hematopoietic/cytokine receptor superfamily. Theoretically, dysregulation of CIS or SOCS may affect IGF-I-mediated effects on body growth, cell differentiation, proliferation, and cell survival. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

  8. The effect of local application of insulin-like growth factor for prevention of inner-ear damage caused by electrode trauma.

    Science.gov (United States)

    Gur, H; Alimoglu, Y; Duzenli, U; Korkmaz, S; Inan, S; Olgun, L

    2017-03-01

    Electrode insertion during cochlear implantation causes cochlear damage and apoptosis. Insulin-like growth factor applied locally was investigated in 21 rats. In the sham group, an intracochlear dummy electrode was inserted through the round window. In the control group, after the same insertion procedure, saline-soaked porcine skin gelatine was placed on the round window. In the study group, insulin-like growth factor 1 soaked gelatine was placed on the round window. Auditory brainstem response thresholds were measured and histopathological examination was performed. In the study group, at 2-4 kHz, one rat had deterioration, one showed improvement and the rest had stable thresholds 14 days after intervention. At 6 kHz, four rats showed improvement and the rest remained stable. At 8 kHz, four showed improvement, one had deterioration and two remained stable. In the other groups, hearing loss deteriorated in about half of the rats and remained stable in the rest. The mean post-operative 6 kHz threshold was significantly lower than that immediately after the intervention in the study group, contrary to the other groups. The study group had significantly better mean histopathological grading than the other groups. Local insulin-like growth factor 1 application may protect hearing after cochlear implantation.

  9. The relationships among bone health, insulin-like growth factor-1 and sex hormones in adolescent female athletes.

    Science.gov (United States)

    Gruodyte, Rita; Jürimäe, Jaak; Saar, Meeli; Jürimäe, Toivo

    2010-05-01

    The aim of this study was to determine the relationships of bone mineral density (BMD) and content (BMC) with insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3) and estradiol in pubertal female athletes. The participants were 170 healthy adolescent girls (13-15 years) who participated in competitive extramural athletic programs, i.e., sports games (n = 49), track sprinting (n = 24), rhythmic gymnastics (n = 23), swimming (n = 24) and cross-country skiing (n = 17). The control group (n = 33) consisted of girls who took part only in compulsory physical education classes at school. The whole-body BMD and femoral neck and lumbar spine BMD and BMC were measured using DXA, and the volumetric BMD was calculated. Venous blood samples to determine the concentration of IGF-1, IGFBP-3 and estradiol were drawn after an overnight fasting. After adjusting for age, body height and body mass, the relationships among BMD variables, IGF-1 and the IGF-1/IGFBP-3 molar ratio remained significant only in the rhythmic gymnast group. BMDs at the femoral neck and lumbar spine were also related to estradiol levels (r = 0.45-0.60; p rhythmic gymnast group. No relationships were found among the measured BMD, IGF axis and estradiol in other athletic groups. Only BMC at the femoral neck remained associated with the IGF-1/IGFBP-3 molar ratio in the rhythmic gymnast group after adjusting for age, body height and body mass. Stepwise multiple regression analysis indicated that IGF-1 and estradiol together explained 42.6% (R(2) x 100) of total variance in the femoral neck BMD and IGF-1 alone 35.4% (R(2) x 100) of the total variance in the femoral neck BMC only in the rhythmic gymnast group. We conclude that femoral neck and lumbar spine BMD correlated with IGF-1, IGF-1/IGFBP-3 molar ratio and estradiol in rhythmic gymnasts. No relationships were found between bone parameters and the hormones used in other athletic groups.

  10. Equine insulin receptor and insulin-like growth factor-1 receptor expression in digital lamellar tissue and insulin target tissues.

    Science.gov (United States)

    Kullmann, A; Weber, P S; Bishop, J B; Roux, T M; Norby, B; Burns, T A; McCutcheon, L J; Belknap, J K; Geor, R J

    2016-09-01

    Hyperinsulinaemia is implicated in the pathogenesis of endocrinopathic laminitis. Insulin can bind to different receptors: two insulin receptor isoforms (InsR-A and InsR-B), insulin-like growth factor-1 receptor (IGF-1R) and InsR/IGF-1R hybrid receptor (Hybrid). Currently, mRNA expression of these receptors in equine tissues and the influence of body type and dietary carbohydrate intake on expression of these receptors is not known. The study objectives were to characterise InsR-A, InsR-B, IGF-1R and Hybrid expression in lamellar tissue (LT) and insulin responsive tissues from horses and examine the effect of dietary nonstructural carbohydrate (NSC) on mRNA expression of these receptors in LT, skeletal muscle, liver and two adipose tissue (AT) depots of lean and obese ponies. In vivo experiment. Lamellar tissue samples were evaluated by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for receptor mRNA expression (n = 8) and immunoblotting for protein expression (n = 3). Archived LT, skeletal muscle, liver and AT from lean and obese mixed-breed ponies fed either a low (~7% NSC as dry matter; 5 lean, 5 obese) or high NSC diet (~42% NSC as dry matter; 6 lean, 6 obese) for 7 days were evaluated by RT-qPCR to determine the effect of body condition and diet on expression of the receptors in different tissues. Significance was set at P≤0.05. Lamellar tissue expresses both InsR isoforms, IGF-1R and Hybrid. LT IGF-1R gene expression was greater than either InsR isoform and InsR-A expression was greater than InsR-B (P≤0.05). Obesity significantly lowered IGF-1R, InsR-A and InsR-B mRNA expression in LT and InsR-A in tailhead AT. High NSC diet lowered expression of all three receptor types in liver; IGF-1R and InsR-A in LT and InsR-A in tailhead AT. Lamellar tissue expresses IGF-1R, InsR isoforms and Hybrids. The functional characteristics of these receptors and their role in endocrinopathic laminitis warrants further investigation. © 2015 EVJ

  11. Effect of insulin-like growth factor-1 during in vitro oocyte maturation and in vitro culture of bovine embryos

    Directory of Open Access Journals (Sweden)

    Quetglas M.D.

    2001-01-01

    Full Text Available The effects of insulin-like growth factor-I (IGF-I on in vitro maturation (IVM (experiment I and on in vitro embryo development (experiment II of bovine oocytes fertilized in vitro, were evaluated in terms of cleavage (CR, blastocyst (BR and hatching (HR rates. For IVM, immature cumulus-oocyte complexes were cultured in TCM-199 medium supplemented with Hepes, sodium bicarbonate, sodium pyruvate, additives, fetal calf serum (B-199 medium and gonadotropins (14 U/ml PMSG and 7 U/ml hCG. For embryo development, the oocytes/zygotes were cultured in B-199 medium with bovine oviduct epithelial cells in suspension under silicon oil. Treatments for in vitro culture conditions for both experiments were: 1- B-199 + 200 ng/ml IGF-I; 2- B-199 + 100 ng/ml IGF-I; 3- B-199 + 50 ng/ml IGF-I; 4- B-199 + 10 ng/ml IGF-I; 5- B-199 + 0 ng/ml IGF-I. All cultures were performed at 38.5ºC in 5% CO2 in air and the data were analyzed by chi-square test. In experiment I, there were no differences (P>0.05 among treatments for CR, BR or HR. In experiment II, the addition of IGF-I to the embryo culture medium (ECM resulted in a significant increase in CR while for BR and HR this effect was not observed. The addition of 200 ng/ml IGF-I to ECM increased CR (71.1% when compared to 100 ng/ml IGF-I (57.6% or control (56.7% groups, however, there were no differences when compared to 50 (69.4% or 10 ng/ml (73.1% groups. There was no beneficial effect of the addition of IGF-I in the IVM or ECM media on the in vitro development of embryos produced from oocytes matured and fertilized in vitro.

  12. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes.

    Science.gov (United States)

    Logan, Sreemathi; Pharaoh, Gavin A; Marlin, M Caleb; Masser, Dustin R; Matsuzaki, Satoshi; Wronowski, Benjamin; Yeganeh, Alexander; Parks, Eileen E; Premkumar, Pavithra; Farley, Julie A; Owen, Daniel B; Humphries, Kenneth M; Kinter, Michael; Freeman, Willard M; Szweda, Luke I; Van Remmen, Holly; Sonntag, William E

    2018-02-01

    A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-Cre TAM /igfr f/f ). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfr f/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30-50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H 2 O 2 -induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain. Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction

  13. FETAL FIBRONECTIN AND PHOSPHORILATED INSULIN- LIKE GROWTH FACTOR BINDING PROTEIN-1 AS PREDICTORS OF SPONTANEUS PRETERM DELIVERY

    Directory of Open Access Journals (Sweden)

    Marija Hadži-Lega

    2014-09-01

    Full Text Available The aim of the paper was to assess the combined use of cervical length, fetal fibronectin and cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1 in the prediction of preterm delivery in symptomatic women in the following 14 days. Cervical length was prospectively measured in 58 consecutive singleton pregnancies with intact membranes and regular contractions at 24–36 weeks; fetal fibronectin and phIGFBP-1 were also assessed. Demographic data was evaluated (history of previous preterm delivery, history of spontaneous abortion, parity, BMI, maternal age, Islamic or Orthodox religion. Values of all variables were evaluated (demographic data, cervical length and values of phIGFBP1 and fetal fibronectin alone and in combination with cervical length of ≤ 15mm and more than 15 mm. PhIGFPB was positive in 30 patients (22 of them gave birth in 14 days. In women with cervical length less than 15 mm phIGFBP-1, it was positive in 9 pregnant women who were delivered in 14 days. In women with cervical length less than 25 mm phIGFBP-1 was positive in 26 patients (2 of them gave birth in 14 days. In patients with cervical length more than 25 mm phIGFBP-1 was positive in 4 patients (2 of them gave birth in 14 days. Using logistic regression we confirmed that with OR 0.117 and CI 95% (0.046-0.295 and p<0.01 odds for preterm birth among patients with negative test results, phIGFBP-1 was by 0.117 lower than the odds for preterm birth among patients with positive test results. Using the same test, we confirmed that with OR=14,722 (CI 95% 5.27-41.1, (p<0.01 cervical length less than 25 mm was a good predictor of preterm delivery in symptomatic patients. Probability for delivery in the following 14 days in patients with positive phIGFBP-1 and cervical length≤15 mm is 0.88 or probability for not delivering in those patients is 0.12. Eighty-eight percents of patients with positive phIGFBP-1 and cervical length ≤15 mm will give birth

  14. Fetal growth restriction and the programming of heart growth and cardiac insulin-like growth factor 2 expression in the lamb.

    Science.gov (United States)

    Wang, Kimberley C W; Zhang, Lei; McMillen, I Caroline; Botting, Kimberley J; Duffield, Jaime A; Zhang, Song; Suter, Catherine M; Brooks, Doug A; Morrison, Janna L

    2011-10-01

    Reduced growth in fetal life together with accelerated growth in childhood, results in a ~50% greater risk of coronary heart disease in adult life. It is unclear why changes in patterns of body and heart growth in early life can lead to an increased risk of cardiovascular disease in adulthood. We aimed to investigate the role of the insulin-like growth factors in heart growth in the growth-restricted fetus and lamb. Hearts were collected from control and placentally restricted (PR) fetuses at 137-144 days gestation and from average (ABW) and low (LBW) birth weight lambs at 21 days of age. We quantified cardiac mRNA expression of IGF-1, IGF-2 and their receptors, IGF-1R and IGF-2R, using real-time RT-PCR and protein expression of IGF-1R and IGF-2R using Western blotting. Combined bisulphite restriction analysis was used to assess DNA methylation in the differentially methylated region (DMR) of the IGF-2/H19 locus and of the IGF-2R gene. In PR fetal sheep, IGF-2, IGF-1R and IGF-2R mRNA expression was increased in the heart compared to controls. LBW lambs had a greater left ventricle weight relative to body weight as well as increased IGF-2 and IGF-2R mRNA expression in the heart, when compared to ABW lambs. No changes in the percentage of methylation of the DMRs of IGF-2/H19 or IGF-2R were found between PR and LBW when compared to their respective controls. In conclusion, a programmed increased in cardiac gene expression of IGF-2 and IGF-2R may represent an adaptive response to reduced substrate supply (e.g. glucose and/or oxygen) in order to maintain heart growth and may be the underlying cause for increased ventricular hypertrophy and the associated susceptibility of cardiomyocytes to ischaemic damage later in life.

  15. A controlled study on serum insulin-like growth factor-I and urinary excretion of growth hormone in fibromyalgia

    DEFF Research Database (Denmark)

    Jacobsen, S; Main, K; Danneskiold-Samsøe, B

    1995-01-01

    It has been hypothesized that secretory deficiencies of growth hormone may play a pathophysiological role in fibromyalgia (FM). Our objective was thus to evaluate the secretion of growth hormone in FM.......It has been hypothesized that secretory deficiencies of growth hormone may play a pathophysiological role in fibromyalgia (FM). Our objective was thus to evaluate the secretion of growth hormone in FM....

  16. A controlled study on serum insulin-like growth factor-I and urinary excretion of growth hormone in fibromyalgia

    DEFF Research Database (Denmark)

    Jacobsen, S; Main, K; Danneskiold-Samsøe, B

    1995-01-01

    OBJECTIVE. It has been hypothesized that secretory deficiencies of growth hormone may play a pathophysiological role in fibromyalgia (FM). Our objective was thus to evaluate the secretion of growth hormone in FM. METHODS. The 24-h urinary growth hormone excretion and serum levels of insulin...

  17. An insulin-like growth factor found in hepatopancreas implicates carbohydrate metabolism of the blue crab Callinectes sapidus.

    Science.gov (United States)

    Chung, J Sook

    2014-04-01

    Hyperglycemia that is caused by the release of crustacean hyperglycemic hormone (CHH) from the sinus gland to hemolymph is one of the hallmark physiological phenomena, occurring in decapod crustaceans experiencing stressful conditions. However, the mechanism(s) by which such elevated glucose levels return to resting levels is still unknown. Interestingly, noted is a difference in the clearance rate of hemolymph glucose between adult females and adult males of the blue crab, Callinectes sapidus: the former with more rapid clearance than the latter. The presence of an endogenous-insulin-like molecule is suggested in C. sapidus because an injection of bovine insulin, significantly reduces the levels of hemolymph glucose that were previously elevated by emersion stress or the glucose injection. Using 5' and 3' RACE, the full-length cDNA of an insulin-like molecule is isolated from the hepatopancreas of an adult female C. sapidus and shows the same putative sequence of an insulin-like androgenic gland factor (IAG) but differs in 5' and 3' UTR sequences. A knock-down study using five injections of double-stranded RNA of CasIAG-hep (dsRNA-CasIAG-hep, 10μg/injection) over a 10-day period reduces CasIAG-hep expression by ∼50%. The levels of hemolymph glucose are also kept higher in dsRNA-CasIAG-hep injected group than those treated with dsRNA-green fluorescent protein (dsRNA-IAG-hep) or saline. Most importantly, the hepatopancreas of dsRNA-CasIAG-hep injected animals contains amounts of carbohydrate (glucose, trehalose, and glycogen) significantly lower than those of control groups, indicating that the function of CasIAG-hep in carbohydrate metabolism in crustaceans is similar to carbohydrate metabolism in vertebrates. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Association of insulin-like growth factor I and insulin-like growth factor-binding protein-3 with intelligence quotient among 8- to 9-year-old children in the Avon Longitudinal Study of Parents and Children.

    Science.gov (United States)

    Gunnell, David; Miller, Laura L; Rogers, Imogen; Holly, Jeff M P

    2005-11-01

    Insulin-like growth factor I (IGF-I) is a hormone that mediates the effects of growth hormone and plays a critical role in somatic growth regulation and organ development. It is hypothesized that it also plays a key role in human brain development. Previous studies have investigated the association of low IGF-I levels attributable to growth hormone receptor deficiency with intelligence but produced mixed results. We are aware of no studies that investigated the association of IGF-I levels with IQ in population samples of normal children. To investigate the association of circulating levels of IGF-I and its principle binding protein, IGF-binding protein-3 (IGFBP-3), in childhood with subsequent measures of IQ. The cohort study was based on data for 547 white singleton boys and girls, members of the Avon Longitudinal Study of Parents and Children, with IGF-I and IGFBP-3 measurements (obtained at a mean age of 8.0 years) and IQ measured with the Wechsler Intelligence Scale for Children (at a mean age of 8.7 years). We also investigated associations with measures of speech and language based on the Wechsler Objective Reading Dimensions test (measured at an age of 7.5 years) and the Wechsler Objective Language Dimensions test (listening comprehension subtest only, measured at an age of 8.7 years). For some children (n = 407), IGF-I (but not IGFBP-3) levels had been measured at approximately 5 years of age in a previous study. Linear regression models were used to investigate associations of the IGF-I system with the measures of cognitive function. Three hundred one boys and 246 girls were included in the sample. IGF-I levels (mean +/- SD) were 142.6 +/- 53.9 ng/mL for boys and 154.4 +/- 51.6 ng/mL for girls. IQ scores (mean +/- SD) were 106.05 +/- 16.6 and 105.27 +/- 15.6 for boys and girls, respectively. IGF-I levels were associated positively with intelligence. For every 100 ng/mL increase in IGF-I, IQ increased by 3.18 points (95% confidence interval [CI]: 0.52 to 5

  19. Rapid stimulation of fluid-phase endocytosis and exocytosis by insulin, insulin-like growth factor-I, and epidermal growth factor in KB cells.

    Science.gov (United States)

    Miyata, Y; Hoshi, M; Koyasu, S; Kadowaki, T; Kasuga, M; Yahara, I; Nishida, E; Sakai, H

    1988-09-01

    Effects of growth factors on fluid-phase endocytosis and exocytosis in human epidermoid carcinoma KB cells were examined by measuring horseradish peroxidase (HRP) as a marker. Insulin, insulin-like growth factor-I (IGF-I), and epidermal growth factor (EGF) promoted HRP accumulation. They also stimulated the efflux of the preloaded HRP from the cells. From these results it follows that these growth factors stimulate the influx as well as the efflux of HRP, because the accumulation rate is the sum of the influx rate and the efflux rate. The stimulation of both HRP accumulation and HRP efflux was rapidly induced within 2-4 min of the addition of growth factors and persisted for at least 60 min. The concentrations eliciting half-maximal stimulatory effects of insulin, IGF-I, and EGF were about 5 X 10(-7), 1 X 10(-9), and 5 X 10(-10) M, respectively. aIR-3 (anti-type I IGF receptor antibody) completely blocked the stimulation of HRP accumulation by IGF-I but very slightly inhibited the stimulation by insulin. The 528 IgG (anti-EGF receptor antibody) inhibited the stimulation of HRP accumulation by EGF. These results indicated that each of these growth factors stimulates the HRP accumulation mediated by the corresponding (homologous) growth factor receptors. The rapid stimulation of fluid-phase influx and efflux may constitute one of the common early cellular responses to growth factors.

  20. Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, M H; Hvidberg, A; Juul, A

    1995-01-01

    In the present study, we 1) determined whether the impaired spontaneous 24-h GH secretion as well as the blunted GH response to provocative testing in obese subjects are persistent disorders or transient defects reversed with weight loss and 2) investigated 24-h urinary GH excretion and basal...... levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), as well as insulin in obese subjects before and after a massive weight loss. We studied 18 obese subjects (age, 26 +/- 1 yr; body mass index, 40.9 +/- 1.1 kg/m2); 18 normal age-, and sex-matched control subjects; and 9...... reversible defects in 24-h spontaneous GH release profiles, basal IGF-I levels, and the IGF-I/IGFBP-3 molar ratio in obese subjects. The recovery of the 24-h GH release points to an acquired transient defect rather than a persistent preexisting disorder....

  1. Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency.

    Science.gov (United States)

    Grimberg, Adda; DiVall, Sara A; Polychronakos, Constantin; Allen, David B; Cohen, Laurie E; Quintos, Jose Bernardo; Rossi, Wilma C; Feudtner, Chris; Murad, Mohammad Hassan

    2016-01-01

    On behalf of the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society, we sought to update the guidelines published in 2003 on the use of growth hormone (GH). Because idiopathic short stature (ISS) remains a controversial indication, and diagnostic challenges often blur the distinction between ISS, GH deficiency (GHD), and primary IGF-I deficiency (PIGFD), we focused on these three diagnoses, thereby adding recombinant IGF-I therapy to the GH guidelines for the first time. This guideline was developed following the GRADE approach (Grading of Recommendations, Assessment, Development, and Evaluation). This guideline provides recommendations for the clinical management of children and adolescents with growth failure from GHD, ISS, or PIGFD using the best available evidence. The taskforce suggests that the recommendations be applied in clinical practice with consideration of the evolving literature and the risks and benefits to each individual patient. In many instances, careful review highlights areas that need further research. © 2016 S. Karger AG, Basel.

  2. Active immunization of pigs against growth hormone-releasing factor: effect on concentrations of growth hormone and insulin-like growth factor 1.

    Science.gov (United States)

    Armstrong, J D; Esbenshade, K L; Johnson, J L; Coffey, M T; Heimer, E; Campbell, R M; Mowles, T; Felix, A

    1990-02-01

    Cyclic gilts (96 +/- 1 kg) were used to determine the effect of active immunization against growth hormone-releasing factor GRF(1-29)-NH2 on concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Gilts were immunized against GRF conjugated to human serum albumin (GRF-HSA, n = 5) or HSA alone at 180 d of age (wk 0). Booster doses were administered at wk 9 and 13. Seven days after the second booster (wk 14), blood samples were collected at 15-min intervals for 6 h before feeding and 30, 60, 120, 180 and 240 min after feeding. Eight days after the second booster, all gilts were administered a GRF analog, [desNH2Tyr1,Ala15]-GRF(1-29)-NH2, followed by an opioid agonist, FK33-824. Blood samples were collected at 15-min intervals from -30 to 240 min after injection. Immunization against GRF-HSA resulted in antibody titers, expressed as dilution required to bind 50% of [125I]GRF, ranging from 1:11,000 to 1:60,000 (wk 11 and 14); binding was not detectable or was less than 50% at 1:100 in HSA gilts (P less than .05). Episodic release of GH was abolished by immunization against GRF-HSA (P less than .05). Mean GH was decreased (P less than .07), but basal GH concentrations were not altered (P greater than .15) by immunization against GRF-HSA. Serum concentrations of IGF-1 were similar at wk 0, but concentrations were lower in GRF-HSA than in HSA gilts (P less than .05) at wk 14.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. The Insulin-like Growth Factor (IGF)-I E-Peptides Modulate Cell Entry of the Mature IGF-I Protein

    OpenAIRE

    Pfeffer, Lindsay A.; Brisson, Becky K.; Lei, Hanqin; Barton, Elisabeth R.

    2009-01-01

    Insulin-like growth factor (IGF)-I is a critical protein for cell development and growth. Alternative splicing of the igf1 gene gives rise to multiple isoforms. In rodents, proIGF-IA and proIGF-IB have different carboxy-terminal extensions called the E-peptides (EA and EB) and upon further posttranslational processing, produce the identical mature IGF-I protein. Rodent EB has been reported to have mitogenic and motogenic effects independent of IGF-I. However, effects of EA or EB on mature IGF...

  4. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty

    DEFF Research Database (Denmark)

    Juul, A; Scheike, Thomas Harder; Nielsen, C T

    1995-01-01

    Central precocious puberty (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed that gonadal sex steroids stimulate pulsatile GH secretion, which, in turn......, stimulates insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) production. However, little is known about GH, IGF-I, and IGFBP-3 serum levels in children with precocious puberty. Treatment of CPP by GnRH agonists has become the treatment of choice. However, the effect of long term...

  5. Serum insulin-like growth factor-I (IGF-I) and growth in children born after assisted reproduction

    DEFF Research Database (Denmark)

    Kai, Claudia Mau; Main, Katharina M; Andersen, Anders Nyboe

    2006-01-01

    CONTEXT: Concern has been raised about the safety of assisted reproduction techniques for the offspring. OBJECTIVES: The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF...... cohorts was normal. Our findings of subtle differences in target height attainment and serum IGF-I levels between infants born after assisted reproduction techniques and controls may not be clinically significant. However, these observations indicate that further systematic follow-up of growth and puberty...

  6. Anti-insulin-like growth factor-IIP3 DNAzymes inhibit cell proliferation and induce caspase-dependent apoptosis in human hepatocarcinoma cell lines

    Directory of Open Access Journals (Sweden)

    Zhang M

    2013-10-01

    Full Text Available Min Zhang,1 Gregor PC Drummen,2 Su Luo11Medical Department, Beihua University, Jilin, People's Republic of China; 2Cellular Stress and Ageing Program, Bionanoscience and Bio-Imaging Program, Bio & Nano-Solutions, Düsseldorf, GermanyBackground: Insulin-like growth factor II (IGF-II is a fetal growth protein and an important proangiogenic factor controlled by four promoters (P, of which P2–P4 are inactive in the adult liver. Reactivation and dysregulation of IGF-IIP3 in particular is associated with the attenuation of apoptosis and increased proliferation in a number of liver cancer cell types. Its involvement in experimental liver carcinogenesis makes it a potential target for cancer gene therapy. We designed two IGF-IIP3 specific DNAzymes (DRz1 and DRz2 that target IGF-IIP3 messenger RNA (mRNA with the aim of reducing IGF-II expression through promoter 3.Methods: IGF-IIP3 mRNA and protein expression levels were assessed using real-time polymerase chain reaction and gel electrophoresis/western blotting after transfection with Lipofectamine® in SMMC-7721, Huh7, and HepG2 cell lines. Cell proliferation was determined via MTT assay; apoptosis was evaluated by fluorescence microscopy and with flow cytometry; procaspase-3 and -9 expression were detected via western blotting; and caspase activity was assayed colorimetrically. Standard procedures were used to calculate means and standard deviations, and P-values below 0.05 were considered to indicate significant differences.Results: DRzs were transfected into hepatocellular carcinoma cells and the results showed that DRz1, in particular, could decrease the expression of IGF-IIP3 by nearly 50%. Furthermore, DRz1 significantly inhibited cell proliferation and induced apoptosis. In addition, the downregulation of IGF-IIP3 expression was associated with increased caspase-3 and -9 activity in SMMC-7721 cells after 24 hours of transfection. In all experiments, the efficacy of DRz2 to influence IGF-IIP3

  7. Effects of Growth Hormone and Insulin-Like Growth Factor-1 on Postoperative Muscle and Substrate Metabolism

    Directory of Open Access Journals (Sweden)

    Folke Hammarqvist

    2010-01-01

    To conclude, growth factors influences urea metabolism, protein degradation and protein synthesis. There was no clearcut additional effect when combining GH and IGF-1 but the study was probably underpowered to outrule this and effects on nitrogen balance.

  8. Polymorphism of Insulin-like growth factor-I (IGF-I gene and their effect on growth traits in Indonesia native chicken

    Directory of Open Access Journals (Sweden)

    M.A Mu'in

    2009-12-01

    Full Text Available The research was aimed is to detect Insulin-like growth factor-I (IGF-I gene polymorphism and their effect on growth traits in Indonesia natives chicken. Seventy two Indonesian native chicken are going to be used in this research. The polymorphism of IGF-I gene was detected by PCR-RFLP/Pst-I. Four growth traits (body weight at 1, 2, 3, and 4 months were recorded for analyzing the association between IGF-I gene polymorphism and growth performance.The results showed that allele A (621 bp and allele B (364 and 257 bp were found in this research. It was found that Indonesian native chicken carried high frequencies of allele A (0.82, and frequencies of IGF-I genotypes (AA, AB, BB were 68.0, 27.8, and 4,2%, respectively. When compared to the IGF-I genotypes, the BB genotype had the highest body weight at 1, 2, 3, and 4 month (P<0.05. The results showed that the B allele was positive of associated to a higher growth rate. Therefore, these results suggest that there is a possibility of IGF-I genotypes acting as a molecular marker for growth rate of Indonesia native.

  9. Plerocercoid growth factor (PGF), a human growth hormone (hGH) analogue produced by the tapeworm Spirometra mansonoides, has direct insulin-like action in adipose tissue of normal rats in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Salem, M.A.M.; Phares, C.K.

    1986-03-01

    The metabolic actions of GH can be divided into acute (insulin-like) and chronic (lipolytic/anti-insulin). The insulin-like actions of GH are most readily elicited in GH-deficient animals as GH induces resistance to its own insulin-like action. Like GH, PGF stimulates growth and cross-reacts with anti-hGH antibodies. Independent experiments were conducted comparing the direct actions of PGF to insulin or hGH in vitro. Insulin-like effects were determined by the ability of PGF, insulin or hGH to stimulate (U-/sup 14/C)glucose metabolism in epidydimal fat pads from normal rats and by inhibition of epinephrine-stimulated lipolysis. Direct stimulation of lipolysis was used as anti-insulin activity. To determine if PGF competes for insulin or GH receptors, adipocytes (3 x 10/sup 5/ cells/ml) were incubated with either (/sup 125/I)insulin or (/sup 125/I)hGH +/- PGF, +/- insulin or +/- hGH. PGF stimulated glucose oxidation and /sup 14/C-incorporation into lipids. Insulin, hGH and PGF inhibited lipolysis (33%, 29% and 34%, respectively). Adipose tissue was very sensitive to the lipolytic effect of hGH but PGF was neither lipolytic nor did it confer refractoriness to its insulin-like action. PGF bound to GH but not to insulin receptors. Therefore, PGF had direct insulin-like effects but did not stimulate lipolysis in tissue from normal rats in vitro.

  10. Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors.

    Science.gov (United States)

    Jones, Robin L; Kim, Edward S; Nava-Parada, Pilar; Alam, Salma; Johnson, Faye M; Stephens, Andrew W; Simantov, Ronit; Poondru, Srinivasu; Gedrich, Rich; Lippman, Scott M; Kaye, Stan B; Carden, Craig P

    2015-02-15

    We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study. Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3-4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1-2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. ©2014 American Association for Cancer Research.

  11. Validation of a Modified Child-Turcotte-Pugh Classification System Utilizing Insulin-Like Growth Factor-1 for Patients with Hepatocellular Carcinoma in an HBV Endemic Area.

    Directory of Open Access Journals (Sweden)

    Dong Hyeon Lee

    Full Text Available Recently, a modified insulin-like growth factor-1 (IGF-Child-Turcotte-Pugh (CTP classification was proposed to improve the original CTP classification. This study aimed to validate the new IGF-CTP classification system as a prognostic maker for patients with hepatocellular carcinoma (HCC in a hepatitis B virus endemic area.We conducted a post-hoc analysis of a prospective cohort study. We used Harrell's C-index and U-statistics to compare the prognostic performance of both IGF-CTP and CTP classifications for overall survival. We evaluated the relationship between HCC stage and the four components of the IGF-CTP classification (serum levels of IGF-1, albumin, and total bilirubin and prothrombin time [PT] using nonparametric trend analysis.We included a total of 393 patients in this study. In all, 55 patients died during the median follow-up of 59.1 months. There was a difference between IGF-CTP class and CTP class in 14% of patients. Overall, the IGF-CTP classification system had a higher prognostic value (C-index = 0.604, 95% confidence interval [CI] = 0.539-0.668 than the CTP system (C-index = 0.558, 95% CI = 0.501-0.614, but the difference was not statistically significant (P = .07 by U-statistics. A lower serum level of IGF-1 was related to a more advanced cancer stage (P < .01. The remaining components of the IGF-CTP classification were not significantly related to tumor stage (P = .11 for total bilirubin; P = .33 for albumin; and P = .39 for PT.The IGF-CTP classification was slightly better than the original CTP classification for predicting survival of patients with HCC in a chronic hepatitis B endemic area. This is most likely due to the fact that serum IGF-1 levels reflect underlying HCC status.

  12. Red Deer Antler Extract Accelerates Hair Growth by Stimulating Expression of Insulin-like Growth Factor I in Full-thickness Wound Healing Rat Model

    Directory of Open Access Journals (Sweden)

    ZhiHong Yang

    2012-05-01

    Full Text Available In order to investigate and evaluate the effects of red deer antlers on hair growth in the full-thickness wound healing model, Sprague-Dawley rats were given incision wounds through the full thickness of their dorsal skin and deer antler was applied for 40 days. At specified intervals thereafter (4, 8, 16, 32 and 40 days, the animals were sacrificed and the wound site skins were excised, processed, and sectioned. At post-injury days 16, 32 and 40, longer and more active new hair appeared around the healing wound of antler-treated skin. Histological studies showed that the antler extract markedly increases the depth, size, and number of hair follicles. Expression of IGF-I (insulin-like growth factor mRNA was detected by RT-PCR and real time RT-PCR. The result showed that the expression of IGF-I (days 16, 32, and 40 was obviously up-regulated in antler-treated skins compared to control skins. Similar results were seen in the ELISA analysis to quantify the IGF-I expression. These results support the notion that wound healing can cause hair growth by enhancing the expression of IGF-I. Deer antler extract appears to have the potential to promote hair growth and could be used in hair growth products.

  13. Sorbic acid improves growth performance and regulates insulin-like growth factor system gene expression in swine.

    Science.gov (United States)

    Luo, Z-F; Fang, X-L; Shu, G; Wang, S-B; Zhu, X-T; Gao, P; Chen, L-L; Chen, C-Y; Xi, Q-Y; Zhang, Y-L; Jiang, Q-Y

    2011-08-01

    Sorbic acid (SA) is a PUFA with a conjugated double bond. The conjugated fatty acids, including CLA, are multifunctional bioactive fatty acids with the ability to improve growth performance. The effect of SA on pig growth performance was examined to determine its mechanism of action. The ADG, ADFI, and serum IGF-I concentration were examined, as were IGF-I secretion and IGF system gene expression in hepatocytes. Two hundred forty 21-d-old Duroc × Landrace × Yorkshire weaned piglets (6.86 ± 0.02 kg) were randomly divided into 4 groups, each consisting of 3 pens of 20 piglets (10 female and 10 male). The 4 groups of piglets were kept in a temperature-controlled room (26 to 28 °C), and feed and water were provided to the pigs ad libitum. Weanling piglets were fed diets that included 0, 0.5, 2, or 4 g of SA/kg for 42 d. The diet supplemented with 0.5 g/kg of SA improved (P 0.05; 1 g of SA/kg, P 0.05) IGFBP or PPARγ mRNA expression, in pig primary hepatocytes. These results indicate that SA improves growth performance by regulating IGF system gene expression and hormone secretion. © 2011 American Society of Animal Science. All rights reserved.

  14. Associations between plasma insulin-like growth factor-I and the markers of inflammation interleukin 6, C-reactive protein and YKL-40 in an elderly background population

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Raymond, Ilan; Hildebrandt, Per

    2010-01-01

    The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population....

  15. Relationship of serum insulin-like growth factor I (IGF-I) with nutritional status in pediatric patients with malignant diseases--a single Romanian center experience.

    Science.gov (United States)

    Chinceşan, Mihaela Ioana; Mărginean, Oana; Pitea, Ana-Maria; Dobreanu, Minodora

    2013-10-01

    The aim of this study was to analyze insulin-like growth factor I (IGF-I) serum level in pediatric patients with cancer compared with pediatric patients with nononcological diseases and to assess the relationship between IGF-I and nutritional status of oncological patients. From January 2009 to July 2012, we assessed 151 consecutively hospitalized patients in a tertiary emergency pediatric hospital. The patients were divided into two groups: group I, consisting of patients with malignant diseases (64 patients), and group II, the control group, consisting of 87 age- and gender-matched patients with different pediatric diseases. The anthropometric parameters (weight, height, body mass index, middle upper arm circumference (MUAC), and tricipital skinfold thickness (TST) and biochemical parameters (proteins, albumin, and total IGF-I) were comparatively evaluated at the diagnosis and after intensive chemotherapy in the malignant group. Anthropometric and biochemical parameters in group I were significantly different from those in group II for height, MUAC, TST, total proteins, and albumin (p patients with malignant diseases and 5 out of 87 patients in the control group had malnutrition. IGF-I in patients with cancer was much lower than in the control group (median 48.3 ng/ml, range 25.00-662.00 ng/ml vs 129.00 ng/ml, range 25.00-745.00 ng/ml) (p = 0.014). We found a positive correlation between IGF-I, MUAC, and TST at the diagnosis of the malignant disease. Also, we identified positive correlations between IGF-I, protein, and albumin. Serum IGF-I levels in cancer patients were significantly lower at diagnosis than after chemotherapy (48.3 ng/ml, range 25.00-662.00 ng/ml vs 110.0 ng/ml, range 25.00-573.00 ng/ml; p = 0.04). IGF-I seems to be an accurate biochemical parameter used in malnutrition assessment of children with cancer. IGF-I correlated with the anthropometric parameters of the arm, serum protein, and albumin. These parameters most accurately characterize the

  16. Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Pedersen, S B

    1997-01-01

    .MATERIALS AND METHODS: Eight week old Wistar rats were allocated into groups of eight, receiving systemic treatment for 3 and 7 days with either IGF-I (400 micrograms/rat/day) or EGF (30 micrograms/rat/day) alone or in combination with DFMO.RESULTS: Systemic treatment with IGF-I for 7 days resulted in a 29% (p ...-I after 3 days of treatment, and administration of IGF-I concomitantly with DFMO significantly inhibited ODC activity and the weight increase of the prostate. Stereological examination of the prostate in the IGF-I-treated animals showed growth of the epithelial component of the gland. Systemic treatment...

  17. Low Levels of the 150-kD Insulin -Like Growth Factor Binding Protein 3 Ternary complex in Patients with Anorexia nervosa

    DEFF Research Database (Denmark)

    Støving, René K; Hangaard, Jørgen; Hagen, Claus

    2003-01-01

    BACKGROUND/AIM: In healthy adults, serum insulin-like growth factor I (IGF), IGF-binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) form a 150-kD ternary complex under the control of growth hormone (GH). Circulating IGF-I half-life, bioavailability, and endocrine actions depend on the ter......BACKGROUND/AIM: In healthy adults, serum insulin-like growth factor I (IGF), IGF-binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) form a 150-kD ternary complex under the control of growth hormone (GH). Circulating IGF-I half-life, bioavailability, and endocrine actions depend...... women with AN at the time of diagnosis and after partial weight recovery and in 6 healthy age-matched women serving as controls. RESULTS: Patients with AN had low levels of ALS and IGFBP-3 contained in the 150-kD ternary complex and in the non-150-kD fraction. Following partial weight recovery, the 150...

  18. Women with osteoarthritis have elevated synovial fluid levels of insulin-like growth factor (IGF)-1 and IGF-binding protein-3.

    Science.gov (United States)

    Hooshmand, Shirin; Juma, Shanil; Khalil, Dania A; Shamloufard, Pouneh; Arjmandi, Bahram H

    2015-01-01

    The present study explores the possible connection between synovial fluid concentrations of insulin like growth factor (IGF-1), IGF-binding protein (IGFBP-3), leptin, and C-reactive protein (CRP) in osteoarthritis (OA). Synovial fluid specimens were obtained from a total of thirty-four individuals with and without OA. Protein-normalized measurements of IGF-1, IGFBP-3, and leptin concentrations in synovial fluid showed significantly (P leptin levels increase in synovial fluid of women but not in men with OA versus those without OA.

  19. Comparing two acromegalic patients with respect to central corneal thickness, intraocular pressure, and tear insulin-like growth factor levels before and after treatment.

    Science.gov (United States)

    Emrah, Kan; Elif, Kilic Kan; Ali, Okuyucu

    2015-09-01

    The aim of the study was to compare the central corneal thickness (CCT), intraocular pressure (IOP), and tear insulin-like growth factor-1 (IGF-1) levels of 2 patients with acromegaly before and after the surgical treatment of the disease. CCTs, IOP levels, and tear IGF-1 values showed a decrease after the treatment in 2 patients. As we found higher CCT, IOP, and tear IGF-1 levels in the active phase of the disease in two acromegaly patients, detailed information about the activity of the disease may be important before the examination of these patients.

  20. Prenatal unhealthy diet, insulin?like growth factor 2 gene ( IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early?onset conduct problems

    OpenAIRE

    Rijlaarsdam, Jolien; Charlotte A. M. Cecil; Walton, Esther; Mesirow, M.S.C. (Maurissa S. C.); Relton, Caroline; Gaunt, Tom; McArdle, Wendy; Barker, E. D.

    2016-01-01

    BACKGROUND: Conduct problems (CP) and attention deficit hyperactivity disorder (ADHD) are often comorbid and have each been linked to 'unhealthy diet'. Early-life diet also associates with DNA methylation of the insulin-like growth factor 2 gene (IGF2), involved in fetal and neural development. We investigated the degree to which prenatal high-fat and -sugar diet might relate to ADHD symptoms via IGF2 DNA methylation for early-onset persistent (EOP) versus low CP youth.METHODS: Participants w...

  1. Associations between plasma insulin-like growth factor-I and the markers of inflammation interleukin 6, C-reactive protein and YKL-40 in an elderly background population

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Raymond, Ilan; Hildebrandt, Per

    2010-01-01

    The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population.......The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population....

  2. Effect of plant extracts on growth performance and insulin-like growth factor 1 secretion in growing pigs

    Directory of Open Access Journals (Sweden)

    Subramaniam Mohana Devi

    2015-10-01

    Full Text Available ABSTRACTThe objective of the present study is to evaluate the effects of plant extracts on growth performance, nutrient digestibility, and immune blood characteristics in growing pigs. A total of 80 [(Landrace × Yorkshire × Duroc] pigs with an initial body weight (BW of 27.31±2.15 kg were used in a 6-wk experiment. Pigs were allotted to one of four treatments (1 - Control (CON (basal diet; 2 - PE1 (CON + 0.05% plant extracts; 3 - PE2 (CON + 0.10% plant extracts; and 4 - PE3 (CON + 0.15% plant extracts in a randomized complete block design according to sex and initial BW. The PE1 and PE2 treatments provided a greater average daily gain than the CON treatment. From weeks 0 to 6 the pigs fed diets PE2 and PE3 showed greater apparent total tract digestibility of dry matter than those fed the CON diet. Pigs fed the plant-extract treatments had a reduction in total mercaptan emission on day 3 compared with control treatment. On day 5, fecal acetic acid content was decreased with increased blood WBC (white blood cells and lymphocyte counts and serum IGF-1concentration by plant extract supplementation compared with the control treatment. All the results showed a 95% significance level. Supplementation of plant extracts can improve growth performance and nutrient digestibility in growing pigs, decrease fecal gas emission, and increase immune components such as WBC and lymphocytes, and serum IGF-1 concentration in growing pigs.

  3. [Insulin-like growth factor 1 levels and their association with growth and development in infants aged 1-24 months].

    Science.gov (United States)

    Wang, Xin-Li; Ge, Mei-Ru; Wu, Wen-Yan; Zhang, Juan

    2010-06-01

    To study serum insulin-like growth factor 1 (IGF-1) levels and their association with growth and development in infants aged 1-24 mouths. A total of 525 healthy infants (125 preterm, 400 term) were enrolled. Serum IGF-1 levels were measured using ELISA 1.5, 4, 6, 8, 12, 18 and 24 months after birth. The body weight and body length were simultaneously measured. Serum IGF-1 levels were the lowest in preterm infants 1.5 months after birth (86+/-60 ng/mL). Thereafter, serum IGF-1 levels increased, and were significantly higher than those in term infants between 4 and 12 months after birth. Serum IGF-1 levels in term infants were the highest (116+/-52 ng/mL) 1.5 months after birth during their life of 12 months old. Thereafter, serum IGF-1 levels decreased and reached to a nadir (69+/-58 ng/mL) 8 months after birth. IGF-I levels were positively correlated with the weight and the height (SDS) in both preterm and term infants. Serum IGF-1 levels are closely associated with growth and development in infants.

  4. Sustained delivery of insulin-like growth factor-1/hepatocyte growth factor stimulates endogenous cardiac repair in the chronic infarcted pig heart.

    Science.gov (United States)

    Koudstaal, Stefan; Bastings, Maartje M C; Feyen, Dries A M; Waring, Cheryl D; van Slochteren, Frebus J; Dankers, Patricia Y W; Torella, Daniele; Sluijter, Joost P G; Nadal-Ginard, Bernardo; Doevendans, Pieter A; Ellison, Georgina M; Chamuleau, Steven A J

    2014-03-01

    Activation of endogenous cardiac stem/progenitor cells (eCSCs) can improve cardiac repair after acute myocardial infarction. We studied whether the in situ activation of eCSCs by insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) could be increased using a newly developed hydrogel in chronic myocardial infarction (MI). One-month post-MI pigs underwent NOGA-guided intramyocardial injections of IGF-1/HGF (GF: both 0.5 μg/mL, n = 5) or IGF-1/HGF incorporated in UPy hydrogel (UPy-GF; both 0.5 μg/mL, n = 5). UPy hydrogel without added growth factors was administered to four control (CTRL) pigs. Left ventricular ejection fraction was increased in the UPy-GF and GF animals compared to CTRLs. UPy-GF delivery reduced pathological hypertrophy, led to the formation of new, small cardiomyocytes, and increased capillarization. The eCSC population was increased almost fourfold in the border zone of the UPy-GF-treated hearts compared to CTRL hearts. These results show that IGF-1/HGF therapy led to an improved cardiac function in chronic MI and that effect size could be further increased by using UPy hydrogel.

  5. Manipulation of the Growth Hormone-Insulin-Like Growth Factor (GH-IGF) Axis: A Treatment Strategy to Reverse the Effects of Early Life Developmental Programming.

    Science.gov (United States)

    Reynolds, Clare M; Perry, Jo K; Vickers, Mark H

    2017-08-08

    Evidence from human clinical, epidemiological, and experimental animal models has clearly highlighted a link between the early life environment and an increased risk for a range of cardiometabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and overnutrition, spanning exposure windows that cover the period from preconception through to early infancy, clearly highlight an increased risk for a range of disorders in offspring in later life. This process, preferentially termed "developmental programming" as part of the developmental origins of health and disease (DOHaD) framework, leads to phenotypic outcomes in offspring that closely resemble those of individuals with untreated growth hormone (GH) deficiency, including increased adiposity and cardiovascular disorders. As such, the use of GH as a potential intervention strategy to mitigate the effects of developmental malprogramming has received some attention in the DOHaD field. In particular, experimental animal models have shown that early GH treatment in the setting of poor maternal nutrition can partially rescue the programmed phenotype, albeit in a sex-specific manner. Although the mechanisms remain poorly defined, they include changes to endothelial function, an altered inflammasome, changes in adipogenesis and cardiovascular function, neuroendocrine effects, and changes in the epigenetic regulation of gene expression. Similarly, GH treatment to adult offspring, where an adverse metabolic phenotype is already manifest, has shown efficacy in reversing some of the metabolic disorders arising from a poor early life environment. Components of the GH-insulin-like growth factor (IGF)-IGF binding protein (GH-IGF-IGFBP) system, including insulin-like growth factor 1 (IGF-1), have also shown promise in ameliorating programmed metabolic disorders, potentially acting via epigenetic processes including changes in miRNA profiles and altered DNA methylation. However, as

  6. Novel nuclear localization and potential function of insulin-like growth factor-1 receptor/insulin receptor hybrid in corneal epithelial cells.

    Directory of Open Access Journals (Sweden)

    Yu-Chieh Wu

    Full Text Available BACKGROUND: Type I insulin-like growth factor receptor (IGF-1R and insulin receptor (INSR are highly homologous molecules, which can heterodimerize to form an IGF-1R/INSR hybrid (Hybrid-R. The presence and biological significance of the Hybrid-R in human corneal epithelium has not yet been established. In addition, while nuclear localization of IGF-1R was recently reported in cancer cells and human corneal epithelial cells, the function and profile of nuclear IGF-1R is unknown. In this study, we characterized the nuclear localization and function of the Hybrid-R and the role of IGF-1/IGF-1R and Hybrid-R signaling in the human corneal epithelium. METHODOLOGY/PRINCIPLE FINDINGS: IGF-1-mediated signaling and cell growth were examined in a human telomerized corneal epithelial (hTCEpi cell line using co-immunoprecipitation, immunoblotting and cell proliferation assays. The presence of Hybrid-R in hTCEpi and primary cultured human corneal epithelial cells was confirmed by immunofluorescence and reciprocal immunoprecipitation of whole cell lysates. We found that IGF-1 stimulated Akt and promoted cell growth through IGF-1R activation, which was independent of the Hybrid-R. The presence of Hybrid-R, but not IGF-1R/IGF-1R, was detected in nuclear extracts. Knockdown of INSR by small interfering RNA resulted in depletion of the INSR/INSR and preferential formation of Hybrid-R. Chromatin-immunoprecipitation sequencing assay with anti-IGF-1R or anti-INSR was subsequently performed to identify potential genomic targets responsible for critical homeostatic regulatory pathways. CONCLUSION/SIGNIFICANCE: In contrast to previous reports on nuclear localized IGF-1R, this is the first report identifying the nuclear localization of Hybrid-R in an epithelial cell line. The identification of a nuclear Hybrid-R and novel genomic targets suggests that IGF-1R traffics to the nucleus as an IGF-1R/INSR heterotetrameric complex to regulate corneal epithelial homeostatic

  7. Early origins of heart disease: low birth weight and the role of the insulin-like growth factor system in cardiac hypertrophy.

    Science.gov (United States)

    Wang, Kimberley C W; Botting, Kimberley J; Padhee, Monalisa; Zhang, Song; McMillen, I Caroline; Suter, Catherine M; Brooks, Doug A; Morrison, Janna L

    2012-11-01

    Epidemiological studies indicate that poor growth before birth is associated with left ventricular hypertrophy and an increased risk of death from heart disease later in life. In fetal life, the insulin-like growth factor (IGF) system has been implicated in physiological growth of the heart, whereas in postnatal life IGFs can be involved in both physiological and pathological cardiac hypertrophy. A reduction in substrate supply in fetal life, resulting in chronic hypoxaemia and intrauterine growth restriction, results in increased cardiac IGF-1R, IGF-2 and IGF-2R gene expression; and there is also evidence for a role of the IGF-2 receptor in the ensuing cardiac hypertrophy. The persistent high level of cardiac IGF-2R gene expression from fetal to postnatal life may be due to epigenetic changes in key cardiac hypertrophy regulatory pathways. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.

  8. Complementary therapeutic effects of dual delivery of insulin-like growth factor-1 and vascular endothelial growth factor by gelatin microspheres in experimental heart failure.

    Science.gov (United States)

    Cittadini, Antonio; Monti, Maria Gaia; Petrillo, Valentina; Esposito, Giovanni; Imparato, Giorgia; Luciani, Alessia; Urciuolo, Francesco; Bobbio, Emanuele; Natale, Carlo F; Saccà, Luigi; Netti, Paolo A

    2011-12-01

    Strategies to prevent adverse left ventricular (LV) remodelling after myocardial infarction have included several traditional approaches and novel cell-based or gene therapies. Delivery of growth factors in post-infarction heart failure has emerged as a valuable alternative strategy. Our aim was to investigate the effects of sequential release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) from biodegradable gelatin microspheres in experimental heart failure. Gelatin hydrogel microspheres were known to guarantee a sustained release of encapsulated growth factors, characterized by an initial burst followed by a slower release. Rats with moderate myocardial infarction were randomized to receive empty microspheres (MI), microspheres loaded with IGF-1 or VEGF, or a combination thereof (DUAL). Myocardial injections of microspheres were performed at the time of surgery, and treatment lasted 4 weeks. Echocardiography, LV catheterization, morphometric histology and immunohistochemistry, and molecular assessment of downstream mediators [e.g. Akt, endothelial nitric oxide synthase (eNOS), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA-2)] were assessed at the end of the treatment period. Infarct sizes were 33 ± 2, 28 ± 4, 24 ± 3, and 16 ± 3% in the MI, IGF-1, VEGF, and DUAL groups, respectively. IGF-1 attenuated LV remodelling, improved LV systolic and diastolic function, increased myocyte size, and reduced apoptotic deaths, capillary loss, and indexes of inflammation. VEGF-treated animals displayed a marked myocardial neoangiogenesis that led to the formation of mature vessels if combined with IGF-1 delivery. Downstream effects of IGF-1 were principally mediated by the Akt-mTOR (mammalian target of rapamycin)-dependent pathway, and both growth factors, particularly VEGF, induced a robust and sustained increase of eNOS. IGF-1 and VEGF exerted complementary therapeutic effects in post-infarction heart failure. Biodegradable

  9. Growth hormone-releasing peptide-biotin conjugate stimulates myocytes differentiation through insulin-like growth factor-1 and collagen type I.

    Science.gov (United States)

    Lim, Chae Jin; Jeon, Jung Eun; Jeong, Se Kyoo; Yoon, Seok Jeong; Kwon, Seon Deok; Lim, Jina; Park, Keedon; Kim, Dae Yong; Ahn, Jeong Keun; Kim, Bong-Woo

    2015-09-01

    Based on the potential beneficial effects of growth hormone releasing peptide (GHRP)-6 on muscle functions, a newly synthesized GHRP-6-biotin conjugate was tested on cultured myoblast cells. Increased expression of myogenic marker proteins was observed in GHRP-6-biotin conjugate-treated cells. Additionally, increased expression levels of insulin-like growth factor-1 and collagen type I were observed. Furthermore, GHRP-6-biotin conjugate-treated cells showed increased metabolic activity, as indicated by increased concentrations of energy metabolites, such as ATP and lactate, and increased enzymatic activity of lactate dehydrogenase and creatine kinase. Finally, binding protein analysis suggested few candidate proteins, including desmin, actin, and zinc finger protein 691 as potential targets for GHRP6-biotin conjugate action. These results suggest that the newly synthesized GHRP-6-biotin conjugate has myogenic stimulating activity through, at least in part, by stimulating collagen type I synthesis and several key proteins. Practical applications of the GHRP-6-biotin conjugate could include improving muscle condition.

  10. Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2012-02-01

    OBJECTIVE: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET). METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a University teaching hospital in London. Statistical analysis was performed using commercial software (SPSS for Windows, version 6.1, SPSS, Chicago, IL), with P < 0.05 as significant. Maternal IGF 1, IGF 2 and IGF BP-3 were assessed on maternal blood at booking. Blood pressure was checked at each visit in conjunction with urine analysis. The Davey & MacGillivray 1988 classification system was used in making the diagnosis of PET. RESULTS: There was no significant correlation between maternal IGF-1 or IGFBP-3 levels and gestational hypertension or PET. However, a significant positive correlation does exist between maternal IGF-2 levels and PET. CONCLUSIONS: Maternal IGF-2 has a significant positive correlation with PET.

  11. Long-term auxological and pubertal outcome of patients with hereditary insulin-like growth factor-I deficiency (Laron and growth hormone-gene deletion syndrome) treated with recombinant human insulin-like growth factor-I.

    Science.gov (United States)

    Messina, M F; Arrigo, T; Valenzise, M; Ghizzoni, L; Caruso-Nicoletti, M; Zucchini, S; Chiabotto, P; Crisafulli, G; Zirilli, G; De Luca, F

    2011-04-01

    GH-IGF-I axis is mainly involved in the complex process of somatic growth but emerging evidence suggests that it also influences hypothalamic-pituitary-gonadal (HPG) function. We report some data regarding long-term auxological and pubertal outcome of five female patients with hereditary forms of GH-IGF-I deficiency (Laron and GH-gene deletion syndrome) and a mean age of 23.4±5.3 yr (range 19-32). All the patients received recombinant human IGF-I (rhIGF-I, Pharmacia and Upjohn, Stockholm, Sweden, and rhIGF-I, Genentech, San Francisco, CA, USA) from a mean age of 8.6 yr (range 3.2-14.2) up to the final height. Final height was very disappointing (≤ -5.0 SD scores) and lower than target height in all the patients. Pubertal onset was delayed in most of them but menarche occurred spontaneously in all the patients. Median age at menarche was 15.1 yr. Menstrual cycles were regular for several years. Median duration of gynecological follow- up was 8.3 yr with the longest span of 17.2 yr. We can assert that GH-IGF-I axis has an essential role in promoting linear growth in humans and its physiological action cannot be replaced by pharmacological treatment in most patients with hereditary forms of IGF-I insufficiency as demonstrated by their subnormal final height. Our clinical observations can also support an essential role of IGF-I in genitalia growth but not in the function of HPG axis as demonstrated by the maintenance of regular menstrual cycles in the presence of subnormal levels of IGF-I after treatment discontinuation.

  12. Novel Single Nucleotide Polymorphisms of the Insulin-Like Growth Factor-I Gene and Their Associations with Growth Traits in Common Carp (Cyprinus carpio L.

    Directory of Open Access Journals (Sweden)

    Xiu Feng

    2014-12-01

    Full Text Available Insulin-like growth factor-I (IGF-I plays an important role in the growth and development of vertebrates. To study polymorphisms of IGF-I, we screened a total of 4555 bp of genomic sequences in four exons and partial introns for the discovery of single nucleotide polymorphism (SNP in common carp (Cyprinus carpio. Three SNPs (g.3759T>G, g.7627T>A and g.7722T>C in intron 2 and a nonsynonymous SNP (g.7892C>T in exon 3 were identified in a pilot population including random parents and their progenies. 289 progenies were further genotyped for studying possible associations between genotypes or combined genotypes and growth traits. The results showed that the locus g.7627T>A was significantly associated with body weight and body length, and fish with genotype AA had a mean body weight 5.9% higher than those with genotype TT. No significant associations were observed between genotypes of other loci and growth traits. However, when both g.7627T>A and g.7722T>C were considered, the combined genotype TT/TT was extremely associated with the lowest values of body length and body weight and the highest K value in comparison with other diplotypes (p < 0.01. These results suggest that genotype AA at g.7627T>A and its combined genotypes with alleles from another locus have positive effects on growth traits, which would be a candidate molecular marker for further studies in marker-assisted selection in common carp.

  13. Calorie restriction decreases murine and human pancreatic tumor cell growth, nuclear factor-κB activation, and inflammation-related gene expression in an insulin-like growth factor-1-dependent manner.

    Directory of Open Access Journals (Sweden)

    Alison E Harvey

    Full Text Available Calorie restriction (CR prevents obesity and has potent anticancer effects that may be mediated through its ability to reduce serum growth and inflammatory factors, particularly insulin-like growth factor (IGF-1 and protumorigenic cytokines. IGF-1 is a nutrient-responsive growth factor that activates the inflammatory regulator nuclear factor (NF-κB, which is linked to many types of cancers, including pancreatic cancer. We hypothesized that CR would inhibit pancreatic tumor growth through modulation of IGF-1-stimulated NF-κB activation and protumorigenic gene expression. To test this, 30 male C57BL/6 mice were randomized to either a control diet consumed ad libitum or a 30% CR diet administered in daily aliquots for 21 weeks, then were subcutaneously injected with syngeneic mouse pancreatic cancer cells (Panc02 and tumor growth was monitored for 5 weeks. Relative to controls, CR mice weighed less and had decreased serum IGF-1 levels and smaller tumors. Also, CR tumors demonstrated a 70% decrease in the expression of genes encoding the pro-inflammatory factors S100a9 and F4/80, and a 56% decrease in the macrophage chemoattractant, Ccl2. Similar CR effects on tumor growth and NF-κB-related gene expression were observed in a separate study of transplanted MiaPaCa-2 human pancreatic tumor cell growth in nude mice. In vitro analyses in Panc02 cells showed that IGF-1 treatment promoted NF-κB nuclear localization, increased DNA-binding of p65 and transcriptional activation, and increased expression of NF-κB downstream genes. Finally, the IGF-1-induced increase in expression of genes downstream of NF-κB (Ccdn1, Vegf, Birc5, and Ptgs2 was decreased significantly in the context of silenced p65. These findings suggest that the inhibitory effects of CR on Panc02 pancreatic tumor growth are associated with reduced IGF-1-dependent NF-κB activation.

  14. Ten-year improvement of insulin resistance and growth with recombinant human insulin-like growth factor 1 in a patient with insulin receptor mutations resulting in leprechaunism.

    Science.gov (United States)

    de Kerdanet, M; Caron-Debarle, M; Nivot, S; Gaillot, T; Lascols, O; Fremont, B; Bonnaure-Mallet, M; Gie, S; Massart, C; Capeau, J

    2015-09-01

    Leprechaunism, a rare genetic disease resulting from mutations in two alleles of the insulin receptor gene, is characterized by severe insulin resistance, retarded growth and, usually, premature death. The ability of treatment with recombinant human insulin-like growth factor 1 (rhIGF1) to improve metabolic and clinical parameters in the long-term is still controversial. Mutations were looked for in the insulin receptor gene of a four-month-old female baby with leprechaunism. The patient's skin fibroblasts were analyzed for response to insulin and IGF1. At the clinical level, the very long-term effects of treatment with rhIGF1/rhIGFBP3 were evaluated by clinical and metabolic parameters. The patient's diagnosis was based on compound heterozygous mutations in two alleles of the insulin receptor gene, thus confirming leprechaunism. Cultured fibroblasts showed a decreased number of insulin receptors and were insulin-resistant. However, IGF1 was able to stimulate IGF1 receptor signalling, suggesting possible activation of a salvage pathway. Treatment with IGF1/IGFBP3 for 8.7 years, then IGF1 for 2 years, resulted in normalization of circulating levels of IGF1 and IGFBP3. Large daily variations in glycaemia and insulinaemia persisted, but mean glycaemia decreased. Regarding growth, the patient's BMI Z score normalized and length/height score improved. Our patient presented normal neurological development and academic achievement. The treatment was free of adverse effects. Our results provide evidence that rhIGF1 with and without rhIGFBP3 can prevent fatal outcomes, and improve growth and metabolic parameters, for more than 10 years in a patient with leprechaunism. Long-term rhIGF1 for severe insulin resistance syndrome should be considered. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Two grass carp (Ctenopharyngodon idella) insulin-like growth factor-binding protein 5 genes exhibit different yet conserved functions in development and growth.

    Science.gov (United States)

    Zheng, Guo-Dong; Zhou, Chun-Xue; Lin, Si-Tong; Chen, Jie; Jiang, Xia-Yun; Zou, Shu-Ming

    2017-02-01

    Insulin-like growth factor binding-protein 5 (igfbp5), the most conserved member of the IGFBP family in vertebrates, plays a critical role in controlling cell survival, growth, differentiation, and apoptosis. Here, we characterized the expression patterns of igfbp5a and igfbp5b in grass carp (Ctenopharyngodon idella), which are retained in many fish species, likely from the teleost-specific whole-genome duplication. Both igfbp5a and igfbp5b encode 268- and 263-aa peptides, respectively, which share a sequence identity of 71%. Their mRNAs are not detected in zygotes. At 14hpf, grass carp igfbp5b mRNA was detected in the somites, while igfbp5a mRNA has some possible signal around the eye and head region. At 24hpf, both igfbp5a and igfbp5b mRNA appear to be limited to the presomitic mesoderm. At 36hpf, igfbp5a mRNA was only detected in the midbrain, while igfbp5b mRNA was detected in both the midbrain and notochord. Overall, both mRNAs were expressed in most adult tissues. igfbp5a and igfbp5b were significantly upregulated in the muscle and liver after injection of 10μg per kilogram body weight of zebrafish growth hormone (zGH), while their hepatic expression was downregulated by 50μg zGH. During fasting, both igfbp5a and igfbp5b mRNAs were significantly downregulated in the muscle but upregulated in the liver. Collectively, the results suggest that the two igfbp5 genes play important but different roles in the regulation of growth and development in grass carp. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, M H; Hvidberg, A; Juul, A

    1995-01-01

    In the present study, we 1) determined whether the impaired spontaneous 24-h GH secretion as well as the blunted GH response to provocative testing in obese subjects are persistent disorders or transient defects reversed with weight loss and 2) investigated 24-h urinary GH excretion and basal...... levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), as well as insulin in obese subjects before and after a massive weight loss. We studied 18 obese subjects (age, 26 +/- 1 yr; body mass index, 40.9 +/- 1.1 kg/m2); 18 normal age-, and sex-matched control subjects; and 9...... reduced weight obese subjects after a diet-induced average weight loss of 30.3 +/- 4.6 kg. Twenty-four-hour spontaneous GH secretion was estimated by obtaining 3240 integrated 20-min blood samples using a constant blood withdrawal technique and computerized algorithms. Body composition was determined...

  17. Insulin Like Growth Factor 2 Expression in the Rat Brain Both in Basal Condition and following Learning Predominantly Derives from the Maternal Allele.

    Directory of Open Access Journals (Sweden)

    Xiaojing Ye

    Full Text Available Insulin like growth factor 2 (Igf2 is known as a maternally imprinted gene involved in growth and development. Recently, Igf2 was found to also be regulated and required in the adult rat hippocampus for long-term memory formation, raising the question of its allelic regulation in adult brain regions following experience and in cognitive processes. We show that, in adult rats, Igf2 is abundantly expressed in brain regions involved in cognitive functions, like hippocampus and prefrontal cortex, compared to the peripheral tissues. In contrast to its maternal imprinting in peripheral tissues, Igf2 is mainly expressed from the maternal allele in these brain regions. The training-dependent increase in Igf2 expression derives proportionally from both parental alleles, and, hence, is mostly maternal. Thus, Igf2 parental expression in the adult rat brain does not follow the imprinting rules found in peripheral tissues, suggesting differential expression regulation and functions of imprinted genes in the brain.

  18. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty

    DEFF Research Database (Denmark)

    Juul, A; Scheike, Thomas Harder; Nielsen, C T

    1995-01-01

    Central precocious puberty (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed that gonadal sex steroids stimulate pulsatile GH secretion, which, in turn......, stimulates insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) production. However, little is known about GH, IGF-I, and IGFBP-3 serum levels in children with precocious puberty. Treatment of CPP by GnRH agonists has become the treatment of choice. However, the effect of long term...... treatment with GnRH in combination with an antiandrogen (cyproterone acetate) to block the possible effect of adrenal androgens has not previously been evaluated. We, therefore, studied 40 patients with idiopathic CPP that were treated for 24 months with either GnRH analog (Buserelin) in combination...

  19. Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents

    DEFF Research Database (Denmark)

    Juul, A; Dalgaard, P; Blum, W F

    1995-01-01

    in puberty. We found that IGFBP-3 levels increase with age in children, with maximal levels in puberty; girls experience peak values approximately 1 yr earlier than boys. Age, sex, height, BMI, and pubertal maturation were all important factors in determining the circulating levels of IGFBP-3, whereas IGF......Circulating IGF-I and -II are bound to specific insulin-like growth factor (IGF)-binding proteins (IGFBPs), of which IGFBP-3 binds the majority of the IGFs. IGFBP-3 levels are regulated by GH and have been suggested to provide additional information on GH secretory capacity compared to IGF...... growth velocity is high. Concomitantly, IGF-II and IGFBP-2 levels were unchanged throughout puberty, whereas IGFBP-1 levels declined with age in prepubertal children, with lowest values in puberty. There was a highly significant correlation between IGF-I and -II and IGFBP-3 on a molar basis (r = 0.84; P...

  20. Insulin-like growth factors (IGFs) and IGF binding proteins, serum acid-labile subunit and growth hormone binding protein in nephrotic children.

    Science.gov (United States)

    Haffner, D; Tönshoff, B; Blum, W F; Vickers, M; Siebler, T; Cronin, M J; Baxter, R C; Mehls, O

    1997-09-01

    We hypothesized that the increased glomerular permeability to serum proteins in the nephrotic syndrome might lead to alterations of the somatotropic hormone axis, thereby contributing to growth failure and catabolism in the nephrotic state. The insulin-like growth factors (IGF)-I and -II and the IGF binding proteins (IGFBP)-1, -2 and -3 were analyzed in serum and urine of 21 children with the nephrotic syndrome and normal glomerular filtration rate. Mean age-related serum IGF-I levels by RIA (-0.53 +/- 0.34 SD) were slightly, but significantly (P excretion rate of both peptides was enhanced fivefold. By RIA, mean age-related serum IGFBP-1 (2.05 +/- 0.19 SD) and, even more pronounced, IGFBP-2 (5.97 +/- 0.65 SD) were clearly elevated despite a 12-fold and 2-fold increase of the respective urinary excretion rate. There was a tight and specific correlation between age-related serum IGFBP-2 levels and the degree of the nephrotic syndrome, as estimated by serum albumin levels (r = -0.78, P 150 kDa IGFBP ternary complex in nephrotic serum, which in the presence of normal concentrations of the acid-labile subunit by RIA appears to be due to a reduction of intact IGFBP-3. Serum levels of the high-affinity GH binding protein that presumably reflects GH receptor status in tissues were normal. In summary, total serum IGFs in children with the nephrotic syndrome are normal, but the binding of IGFs to IGFBPs in the circulation is altered with a shift from the 150 kDa IGFBP complex to an excess of low molecular weight IGFBPs. Because increased unsaturated high-affinity IGFBPs in nephrotic serum have the ability to inhibit IGF action on target tissues by competing with the type 1 IGF receptor for IGF binding, this alteration is likely to contribute to growth failure and tissue catabolism in the nephrotic state.

  1. Association of an insulin-like growth factor 1 gene microsatellite with phenotypic variation and estimated breeding values of growth traits in Canchim cattle.

    Science.gov (United States)

    Andrade, P C; Grossi, D A; Paz, C C P; Alencar, M M; Regitano, L C A; Munari, D P

    2008-10-01

    A population of 1398 Canchim (CA) cattle was genotyped to assess the association of an insulin-like growth factor 1 (IGF1) gene microsatellite with phenotypic variation and estimated breeding values of pre-weaning, weaning and post-weaning growth traits. After an initial analysis, the IGF1 genotype only had a significant effect (P weaning weight adjusted to 240 days (WW240). For these two traits, direct and maternal breeding values were estimated using the restricted maximum likelihood (reml). Two analyses were carried out. In the first (Model I), all fixed effects were fitted. In the second (Model II), the fixed effect of the IGF1 genotype was omitted. The estimated genetic and phenotypic components of variance were similar for every trait in both models. For Model I, estimated direct and maternal heritabilities were 0.26 and 0.16 for BW and 0.23 and 0.14 for WW240 respectively. The genetic and phenotypic correlations between BW and WW240 were 0.38 and 0.38 (Model I) and 0.19 and 0.38 (Model II) respectively. Fifty animals were classified according to their direct and maternal breeding values for both traits. Spearman rank-order correlation between animal rankings in the two models was used to assess the effect of including the IGF1 genotype in the model. Non-significant values from this correlation were indicative of a difference in breeding value rankings between the two approaches. The IGF1 gene was found to be associated with phenotypic variation and breeding values in the early phase of growth.

  2. MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

    Directory of Open Access Journals (Sweden)

    Bin Zhang

    2017-08-01

    Full Text Available Background: MicroRNAs (miRNAs have emerged as key players in various human biological processes, including tumorigenesis. Here, we investigated the roles of miR-375 in the pathogenesis of oral squamous cell carcinoma (OSCC. Methods: We performed quantitative real-time PCR (qRT-PCR to detect miR-375 expression in OSCC tissues and corresponding normal oral epithelial tissues and analyze the correlation of miR-375 expression with OSCC metastasis and patient’s survival. Then, the effects of miR-375 expression on proliferation, cell cycle, apoptosis and radiosensitivity in OSCC cells were determined by using MTT, flow cytometry and clonogenic survival assays. A dual-luciferase reporter assay was performed to test whether miR-375 binds to the 3’-untranslated region (3’-UTR of target mRNA. Results: The expression level of miR-375 in OSCC tissues was significantly lower than that in normal oral epithelial tissues, and low miR-375 expression was correlated with higher incidence of lymph node metastasis and poor survival of OSCC patients. Upregulation of miR-375 significantly inhibits growth, induces cell cycle arrest in G0/G1 phase, increases apoptosis and enhances radiosensitivity in OSCC cells. Analysis of luciferase activity demonstrated that miR-375 binds to the 3’-UTR of insulin like growth factor 1 receptor (IGF-1R. Small interfering RNA (shRNA-mediated IGF-1R knockdown mimics the effects of miR-375 upregulation, while overexpression of IGF-1R partially reverses those effects in OSCC cells. Conclusion: It was obviously demonstrated that miRNA-375 inhibits growth and enhances radiosensitivity in OSCC cells by targeting IGF-1R, suggesting that miR-375 may be a potential therapeutic target for OSCC patients.

  3. Nanowired Delivery of Growth Hormone Attenuates Pathophysiology of Spinal Cord Injury and Enhances Insulin-Like Growth Factor-1 Concentration in the Plasma and the Spinal Cord.

    Science.gov (United States)

    Muresanu, Dafin F; Sharma, Aruna; Lafuente, José V; Patnaik, Ranjana; Tian, Z Ryan; Nyberg, Fred; Sharma, Hari S

    2015-10-01

    Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.

  4. Insulin-like growth factor-I feedback regulation of growth hormone and luteinizing hormone secretion in the pig: evidence for a pituitary site of action.

    Science.gov (United States)

    Barb, C R; Hausman, G J

    2009-06-01

    Three experiments (EXP) were conducted to determine the role of insulin-like growth factor-I (IGF-I) in the control of growth hormone (GH) and LH secretion. In EXP I, prepuberal gilts, 65 ± 6 kg body weight and 140 days of age received intracerebroventricular (ICV) injections of saline (n = 4), 25 μg (n = 4) or 75 μg (n = 4) IGF-I and jugular blood samples were collected. In EXP II, anterior pituitary cells in culture collected from 150-day-old prepuberal gilts (n = 6) were challenged with 0.1, 10 or 1000 nM [Ala15]-h growth hormone-releasing hormone-(1-29)NH2 (GHRH), or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 1000 nM GHRH. Secreted GH was measured at 4 and 24 h after treatment. In EXP III, anterior pituitary cells in culture collected from 150-day-old barrows (n = 5) were challenged with 10, 100 or 1000 nM gonadotropin-releasing hormone (GnRH) or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 100 nM GnRH. Secreted LH was measured at 4 h after treatment. In EXP I, serum GH and LH concentrations were unaffected by ICV IGF-I treatment. In EXP II, relative to control all doses of GHRH increased (P 0.1). In conclusion, under these experimental conditions the results suggest that the pituitary is the putative site for IGF-I modulation of GH and LH secretion. Further examination of the role of IGF-I on GH and LH secretion is needed to understand the inhibitory and stimulatory action of IGF-I on GH and LH secretion.

  5. Signalling through the Type 1 Insulin-Like Growth Factor Receptor (IGF1R Interacts with Canonical Wnt Signalling to Promote Neural Proliferation in Developing Brain

    Directory of Open Access Journals (Sweden)

    Qichen Hu

    2012-05-01

    Full Text Available Signalling through the IGF1R [type 1 IGF (insulin-like growth factor receptor] and canonical Wnt signalling are two signalling pathways that play critical roles in regulating neural cell generation and growth. To determine whether the signalling through the IGF1R can interact with the canonical Wnt signalling pathway in neural cells in vivo, we studied mutant mice with altered IGF signalling. We found that in mice with blunted IGF1R expression specifically in nestin-expressing neural cells (IGF1RNestin–KO mice the abundance of neural β-catenin was significantly reduced. Blunting IGF1R expression also markedly decreased: (i the activity of a LacZ (β-galactosidase reporter transgene that responds to Wnt nuclear signalling (LacZTCF reporter transgene and (ii the number of proliferating neural precursors. In contrast, overexpressing IGF-I (insulin-like growth factor I in brain markedly increased the activity of the LacZTCF reporter transgene. Consistently, IGF-I treatment also markedly increased the activity of the LacZTCF reporter transgene in embryonic neuron cultures that are derived from LacZTCF Tg (transgenic mice. Importantly, increasing the abundance of β-catenin in IGF1RNestin–KO embryonic brains by suppressing the activity of GSK3β (glycogen synthase kinase-3β significantly alleviated the phenotypic changes induced by IGF1R deficiency. These phenotypic changes includes: (i retarded brain growth, (ii reduced precursor proliferation and (iii decreased neuronal number. Our current data, consistent with our previous study of cultured oligodendrocytes, strongly support the concept that IGF signalling interacts with canonical Wnt signalling in the developing brain to promote neural proliferation. The interaction of IGF and canonical Wnt signalling plays an important role in normal brain development by promoting neural precursor proliferation.

  6. Optimization of codon composition and regulatory elements for expression of human insulin like growth factor-1 in transgenic chloroplasts and evaluation of structural identity and function

    Directory of Open Access Journals (Sweden)

    Sandberg Laurence

    2009-04-01

    Full Text Available Abstract Background Transgenic chloroplasts are potential bioreactors for recombinant protein production, especially for achievement of high levels of protein expression and proper folding. Production of therapeutic proteins in leaves provides transgene containment by elimination of reproductive structures. Therefore, in this study, human Insulin like Growth Factor-1 is expressed in transgenic chloroplasts for evaluation of structural identity and function. Results Expression of the synthetic Insulin like Growth Factor 1 gene (IGF-1s, 60% AT was observed in transformed E. coli. However, no native IGF-1 gene (IGF-1n, 41% AT product was detected in the western blots in E. coli. Site-specific integration of the transgenes into the tobacco chloroplast genome was confirmed after transformation using PCR. Southern blot analysis confirmed that the transgenic lines were homoplasmic. The transgenic plant lines had IGF-1s expression levels of 11.3% of total soluble protein (TSP. The IGF-1n plants contained 9.5% TSP as IGF-1n, suggesting that the chloroplast translation machinery is more flexible than E. coli in codon preference and usage. The expression of IGF-1 was increased up to 32% TSP under continuous illumination by the chloroplast light regulatory elements. IgG-Sepharose affinity column chromatographic separation of Z domain containing chloroplast derived IGF-1 protein, single and two dimensional electrophoresis methods and mass spectrometer analysis confirmed the identity of human IGF-1 in transgenic chloroplasts. Two spots analyzed from 2-D focusing/phoresis acrylamide gel showed the correct amino acid sequence of human IGF-1 and the S. aureus Z-tag. Cell proliferation assays in human HU-3 cells demonstrated the biological activity of chloroplast derived IGF-1 even in the presence of the S. aureus Z tag. Conclusion This study demonstrates that the human Insulin like Growth Factor-1 expressed in transgenic chloroplasts is identical to the native

  7. Use of human recombinant growth hormone and human recombinant insulin-like growth factor-I in patients with human immunodeficiency virus infection.

    Science.gov (United States)

    Hirschfeld, S

    1996-01-01

    Infection with the human immunodeficiency virus (HIV) can lead to global alterations in metabolism as well as immunodeficiency. There is dysregulation of endocrine function in adults and children, the extent and magnitude correlating with disease progression. Some of the more prominent abnormalities occur in the thyroid, gonadal, and somatomedin axes. Clinical manifestations of these abnormalities are growth failure in children, which is one of the most sensitive indicators of disease progression, and a wasting syndrome in adults and children. Although there are case reports of growth hormone (GH) deficiency in HIV-infected children, most patients with growth failure have normal serum levels of GH and normal to low levels of insulin-like growth factor-I (IGF-I). Antiretrovial therapy can improve the growth rate in children for a period of time if there is a drop in viral titer, but as the viral load increases, the growth rate decreases again. Administration of GH or IGF-I to these patients can improve the growth rate and lean body mass, and in some patients improve immune function. Although studies on resting energy expenditure in HIV-infected patients have shown increases, these are not proportional to disease progression, but may be dependent upon cytokine activation and other abnormalities. Adult patients with wasting have been shown to have relatively normal total energy expenditure, but decreased intake. Appetite stimulants have been shown to have some benefit, but do not increase lean body mass. The most significant clinical benefit has come from administration of GH in short-term trials. GH and IGF-I are both able to inhibit apoptosis and reconstitute the immune system in rodents treated with ablative therapy. In addition, GH can modulate the marrow suppressive effects of zidovudine and may enhance its ability to inhibit viral reverse transcriptase. Current clinical trials are ongoing in both adults and children. GH and IGF-I may have a role in regimens

  8. Chronic alcohol consumption, type 2 diabetes mellitus, insulin-like growth factor-I (IGF-I), and growth hormone (GH) in ethanol-treated diabetic rats.

    Science.gov (United States)

    Kim, Soo-Jeong; Ju, Anes; Lim, Seul-Gi; Kim, Dai-Jin

    2013-11-13

    Alcohol has deleterious influences on glucose metabolism which may contribute to the development of type 2 diabetes mellitus (T2DM). Insulin-like growth factor I (IGF-I) and growth hormone (GH), which interact with insulin to modulate metabolic control, have been shown to be related to impaired glucose tolerance. This study was conducted to assess the possibility that altered circulating IGF-I and GH levels contribute to the exacerbation of T2DM by alcohol use in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. OLETF rats were pair-fed a Lieber-DeCarli Regular Ethanol diet and LETO rats were pair-fed a control diet for 6 weeks. At 6 weeks, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and IGF-I and GH levels were evaluated. Prior to an IP-GTT, OLETF-Ethanol (O-E) group had significantly a decrease in the mean glucose levels compared to OLETF-Control (O-C) group. At 120 min post IP-GTT, the O-E group had significantly an increase in the mean glucose levels compared to O-C group. The serum IGF-I levels were significantly lower and the serum GH levels were significantly higher in the O-E group than in L-C group. These results suggest that IGF-I and GH are prominent in defining the risk and development of T2DM, and may be adversely affected by heavy alcohol use, possibly mediating its diabetogenic effects. Thus, the overall glucose intolerance in the setting of alcoholism may be attributable to inappropriate alteration of IGF-I and GH levels. © 2013. Published by Elsevier Inc. All rights reserved.

  9. Capromorelin increases food consumption, body weight, growth hormone, and sustained insulin-like growth factor 1 concentrations when administered to healthy adult Beagle dogs.

    Science.gov (United States)

    Zollers, B; Rhodes, L; Smith, R G

    2017-04-01

    This study's objective was to determine the effects in dogs of oral capromorelin, a ghrelin agonist, at different doses for 7 days on food consumption, body weight and serum concentrations of growth hormone (GH), insulin-like growth factor 1 (IGF-1), and cortisol. Adult Beagles (n = 6) were dosed with placebo BID, capromorelin at 3.0 mg/kg SID, 4.5 mg/kg SID, or 3.0 mg/kg BID. Food consumption, body weight, serum capromorelin, GH, IGF-1, and cortisol were measured at intervals on days 1, 4, 7, and 9. Capromorelin increased food consumption and body weight compared to placebo and caused increased serum GH, which returned to the baseline by 8 h postdose. The magnitude of the GH increase was less on days 4 and 7 compared to Day 1. IGF-1 concentrations increased on Day 1 in capromorelin-treated dogs and this increase was sustained through Day 7. Serum cortisol increased postdosing and returned to the baseline concentrations by 8 h. The magnitude of the increase was less on days 4 and 7 compared to Day 1. A dose of 3 mg/kg was chosen for further study in dogs based on this dose causing increased food consumption and sustained IGF-1 serum concentrations that may increase lean muscle mass when administered over extended periods. © 2016 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

  10. Role of the insulin-like growth factor system in epiphyseal cartilage on the development of Langshan and Arbor Acres chickens, Gallus domesticus.

    Science.gov (United States)

    Lu, F Z; Jiang, Z Y; Wang, X X; Luo, Y H; Li, X F; Liu, H L

    2010-05-01

    We measured the mRNA transcript expression patterns for members of the insulin-like growth factor (IGF) system during embryonic and postnatal development in epiphyseal cartilage from Langshan (LS) and Arbor Acres (AA) chickens. Insulin-like growth factor binding protein (IGFBP)-2 expression was positively correlated with IGF-I from embryonic day (E) 14 to postnatal d (P) 0 and with IGF-II from E14 to P14 but negatively correlated with IGF-I from P0 to P42 and IGF-II from P14 to P42. Expression of IGFBP-5 correlated positively with IGF-I from E14 to P0 but negatively from P0 to P28. The results suggest that these genes are regulated in a coordinated fashion during development. A negative correlation was found between IGFBP-7 and IGF-II during P0 to P42. A positive correlation was found between IGFBP-3 (E14 to E18, P14 to P42) and IGF-IR and between IGFBP-3 (E14 to P0, P14 to P42) and IGF-I. The endocrine factors can be integrated with nutrition to regulate animal growth. In our study, AA chickens were fed a nutrient-rich AA diet, and LS chickens were fed either an AA diet or a less-rich diet. The LS and AA chickens fed the same AA diet showed no differences in IGF-I, IGF-I receptor, IGFBP-2, IGFBP-5, IGFBP-7, and IGFBP-3 but did still show differences in IGF-II. Our data indicate that these select genes may show linked expression during certain periods of development and that differences in gene expression respond differently to nutrient intake in LS and AA chickens.

  11. Insulin-like growth factor-1 enhances rat skeletal muscle charge movement and L-type Ca2+ channel gene expression

    Science.gov (United States)

    Wang, Zhong-Min; Laura Messi, María; Renganathan, Muthukrishnan; Delbono, Osvaldo

    1999-01-01

    We investigated whether insulin-like growth factor-1 (IGF-1), an endogenous potent activator of skeletal muscle proliferation and differentiation, enhances L-type Ca2+ channel gene expression resulting in increased functional voltage sensors in single skeletal muscle cells. Charge movement and inward Ca2+ current were recorded in primary cultured rat myoballs using the whole-cell configuration of the patch-clamp technique. Ca2+ current and maximum charge movement (Qmax) were potentiated in cells treated with IGF-1 without significant changes in their voltage dependence. Peak Ca2+ current in control and IGF-1-treated cells was -7·8 ± 0·44 and -10·5 ± 0·37 pA pF−1, respectively (P charge movement and the level of L-type Ca2+ channel α1-subunits through activation of gene expression in skeletal muscle cells. PMID:10087334

  12. Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study

    DEFF Research Database (Denmark)

    van der Spoel, Evie; Rozing, Maarten P; Houwing-Duistermaat, Jeanine J

    2015-01-01

    Reduced insulin/insulin-like growth factor 1 (IGF-1) signaling has been associated with longevity in various model organisms. However, the role of insulin/IGF-1 signaling in human survival remains controversial. The aim of this study was to test whether circulating IGF-1 axis parameters associate...... with old age survival and functional status in nonagenarians from the Leiden Longevity Study. This study examined 858 Dutch nonagenarian (males≥89 years; females≥91 years) siblings from 409 families, without selection on health or demographic characteristics. Nonagenarians were divided over sex.......91) compared to the quartile with the highest ratio (ptrend=0.002). Functional status was assessed by (Instrumental) Activities of Daily Living ((I)ADL) scales. Compared to those in the quartile with the highest IGF-1/IGFBP3 ratio, nonagenarians in the lowest quartile had higher scores for ADL (ptrend=0...

  13. Seminal insulin-like growth factor-I may be involved in the pathophysiology of infertility among patients with clinical varicocele.

    Science.gov (United States)

    Naderi, GholamHossein; Mohseni Rad, Hamed; Tabassomi, Firouzeh; Latif, AmirHossein

    2015-06-01

    Varicocele, the most common cause of male infertility, is defined as abnormal dilation of the pampiniform plexus. Although different mechanisms have been proposed to explain the pathophysiology of infertility caused by varicocele, it is still open to debate. Previous studies have demonstrated the effect of insulin-like growth factor-I (IGF-I) on semen quality in animals and humans, but there are no studies on the probable role of seminal IGF-I in the pathophysiology of infertility among patients with clinical varicocele. We therefore aimed to examine the seminal IGF-I concentration in 49 patients with varicocele and primary infertility before and after varicocelectomy and compare the results with those of 50 healthy fertile men (in the control group). Mean seminal IGF-I level of patients before varicocelectomy (93.7 ± 67.2 ng/mL) was significantly different (P infertility in patients with varicocele or semen.

  14. Biosynthesis of 10 kDa and 7.5 kDa insulin-like growth factor II in a human rhabdomyosarcoma cell line

    DEFF Research Database (Denmark)

    Nielsen, F C; Haselbacher, G; Christiansen, Jan

    1993-01-01

    In the present study we have analysed the expression of insulin-like growth factor II (IGF-II) in the human rhabdomyosarcoma cell line IN157.IN157 cells express high levels of three IGF-II mRNAs of 6.0 kb, 4.8 kb and 4.2 kb. In contrast, normal skeletal muscle expresses a negligible amount of IGF...... produce IGF binding protein-2. The bioactivity of recombinant IGF-IIE21 was compared with human IGF-I and IGF-II. IGF-I, IGF-II and IGF-IIE21 bound with high affinity to human IGF-I receptors (Kd approximately 1 nM), whereas the human IGF-II/mannose 6-phosphate (IGF-II/Man 6-P) receptor bound IGF...

  15. [Insulin-like growth factor 1 and the key markers of proteolysis during the acute period of readaptation of the muscle atrophied as a result of unloading].

    Science.gov (United States)

    Kachaeva, E V; Turtikova, O V; Leĭnsoo, T A; Shenkman, B S

    2010-01-01

    It has been shown that, after prolonged disuse, the accumulation of muscle mass and the recovery of soleus fibers volume are caused by water accumulation rather than protein synthesis intensification. At the same time, expression rate of the main markers of the activity of ubiquitin-proteasome system remained increased on the 3rd day of reloading and decreased to the control by the 7th day. Both the quantity of the insulin-like growth factor 1 and the number of satellite cells fused with muscle fibers and of myonuclei began to increase only on the 7th day of reloading. The data obtained evidenced a significant inertness of the postural muscle during its adaptation to the load (normal gravity) after prolonged disuse.

  16. Role of protein kinase-C in regulation of insulin-like growth factor-binding protein-1 production by HepG2 cells.

    Science.gov (United States)

    Lee, P D; Abdel-Maguid, L S; Snuggs, M B

    1992-08-01

    Insulin-like growth factor binding protein-1 (IGFBP-1) is a liver-derived protein that modulates the mitogenic actions of the insulin-like growth factors (IGFs). IGFBP-1 production is potently inhibited by insulin both in vivo and in HepG2 human hepatoma cells. To further define the pathways of IGFBP-1 regulation, we studied the effects of modulators of protein kinase-C (PKC) on HepG2 cell IGFBP-1 production. Phorbol 12-myristate 13-acetate (PMA) stimulated IGFBP-1 production in a time- and dose-dependent manner, with maximal stimulation occurring at 10-100 nmol/L. The degree of stimulation was dependent on cell density, ranging from about 2-fold in confluent to more than 10-fold in sparse cultures. Preincubation with PMA abolished the inhibitory effect of insulin, while preincubation with insulin did not inhibit PMA stimulation. The transient PKC activator diC8 had no effect, while studies with the PKC inhibitors sphinganine and H-7 were limited by solvent vehicle cytotoxicity. Staurosporine (STS), a potent PKC inhibitor, stimulated IGFBP-1 production 2- to 4-fold and augmented the stimulatory effect of PMA. Concanavalin-A, an inhibitor of PMA-stimulated PKC translocation and down-regulation, inhibited the effects of PMA and STS. Our findings indicate that PKC is involved in the regulation of hepatic IGFBP-1 production. The effects of PMA, which causes rapid activation, followed by membrane translocation and down-regulation of PKC, are similar to those of STS and are countered by Concanavalin-A. These data suggest that PKC activity may mediate tonic inhibition of IGFBP-1 production, while PKC downregulation stimulates the production of this regulatory protein.

  17. Expression of kit ligand and insulin-like growth factor binding protein 3 during in vivo or in vitro development of ovarian follicles in sheep.

    Science.gov (United States)

    Srividya, D; Praveen Chakravarthi, V; Kona, Ssr; Siva Kumar, Avn; Brahmaiah, K V; Rao, V H

    2017-08-01

    Expression of Kit ligand (KL) and insulin-like growth factor binding protein (IGFBP3) genes was studied at different in vivo and corresponding in vitro stages of development of the ovarian follicles in sheep. The expression of both KL and IGFBP3 was significantly higher in the primordial follicles relative to any other stage of development. Compared to the other stages, the KL expression in the cumulus cells from in vivo grown large antral follicles and that of IGFBP3 in COCs' isolated from large antral follicles matured in vitro for 24 hr were significantly higher. In the oocytes from in vivo grown ovarian follicles, the expression of KL was the same at all the stages of development. Insulin-like growth factor binding protein 3 expression was also the same in the oocytes at all the stages of the development except for a significantly lower expression in those from antral follicles. The expression of KL in the cumulus cells decreased significantly in the in vitro grown early antral follicles but did not change further as the development progressed. The expression of IGFBP3 in the cumulus cells from in vitro grown ovarian follicles appeared to increase as the development progressed although the increase was not significant between any two consecutive stages of development. In the oocytes in in vitro grown ovarian follicles, the expression levels of KL and IGFBP3 genes did not change with development. It is concluded that (i) KL and IGFBP3 genes follow specific patterns of expression during ovarian folliculogenesis and (ii) in vitro culture of preantral follicles compromises the development potential through alterations in the stage-specific patterns of expression of these and other developmentally important genes. © 2017 Blackwell Verlag GmbH.

  18. Functional differences in the growth hormone and insulin-like growth factor axis in cattle and pigs: implications for post-partum nutrition and reproduction.

    Science.gov (United States)

    Lucy, M C

    2008-07-01

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) control growth and lactation in cattle and swine. Insulin participates in the endocrinology of growth and lactation because insulin and GH are antagonistic in their actions. Dairy cows experience a period of negative energy balance during the first 4-8 weeks post-partum. During this period, their somatotropic axis (comprised of GH, the GH receptor and IGF-I) becomes uncoupled and there is elevated GH and diminished IGF-I in the circulation. Blood insulin concentrations are low as well. Sows are different from dairy cows because their somatotropic axis remains coupled during lactation and both GH and IGF-I are elevated. Nonetheless, sows that become catabolic during lactation will have reduced IGF-I concentrations. Sows are inseminated after weaning so their metabolic state is different from post-partum beef and dairy cows that are inseminated when they are lactating. Dairy cows are fed ad libitum and naturally have low IGF-I during lactation. Sows have elevated IGF-I when they are well-fed. A threshold of IGF-I protein in follicular fluid may be met by local ovarian (paracrine/autocrine) and endocrine sources of IGF-I. Nutritionally induced changes in insulin and in liver IGF-I secretion that arise from perturbations of the somatotropic axis have a direct effect on the ovary through the endocrine actions of insulin and IGF-I. Sows and cows that are nutritionally compromised have low concentrations of insulin and IGF-I in their blood and this theoretically reduces ovarian responsiveness to gonadotropins. Although sows are inseminated after weaning, there appear to be carry-over effects of the previous lactation on the ovarian follicular populations that develop after the sow is weaned. Understanding the mechanisms through which metabolic hormones control ovarian function may lead to improved reproductive management of both pigs and cattle because lactation and post-partum reproduction are closely tied in

  19. Seasonal response of ghrelin, growth hormone, and insulin-like growth factor I in the free-ranging Florida manatee (Trichechus manatus latirostris)

    Science.gov (United States)

    Tighe, Rachel L; Bonde, Robert K.; Avery, Julie P.

    2016-01-01

    Seasonal changes in light, temperature, and food availability stimulate a physiological response in an animal. Seasonal adaptations are well studied in Arctic, Sub-Arctic, and hibernating mammals; however, limited studies have been conducted in sub-tropical species. The Florida manatee (Trichechus manatus latirostris), a sub-tropical marine mammal, forages less during colder temperatures and may rely on adipose stores for maintenance energy requirements. Metabolic hormones, growth hormone (GH), insulin-like growth factor (IGF)-I, and ghrelin influence growth rate, accretion of lean and adipose tissue. They have been shown to regulate seasonal changes in body composition. The objective of this research was to investigate manatee metabolic hormones in two seasons to determine if manatees exhibit seasonality and if these hormones are associated with seasonal changes in body composition. In addition, age related differences in these metabolic hormones were assessed in multiple age classes. Concentrations of GH, IGF-I, and ghrelin were quantified in adult manatee serum using heterologous radioimmunoassays. Samples were compared between short (winter) and long (summer) photoperiods (n = 22 male, 20 female) and by age class (adult, juvenile, and calf) in long photoperiods (n = 37). Short photoperiods tended to have reduced GH (p = 0.08), greater IGF-I (p = 0.01), and greater blubber depth (p = 0.03) compared with long photoperiods. No differences were observed in ghrelin (p = 0.66). Surprisingly, no age related differences were observed in IGF-I or ghrelin concentrations (p > 0.05). However, serum concentrations of GH tended (p = 0.07) to be greater in calves and juveniles compared with adults. Increased IGF-I, greater blubber thickness, and reduced GH during short photoperiod suggest a prioritization for adipose deposition. Whereas, increased GH, reduced blubber thickness, and decreased IGF-I in long photoperiod suggest prioritization of lean tissue

  20. Paternally expressed, imprinted insulin-like growth factor-2 in chorionic villi correlates significantly with birth weight.

    Directory of Open Access Journals (Sweden)

    Charalambos Demetriou

    Full Text Available Fetal growth involves highly complex molecular pathways. IGF2 is a key paternally expressed growth hormone that is critical for in utero growth in mice. Its role in human fetal growth has remained ambiguous, as it has only been studied in term tissues. Conversely the maternally expressed growth suppressor, PHLDA2, has a significant negative correlation between its term placental expression and birth weight.The aim of this study is to address the role in early gestation of expression of IGF1, IGF2, their receptors IGF1R and IGF2R, and PHLDA2 on term birth weight.Real-time quantitative PCR was used to investigate mRNA expression of IGF1, IGF2, IGF1R, IGF2R and PHLDA2 in chorionic villus samples (CVS (n = 260 collected at 11-13 weeks' gestation. Expression was correlated with term birth weight using statistical package R including correction for several confounding factors.Transcript levels of IGF2 and IGF2R revealed a significant positive correlation with birth weight (0.009 and 0.04, respectively. No effect was observed for IGF1, IGF1R or PHLDA2 and birth weight. Critically, small for gestational age (SGA neonates had significantly lower IGF2 levels than appropriate for gestational age neonates (p = 3.6 × 10(-7.Our findings show that IGF2 mRNA levels at 12 weeks gestation could provide a useful predictor of future fetal growth to term, potentially predicting SGA babies. SGA babies are known to be at a higher risk for type 2 diabetes. This research reveals an imprinted, parentally driven rheostat for in utero growth.

  1. Effects of two oral contraceptives on plasma levels of insulin-like growth factor I (IGF-I) and growth hormone (hGH).

    Science.gov (United States)

    Balogh, A; Kauf, E; Vollanth, R; Gräser, G; Klinger, G; Oettel, M

    2000-11-01

    In 18 healthy women, the effect of two oral contraceptives (OCs) on insulin-like growth factor (IGF-I) and its binding protein-3 (IGFBP-3) and growth hormone (hGH) plasma level were studied before and after intake of either of two OC formulations over 21 days, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). There was a reduction of the mean IGF-I concentration of 30% (p = 0.008) in the women receiving dienogest-containing pills and 12% (p = 0.006) in women taking the levonogestrel-containing preparation. This difference between drug groups was statistically significant (p = 0.002). A correlation between the control values and the basal-treatment difference (r = 0.945; p = 0.000) was observed only in women of group A. Between basal and treatment cycles the mean plasma levels of hGH remained unchanged in both groups tested, but the 23.5-h integrated mean hGH plasma concentrations (AUC(0-23.5h)) were significantly elevated by 36% (p = 0.016) in comparison to basal values before treatment only in women receiving the levonorgestrel-containing pills. Also, in the women who received the dienogest-containing preparation, the changes of integrated mean plasma level were inversely associated with the control values (r = -0.723; p = 0.025). Neither in group A nor in group B was the mean plasma level of IGFB-3 changed. the results of the present analysis indicate that hormonal contraceptives can modulate the GH and IGF-I-axis in the reproductive age. Probably the androgenic progestogen levonorgestrel (0.125 mg/day) opposes the estrogen-induced action. In the women who took the dienogest-containing formulations (anti-androgenic progestogen-group A), the extent of individual changes (hGh and IGF-I) depends on the basal level prior to pill intake. Further studies, especially of long-term intake of OCs, are necessary to confirm these results and to assess the practical relevance for

  2. Effects of growth hormone, insulin-like growth factor I, triiodothyronine, thyroxine, and cortisol on gene expression of carbohydrate metabolic enzymes in sea bream hepatocytes.

    Science.gov (United States)

    Leung, L Y; Woo, Norman Y S

    2010-11-01

    The present study investigated the regulatory effects of growth hormone (GH), human insulin-like growth factor I (hIGF-I), thyroxine (T(4)), triiodothyronine (T(3)) and cortisol, on mRNA expression of key enzymes involved in carbohydrate metabolism, including glucokinase (GK), glucose-6-phosphatase (G6Pase), glycogen synthase (GS), glycogen phosphorylase (GP) and glucose-6-phosphate dehydrogenase (G6PDH) in hepatocytes isolated from silver sea bream. Genes encoding GK, G6Pase, GS and GP were partially cloned and characterized from silver sea bream liver and real-time PCR assays were developed for the quantification of the mRNA expression profiles of these genes in order to evaluate the potential of these carbohydrate metabolic pathways. GK mRNA level was elevated by GH and hIGF-I, implying that GH-induced stimulation of GK expression may be mediated via IGF-I. GH was found to elevate GS and G6Pase expression, but reduce G6PDH mRNA expression. However, hIGF-I did not affect mRNA levels of GS, G6Pase and G6PDH, suggesting that GH-induced modulation of GS, G6Pase and G6PDH expression levels is direct, and occurs independently of the action of IGF-I. T(3) and T(4) directly upregulated transcript abundance of GK, G6Pase, GS and GP. Cortisol significantly increased transcript amounts of G6Pase and GS but markedly decreased transcript abundance of GK and G6PDH. These changes in transcript abundance indicate that (1) the potential of glycolysis is stimulated by GH and thyroid hormones, but attenuated by cortisol, (2) gluconeogenic and glycogenic potential are augmented by GH, thyroid hormones and cortisol, (3) glycogenolytic potential is upregulated by thyroid hormones but not affected by GH or cortisol, and (4) the potential of the pentose phosphate pathway is attenuated by GH and cortisol but unaffected by thyroid hormones. Copyright 2010 Elsevier Inc. All rights reserved.

  3. Fish oil supplementation from 9 to 18 months of age affects the insulin-like growth factor axis in a sex-specific manner in Danish infants

    DEFF Research Database (Denmark)

    Damsgaard, Camilla T.; Harsløf, Laurine B. S.; Andersen, Anders D.

    2016-01-01

    Several studies have investigated the effects of fish oil (FO) on infant growth, but little is known about the effects of FO and sex on insulin-like growth factor-1 (IGF-1), the main regulator of growth in childhood. We explored whether FO v. sunflower oil (SO) supplementation from 9 to 18 months...... of age affected IGF-1 and its binding protein-3 (IGFBP-3) and whether the potential effects were sex specific. Danish infants (n 115) were randomly allocated to 5 ml/d FO (1·2 g/d n-3 long-chain PUFA (n-3 LCPUFA)) or SO. We measured growth, IGF-1, IGFBP-3 and erythrocyte EPA, a biomarker of n-3 LCPUFA...... intake and status, at 9 and 18 months. Erythrocyte EPA increased strongly with FO compared with SO (Ppopulation, but a sex×group interaction (P=0·02). Baseline-adjusted IGF-1 at 18 months was 11·1 µg/l (95 % CI 0·4, 21·8;P=0...

  4. The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1)

    Science.gov (United States)

    Wolfe, Andrew; Divall, Sara; Wu, Sheng

    2014-01-01

    The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. PMID:24929098

  5. Studies on regulation of IGF (insulin-like growth factor)-binding protein (IGFBP) 4 proteolysis by pregnancy-associated plasma protein-A (PAPP-A) in cells treated with phorbol ester.

    OpenAIRE

    Sivanandam, Arun S; Mohan, Subburaman; Kita, Hirohito; Kapur, Sanjay; Chen, Shin-Tai; Linkhart, Thomas A; Bagi, Gyorgy; Baylink, David J; Qin, Xuezhong

    2004-01-01

    PAPP-A (pregnancy-associated plasma protein-A) is produced by hSFs (human skin fibroblasts) and hOBs (human osteoblasts) and enhances the mitogenic activity of IGFs (insulin-like growth factors) by degradation of IGFBP-4 (insulin-like growth factor-binding protein 4). PKC (protein kinase C) activation in these cells led to reduction in IGFBP-4 proteolysis. This study was undertaken to determine the mechanism by which activation of PKC suppresses IGFBP-4 proteolysis. Treatment of hSFs/hOBs wit...

  6. Association of thyroid gland volume, serum insulin-like growth factor-I, and anthropometric variables in euthyroid prepubertal children

    DEFF Research Database (Denmark)

    Boas, M.; Hegedus, L.; Feldt-Rasmussen, U.

    2009-01-01

    . Longitudinal growth data from birth were available. RESULTS: TV increased significantly with age (r = 0.487; P 5 yr, 2.5 +/- 1.3 ml; 6 yr, 2.8 +/- 1.3 ml; 7 yr, 3.2 +/- 1.3 ml; 8 yr, 3.5 +/- 1.3 ml; 9 yr, 3.7 +/- 1.3 ml...