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Claire M Perks, H A Zielinska, Jing Wang, Caroline Jarrett, A Frankow, Michael R Ladomery, Amit Bahl, Anthony Rhodes, Jon Oxley, Jeff M P Holly
Men who develop prostate cancer (PCa) increasingly have one of the co-morbidities associated with a Western lifestyle that are characterized by hyperinsulinemia, hyperglycemia and increased expression of insulin-like growth factors-I (IGF-I) and IGF-II. Each have been associated with poor prognosis and more aggressive cancers that exhibit increased metabolism and increased glucose uptake. The insulin receptor (IR) has two splice isoforms IR-A and IR-B: IR-A has a higher affinity for IGF-II comparable to that for insulin, whereas the IR-B isoform predominantly just binds to insulin...
2016: Frontiers in Endocrinology
Megan E Zavorka, Christopher M Connelly, Rosslyn Grosely, Richard G MacDonald
The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) binds M6P-capped ligands and IGF-II at different binding sites within the ectodomain and mediates ligand internalization and trafficking to the lysosome. Multivalent M6P-based ligands can cross-bridge the M6P/IGF2R, which increases the rate of receptor internalization, permitting IGF-II binding as a passenger ligand and subsequent trafficking to the lysosome, where the IGF-II is degraded. This unique feature of the receptor may be exploited to design novel therapeutic agents against IGF-II-dependent cancers that will lead to decreased bioavailable IGF-II within the tumor microenvironment...
August 22, 2016: Oncotarget
Megan E Zavorka, Christopher M Connelly, Rosslyn Grosely, Richard G MacDonald
The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) binds M6P-capped ligands and IGF-II at different binding sites within the ectodomain and mediates ligand internalization and trafficking to the lysosome. Multivalent M6P-based ligands can cross-bridge the M6P/IGF2R, which increases the rate of receptor internalization, permitting IGF-II binding as a passenger ligand and subsequent trafficking to the lysosome, where the IGF-II is degraded. This unique feature of the receptor may be exploited to design novel therapeutic agents against IGF-II-dependent cancers that will lead to decreased bioavailable IGF-II within the tumor microenvironment...
September 20, 2016: Oncotarget
Leon A Bach
IGFBP-6 binds IGF-II with higher affinity than IGF-I and it is a relatively specific inhibitor of IGF-II actions. More recently, IGFBP-6 has also been reported to have IGF-independent effects on cell proliferation, survival, differentiation and migration. IGFBP-6 binds to several ligands in the extracellular space, cytoplasm and nucleus. These interactions, together with activation of distinct intracellular signaling pathways, may contribute to its IGF-independent actions; for example, IGF-independent migration induced by IGFBP-6 involves interaction with prohibitin-2 and activation of MAP kinase pathways...
September 22, 2016: Growth Hormone & IGF Research
Yuanqi Bei, Qingfeng Huang, Jianhong Shen, Jinlong Shi, Chaoyan Shen, Peng Xu, Hao Chang, Xiaojie Xia, Li Xu, Bin Ji, JianGuo Chen
The insulin-like growth factor binding protein 6 (IGFBP6), as an inhibitor of IGF-II actions, plays an important role in inhibiting survival and migration of tumor cells. In our study, we intended to demonstrate the biological function of IGFBP6 in the development of glioma and its clinical significance. Firstly, Western blot and immunohistochemistry revealed that the expression of IGFBP6 inversely correlated with glioma grade. Secondly, multivariate analysis with the Cox proportional hazards model and Kaplan-Meier analysis indicated that IGFBP6 could be an independent prognostic factor for the survival of glioma patients...
September 21, 2016: Cellular and Molecular Neurobiology
Yuki Saito, Yasuhiro Suzuki, Chie Inomoto, Nobue Kumaki, Kozue Yokoyama, Rin Ogiya, Risa Oshitanai, Mayako Terao, Banri Tsuda, Tooru Morioka, Naoki Niikura, Takuho Okamura, Shinobu Masuda, Yutaka Tokuda
We report a patient with a giant phyllodes tumor of the right breast associated with a hypoglycemic attack. A 48-year-old woman experienced a loss of consciousness and was transferred via ambulance to our hospital emergency department. Upon arrival, her blood glucose level was 26 mg/dl, and a giant tumor (>20 cm in diameter) with skin ulceration was observed on the right breast. Core needle biopsy led to a histological diagnosis of a phyllodes tumor of the breast. Ultrasonography and computed tomography detected neither distant metastasis nor a pancreatic endocrine tumor...
September 20, 2016: Tokai Journal of Experimental and Clinical Medicine
Danira Ashraf Habashy, Hend Mohamed El Tayebi, Injie Omar Fawzy, Karim Adel Hosny, Gamal Esmat, Ahmed Ihab Abdelaziz
AIM: To investigate the effect of microRNA on insulin-like growth factor binding protein-3 (IGFBP-3) and hence on insulin-like growth factor-II (IGF-II) bioavailability in hepatocellular carcinoma (HCC). METHODS: Bioinformatic analysis was performed using, DIANA lab and Segal lab softwares. Total RNA was extracted from 23 HCC and 10 healthy liver tissues using mirVana miRNA Isolation Kit. microRNA-17-5p (miR-17-5p) expression was mimicked and antagonized in HuH-7 cell lines using HiPerFect Transfection Reagent, then total RNA was extracted using Biozol reagent then reverse transcribed into cDNA followed by quantification of miR-17-5p and IGFBP-3 expression using TaqMan real-time quantitative PCR...
August 18, 2016: World Journal of Hepatology
Agata Mierzwicka, Marek Bolanowski
Among new peptides responsible for the pathogenesis of metabolic disorders and carbohydrate metabolism, adipokines are of great importance. Adipokines are substances of hormonal character, secreted by adipose tissue. Apart from the well-known adipokines, adropin and preptin are relatively newly discovered, hence their function is not fully understood. They are peptides not secreted by adipose tissue but their role in the metabolic regulations seems to be significant. Preptin is a 34-amino acid peptide, a derivative of proinsulin growth factor II (pro-IGF-II), secreted by pancreatic β cells, considered to be a physiological enhancer of insulin secretion...
2016: Postȩpy Higieny i Medycyny Doświadczalnej
Mette Faurholdt Gude, Rikke Hjortebjerg, Claus Oxvig, Anne Anker Thyø, Nils Erik Magnusson, Mette Bjerre, Steen B Pedersen, Jan Frystyk
OBJECTIVE: Adipose tissue secretes pregnancy-associated plasma protein-A (PAPP-A), which may increase local IGF-action through cleavage of IGF-binding-protein-4 (IGFBP-4). We tested whether this mechanism was operational in human visceral and subcutaneous adipose tissue (i.e. VAT and SAT). DESIGN: Explants of VAT and SAT from 26 obese subjects (hereof 17 women, BMI 39.8±1.3 kg/m2) and SAT from 8 lean, age-matched women (BMI 23.2±0.7 kg/m2) were incubated with or without GH (100 µg/l) and media harvested...
September 1, 2016: European Journal of Endocrinology
Anastasios Papaioannou, Serdar Kuyucak, Zdenka Kuncic
The insulin-family proteins bind to their own receptors, but insulin-like growth factor II (IGF-II) can also bind to the A isoform of the insulin receptor (IR-A), activating unique and alternative signaling pathways from those of insulin. Although extensive studies of insulin have revealed that its activation is associated with the opening of the B chain-C terminal (BC-CT), the activation mechanism of the insulin-like growth factors (IGFs) still remains unknown. Here, we present the first comprehensive study of the insulin-family proteins comparing their activation process and mechanism using molecular dynamics simulations to reveal new insights into their specificity to the insulin receptor...
2016: PloS One
Wenhong Ma, Xingfang Huang, Xing Yang, Xiaoyan Liang
PURPOSE: The aims of the present study are to identify the mechanism(s) whereby obesity impairs fresh embryos and to clarify the effects of vitrification on lipid droplet content within embryos from maternally obese mice. METHODS: The diet-induced obesity mouse model was established, and the zygotes were captured and cultured to day 3. The eight-cell embryos were selected and divided into fresh and vitrified groups. The blastocysts derived from fresh embryos were used as a control...
August 20, 2016: Journal of Assisted Reproduction and Genetics
Rozálie Hexnerová, Květoslava Křížková, Milan Fábry, Irena Sieglová, Kateřina Kedrová, Michaela Collinsová, Pavlína Ullrichová, Pavel Srb, Christopher Williams, Matthew P Crump, Zdeněk Tošner, Jiří Jiráček, Václav Veverka, Lenka Žáková
Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions with insulin becoming a key regulator of metabolism, whereas insulin-like growth factors (IGF)-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin receptor isoforms A and B (IR-A and IR-B) and insulin-like growth factor type I receptor (IGF-1R). Identification of structural determinants in IGFs and insulin that trigger their specific signaling pathways is of increasing importance in designing receptor-specific analogs with potential therapeutic applications...
September 30, 2016: Journal of Biological Chemistry
Heju Zhong, Hao Li, Guangmang Liu, Haifeng Wan, Yves Mercier, Xiaoling Zhang, Yan Lin, Lianqiang Che, Shengyu Xu, Li Tang, Gang Tian, Daiwen Chen, De Wu, Zhengfeng Fang
BACKGROUND: To determine responses of neonatal intestine to maternal increased consumption of DL-methionine (DLM) or DL-2-hydroxy-4-methylthiobutanoic acid (HMTBA), eighteen primiparous sows (Landrace × Yorkshire) were allocated based on body weight and backfat thickness to the control, DLM and HMTBA groups (n = 6), with the nutritional treatments introduced from postpartum d0 to d14. RESULTS: The DLM-fed sows showed negative energy balance manifested by lost bodyweight, lower plasma glucose, subdued tricarboxylic acid cycle, and increased plasma lipid metabolites levels...
2016: Journal of Animal Science and Biotechnology
Ha Hye-Lin, Taeho Kwon, In Seon Bak, Raymond L Erikson, Bo Yeon Kim, Yu Dae-Yeul
Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer mortality. Prognosis of this disease largely depends on its stage. An Enlarged liver, due to dysplasia, may be a critical point in the multi-step progression to HCC. The mechanism underlying hepatomegaly in human and mouse models are poorly understood. We previously reported we observed enlarged liver in hepatitis B virus X protein (HBx) expressing mice (HBx mice). Here we identify the critical role of HBx induced IGF-II in hepatomegaly in mice and abnormal cell growth in human hepatoma cells...
July 29, 2016: Oncotarget
Tomoki Sumida, Y U Kamata, Yosuke Kobayashi, Akiko Ishikawa, Yoshihide Mori
BACKGROUND: Inhibitor of differentiation or DNA binding 1 (ID1) is overexpressed in human salivary gland cancer (SGC). The insulin growth factor (IGF) system is an attractive target in cancer control because it is associated with various cancer progressions. MATERIALS AND METHODS: The human SGC cell line HSY with abundant ID1 was used. ID1 knockdown and its effect on the IGF system were investigated. Cell proliferation and invasion, as well as associated protein expression, were analyzed...
August 2016: Anticancer Research
Troels Brynskov, Caroline Schmidt Laugesen, Andrea Karen Floyd, Jan Frystyk, Torben Lykke Sørensen
BACKGROUND: Laparoscopic gastric bypass (LGB) abruptly causes remission of type 2 diabetes (T2D). Such dramatic metabolic changes have previously been found to cause worsening of diabetic retinopathy (DR) and circulating insulin-like growth factor I (IGF-I) has been suggested as a causal mediator. We aimed to evaluate baseline imbalances in the circulating IGF-system and changes after LGB in patients with T2D. METHODS: Prospective ocular examinations and measurement of the IGF-axis before and 3 and 12 months after LGB...
July 27, 2016: Obesity Surgery
M Lappas, D Jinks, A Shub, J C Willcox, H M Georgiou, M Permezel
AIMS: Women with previous gestational diabetes mellitus (GDM) are at greater risk of developing type 2 diabetes. In the general population, the insulin-like growth factor (IGF) system has been implicated in the development of type 2 diabetes. The aim of this study was to determine if circulating IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels 12weeks following a GDM pregnancy are associated with an increased risk of developing type 2 diabetes. METHODS: IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels were measured in 98 normal glucose tolerant women, 12weeks following an index GDM pregnancy using enzyme immunoassay...
July 4, 2016: Diabetes & Metabolism
Zhen Meng, Peng Hu, Jilin Lei, Yudong Jia
Insulin-like growth factors I and II (IGF-I and IGF-II) are important regulators of vertebrate growth and development. This study characterized the mRNA expressions of igf-i and igf-ii during turbot (Scophthalmus maximus) metamorphosis to elucidate the possible regulatory role of the IGF system in flatfish metamorphosis. Results showed that the mRNA levels of igf-i significantly increased at the early-metamorphosis stage and then gradually decreased until metamorphosis was completed. By contrast, mRNA levels of igf-ii significantly increased at the pre-metamorphosis stage and then substantially decreased during metamorphosis...
September 1, 2016: General and Comparative Endocrinology
Carolina Bonilla, Sarah J Lewis, Mari-Anne Rowlands, Tom R Gaunt, George Davey Smith, David Gunnell, Tom Palmer, Jenny L Donovan, Freddie C Hamdy, David E Neal, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G Giles, Fredrik Wiklund, Henrik Grönberg, Christopher A Haiman, Johanna Schleutker, Børge G Nordestgaard, Ruth C Travis, Nora Pashayan, Kay-Tee Khaw, Janet L Stanford, William J Blot, Stephen Thibodeau, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Park, Radka Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev Pandha, Mark Lathrop, Richard M Martin, Jeff M P Holly
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 polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3...
October 1, 2016: International Journal of Cancer. Journal International du Cancer
Abhishek S Kashyap, Gary K Shooter, Ali Shokoohmand, Jacqui McGovern, Manaswini Sivaramakrishnan, Tristan I Croll, Gaëlle Cane, David I Leavesley, Ola Söderberg, Zee Upton, Brett G Hollier
We provide proof-of-concept evidence for a new class of therapeutics that target growth factor:extracellular matrix (GF:ECM) interactions for the management of breast cancer. Insulin-like growth factor-I (IGF-I) forms multiprotein complexes with IGF-binding proteins (IGFBP) and the ECM protein vitronectin (VN), and stimulates the survival, migration and invasion of breast cancer cells. For the first time we provide physical evidence for IGFBP-3:VN interactions in breast cancer patient tissues; these interactions were predominantly localized to tumor cell clusters and in stroma surrounding tumor cells...
July 2016: Molecular Cancer Therapeutics
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