IGF-1
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BACKGROUND: The rising incidence of thyroid cancer observed in the last few decades requires an improvement in diagnostic tools and management techniques for patients with thyroid nodules. AIMS: The aim of this study was to assess serum concentrations of IGF-1 and IGF-1R in patients diagnosed with thyroid cancers. METHODS: 36 patients diagnosed with papillary thyroid cancer (PTC), 11 subjects with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and 19 subjects with multinodular nontoxic goiter (MNG) were enrolled to the study. The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum IGF-1 and IGF-1R concentrations were measured using specific ELISA methods. RESULTS: Significantly higher concentrations of IGF-1 were found in patients with PTC as compared with controls but not that obtained from subjects diagnosed with MNG. The concentration of IGF-1R was significantly elevated in subjects with PTC and ATC as compared with healthy volunteers. Similarly, patients diagnosed with PTC or ATC presented significantly higher serum concentration of IGF-1R in comparison to the MNG group. CONCLUSIONS: Our results show that the IGF-1 - IGF-1R axis plays a significant role in the development of PTC and ATC and imply that serum concentrations of both cytokines may be considered as additional markers for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors. These results indicate that IGF-1R serum concentrations allow us to differentiate between MNG and PTC or ATC. Moreover IGF-1R serum values appear to be better predictor of PTC and ATC than IGF-1 concentrations.
- Klíčová slova
- IGF-1, IGF-1R, thyroid cancer,
- MeSH
- dospělí MeSH
- folikulární adenokarcinom krev patologie MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádory štítné žlázy krev patologie MeSH
- papilární karcinom štítné žlázy krev patologie MeSH
- receptor IGF typ 1 krev MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- uzlová struma krev patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- IGF1 protein, human MeSH Prohlížeč
- IGF1R protein, human MeSH Prohlížeč
- insulinu podobný růstový faktor I MeSH
- receptor IGF typ 1 MeSH
The insulin/insulin growth factor (IGF) system plays a central role in regulating metabolism and growth. We identified viral insulin/IGF1-like peptides (VILPs) in Iridoviridae and investigated their role in host-virus interactions. Using grouper iridovirus (GIV) on grouper and zebrafish cells, we show that VILPs are early viral genes and are secreted during infection. VILPs activate insulin receptor (IR) and IGF-1 receptor (IGF1R) phosphorylation and stimulate the phosphatidylinositol 3-kinase (PI3K) pathway. GIV-VILP present in the supernatants of infected cells triggers dose- and time-dependent signaling through selective interaction with IGF1R. Functionally, IR inhibition suppresses GIV replication, whereas IGF1R inhibition enhances it, and IGF-1 stimulation reduces replication. During infection, GIV-VILP competes with IGF-1, attenuating IGF1R signaling and reducing proliferation. Transcriptome analysis confirms negative regulation of cell cycle pathways. Using a zebrafish infection model, we demonstrate VILP expression and IGF-1 signaling inhibition. Our findings reveal a viral mimicry mechanism that modulates host IGF-1 signaling to promote viral replication.
- Klíčová slova
- CP: Metabolism, CP: Microbiology, IGF-1, IGF1R inhibition, VILP, grouper iridovirus, insulin, mimicry, zebrafish,
- MeSH
- dánio pruhované virologie MeSH
- fosforylace MeSH
- insulinu podobný růstový faktor I * metabolismus MeSH
- inzulin * metabolismus MeSH
- Iridovirus * fyziologie MeSH
- lidé MeSH
- peptidy * metabolismus MeSH
- receptor IGF typ 1 * metabolismus antagonisté a inhibitory MeSH
- receptor inzulinu metabolismus MeSH
- replikace viru * MeSH
- signální transdukce * MeSH
- virové proteiny * metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- insulinu podobný růstový faktor I * MeSH
- inzulin * MeSH
- peptidy * MeSH
- receptor IGF typ 1 * MeSH
- receptor inzulinu MeSH
- virové proteiny * MeSH
OBJECTIVE: The insulin/IGF superfamily is conserved across vertebrates and invertebrates. Our team has identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs) closely resembling human insulin and IGF-1. This study aims to characterize the impact of Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-Sa (LCDV-Sa) VILPs on the insulin/IGF system for the first time. METHODS: We chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin like) forms of MFRV and LCDV-Sa VILPs. Using cell lines overexpressing either human insulin receptor isoform A (IR-A), isoform B (IR-B) or IGF-1 receptor (IGF1R), and AML12 murine hepatocytes, we characterized receptor binding, insulin/IGF signaling. We further characterized the VILPs' effects of proliferation and IGF1R and IR gene expression, and compared them to native ligands. Additionally, we performed insulin tolerance test in CB57BL/6 J mice to examine in vivo effects of VILPs on blood glucose levels. Finally, we employed cryo-electron microscopy (cryoEM) to analyze the structure of scMFRV-VILP in complex with the IGF1R ectodomain. RESULTS: VILPs can bind to human IR and IGF1R, stimulate receptor autophosphorylation and downstream signaling pathways. Notably, scMFRV-VILP exhibited a particularly strong affinity for IGF1R, with a mere 10-fold decrease compared to human IGF-1. At high concentrations, scMFRV-VILP selectively reduced IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation (Ras/MAPK pathway), while leaving Akt phosphorylation (PI3K/Akt pathway) unaffected, indicating a potential biased inhibitory function. Prolonged exposure to MFRV-VILP led to a significant decrease in IGF1R gene expression in IGF1R overexpressing cells and AML12 hepatocytes. Furthermore, insulin tolerance test revealed scMFRV-VILP's sustained glucose-lowering effect compared to insulin and IGF-1. Finally, cryo-EM analysis revealed that scMFRV-VILP engages with IGF1R in a manner closely resembling IGF-1 binding, resulting in a highly analogous structure. CONCLUSIONS: This study introduces MFRV and LCDV-Sa VILPs as novel members of the insulin/IGF superfamily. Particularly, scMFRV-VILP exhibits a biased inhibitory effect on IGF1R signaling at high concentrations, selectively inhibiting IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation, without affecting Akt phosphorylation. In addition, MFRV-VILP specifically regulates IGF-1R gene expression and IGF1R protein levels without affecting IR. CryoEM analysis confirms that scMFRV-VILP' binding to IGF1R is mirroring the interaction pattern observed with IGF-1. These findings offer valuable insights into IGF1R action and inhibition, suggesting potential applications in development of IGF1R specific inhibitors and advancing long-lasting insulins.
- Klíčová slova
- Biased signaling, IGF-1, IGF1 receptor, IGF1 receptor inhibition, Insulin, Iridoviridae, Viral insulin/IGF-1 like peptides (VILPs),
- MeSH
- elektronová kryomikroskopie MeSH
- exprese genu MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- fosforylace MeSH
- insulinu podobný růstový faktor I * genetika metabolismus MeSH
- inzulin metabolismus MeSH
- lidé MeSH
- myši MeSH
- protein - isoformy metabolismus MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- receptor IGF typ 1 * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fosfatidylinositol-3-kinasy MeSH
- IGF1R protein, human MeSH Prohlížeč
- insulinu podobný růstový faktor I * MeSH
- inzulin MeSH
- protein - isoformy MeSH
- protoonkogenní proteiny c-akt MeSH
- receptor IGF typ 1 * MeSH
In the submitted review the author discusses two substances secreted into the circulation which can similarly as insulin lower the blood sugar level. These substances are IGF-I (insulin-like growth factor I) and GLP (glucagon-like peptide). While in case of the former it is not certain whether it participates in the glucose homeostasis, this is beyond doubt in the latter. IGF-I prepared by the recombinant technique can be used therapeutically in cases of insulin resistance caused by a receptor or postreceptor disorder, because it may act via its own receptor. Side-effects after larger doses are a problem. GLP-1, the use of which would be useful in type 2 diabetics as it stimulates insulin secretion, is not used so far in therapy because hitherto prepared preparations have a very short period of a effectiveness.
- MeSH
- glukagon * škodlivé účinky fyziologie terapeutické užití MeSH
- glukagonu podobný peptid 1 MeSH
- insulinu podobný růstový faktor I * škodlivé účinky fyziologie terapeutické užití MeSH
- inzulinová rezistence MeSH
- krevní glukóza metabolismus MeSH
- lidé MeSH
- pankreatické hormony fyziologie terapeutické užití MeSH
- peptidové fragmenty * škodlivé účinky fyziologie terapeutické užití MeSH
- peptidy * škodlivé účinky fyziologie terapeutické užití MeSH
- proteinové prekurzory * škodlivé účinky fyziologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- glukagon * MeSH
- glukagonu podobný peptid 1 MeSH
- insulinu podobný růstový faktor I * MeSH
- krevní glukóza MeSH
- pankreatické hormony MeSH
- peptidové fragmenty * MeSH
- peptidy * MeSH
- proteinové prekurzory * MeSH
The insulin receptor (IR, with its isoforms IR-A and IR-B) and the insulin-like growth factor 1 receptor (IGF-1R) are related tyrosine kinase receptors. Recently, the portfolio of solved hormone-receptor structures has grown extensively thanks to advancements in cryo-electron microscopy. However, the dynamics of how these receptors transition between their inactive and active state are yet to be fully understood. The C-terminal part of the alpha subunit (αCT) of the receptors is indispensable for the formation of the hormone-binding site. We mutated the αCT residues Arg717 and His710 of IR-A and Arg704 and His697 of IGF-1R. We then measured the saturation binding curves of ligands on the mutated receptors and their ability to become activated. Mutations of Arg704 and His697 to Ala in IGF-1R decreased the binding of IGF-1. Moreover, the number of binding sites for IGF-1 on the His697 IGF-1R mutant was reduced to one-half, demonstrating the presence of two binding sites. Both mutations of Arg717 and His710 to Ala in IR-A inactivated the receptor. We have proved that Arg717 is important for the binding of insulin to its receptor, which suggests that Arg717 is a key residue for the transition to the active conformation.
- Klíčová slova
- mutagenesis in vitro, peptide hormone, receptor modification, receptor tyrosine kinase, structure–function,
- MeSH
- elektronová kryomikroskopie MeSH
- insulinu podobný růstový faktor I genetika chemie metabolismus MeSH
- inzulin metabolismus MeSH
- ligandy MeSH
- receptor IGF typ 1 * genetika chemie metabolismus MeSH
- receptor inzulinu * genetika chemie metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- insulinu podobný růstový faktor I MeSH
- inzulin MeSH
- ligandy MeSH
- receptor IGF typ 1 * MeSH
- receptor inzulinu * MeSH
BACKGROUND: Polycystic ovary syndrome (PCOS) represents a frequent endocrinopathy among fertile women. Ethiopathogenesis of the syndrome is multifactorial and it is a subject of scientific discussions. Considered is the possibility of intraovarial IGF system disorder affecting maturation of ovarial folicles. The aim of our work was to determine effects of peroral contraceptives with low-androgen progestin on IGF system in PCOS patients and healthy woman controls. METHODS AND RESULTS: 14 patients fulfilling diagnostic criteria of PCOS and 7 healthy controls were included into the study. All persons were examined before and after six months lasting administration of monophasic estrogen-progesteron contraceptive therapy with 35 micrograms of ethinylestradiol per day and 250 micrograms of low-androgen progestin norgestimate per day. In PCOS patients low increase of basal insulinemia levels occurred (16.3 +/- 4.8 vs. 20.8 +/- 4.8 mU.l-1, p < 0.05). IGF-1 serum levels were not influenced (230 +/- 70 vs. 235 +/- 112 pg.ml-1, n.s.), IGFBP-1 serum concentration significantly increased (46.3 +/- 24.1 vs. 75.6 +/- 24.0 pg.ml-1, p < 0.001). Insulinemia in healthy women also slightly increased (15.9 +/- 4.0 vs. 18.4 +/- 4.0 pg.ml-1, p < 0.05). IGF-1 serum concentration significantly increased (140 +/- 65 vs. 241 +/- 89 pg.ml-1, p < 0.001). IGFBP-1 was also higher (45.0 +/- 19.19 vs. 80.0 +/- 15.6 pg.ml-1, p < 0.001). Influence of the hormonal contraception on the followed parameters was estimated using Wilcoxon's test. While BP-1 increase was significant in both groups, the increase of IGF-1 was significant only in healthy controls. CONCLUSIONS: Increased levels of IGFBP-1 were found in both studied groups of women. Women with PCOS had higher serum levels of IGF-1 before the therapy and the treatment did not influence it. Contrary to it, in healthy women the increased value was observed. Explanation of that finding will become the aim of our next study.
- MeSH
- index tělesné hmotnosti * MeSH
- insulinu podobný růstový faktor I analýza MeSH
- inzulin krev MeSH
- kontraceptiva orální hormonální farmakologie MeSH
- lidé MeSH
- luteinizační hormon krev MeSH
- protein 1 vázající insulinu podobné růstové faktory krev MeSH
- syndrom polycystických ovarií krev MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- insulinu podobný růstový faktor I MeSH
- inzulin MeSH
- kontraceptiva orální hormonální MeSH
- luteinizační hormon MeSH
- protein 1 vázající insulinu podobné růstové faktory MeSH
The system of IGF-I and its binding proteins may be involved in the pathogenesis of vascular damage in Type 1 diabetes. The aim of this study was to analyze the relationship between this system and the microvascular reactivity in Type 1 diabetes as measured by laser-Doppler flowmetry. Twenty-two Type 1 diabetic patients (13 women and 9 men) with microangiopathy and fifteen healthy subjects (8 women and 7 men) were examined clinically, underwent laser-Doppler flowmetry and intima-media thickness measurements. Fasting serum levels of IGF-I, free IGF-I, IGFBPs and lipids were examined. The microvascular reactivity was impaired in Type 1 diabetic patients. Maximal perfusion during post-occlusive reactive hyperemia (PORHmax) and during thermal hyperemia (THmax) was significantly decreased in Type 1 diabetes (p<0.01). Percentage perfusion increase in both tests (PORH and TH) was lower in Type 1 diabetes mellitus (p<0.01) and the reaction after heating was slower in diabetic patients (THmax) (p<0.01). We did not find any significant dependence of microvascular reactivity on the parameters of IGF-I or its binding proteins. We conclude that the microvascular reactivity is impaired in Type 1 diabetes mellitus, but this impairment is not clearly dependent on the activity of the IGF-I system. It is probably only a complementary pathogenic factor.
- MeSH
- diabetes mellitus 1. typu patofyziologie MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- krevní oběh * MeSH
- laser doppler flowmetrie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikrocirkulace MeSH
- proteiny vázající IGF metabolismus MeSH
- referenční hodnoty MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- insulinu podobný růstový faktor I MeSH
- proteiny vázající IGF MeSH
BACKGROUND: The relationships between selected steroids, SHBG, growth hormone, IGF-1, IGF BP-3 and indicators of glucose metabolism were studied in the group of 20 female patients (15-20 yrs) on long-term treatment with low prednisone doses (< 0.3 mg/kg/day) (baseline phase) and after adding 1000 mg of metformin per day for following 6 months to improve impaired glucose metabolism (control phase). METHODS AND RESULTS: Lower basal DHEAS and DHEA (DHEA/S) levels were found as compared with reference values. Only DHEAS level returned into the reference range after the treatment with metformin. Decrease of DHEA/S depended on the doses (DHEAS -0.7621, DHEA -0.7685). Positive correlations between DHEA/S and of the results insulin tolerance were found as at the baseline (+0.4452, resp. +0.4455) as well as in the control period after the metformin administration (+0.7549, resp. +0.6073). Testosterone (T) and dihydrotestosterone(DHT) values were within the reference range during the whole study. Due to very low SHBG levels higher free androgen index (FAI) was recorded in more than half of the patients. Significant relationships were revealed between former gonadal androgens and indicators of glucose metabolism deterioration at the control phase: T correlated: with fasting insulin (+0.6005), with HOMAIR (+0.5380), with insulin/glucose (+0.5261), with fasting glucose (+0.9268), with AUC glucose (+0.6792), FAI: with fasting insulin (+0.5560), with HOMAIR (+0.5269), with fasting glucose (+0.9025), with AUC glucose (+0.7143), DHT: with fasting C peptide (+0.7921), with AUC C peptide (+0.7143). SHBG correlated: with fasting glucose (-0.6519), and with AUC glucose (-0.5868). The tendency of GH to lower, and IGF-1, IGF BP-3 to higher values at the baseline changed at the control phase: fasting and AUC value of GH increased (signif.), while were IGF-1 (nonsignif.) and IGF BP-3 (signif.) levels decreased. Surprisingly, no correlation was observed between GH and parameters of glucose metabolism. Contrary to GH, baseline IGFBP-3 values correlated: with HOMAIR (+0.5002), with insulin/glucose (+0.4860). The same relationships were found between AUC IGF BP-3 (+0.5676, +0.5559), IGF-1 (HOMAIR only +0.5412), IGF-1/IGF BP-3 (+0.5059, +0.5716) and parameters of insulin sensitivity (HOMAIR, insulin/glucose) in the control period. For the first time negative correlations between IGF-1, IGF-1 AUC, IGF BP-3, IGF-1/IGF BP-3 and somatostatin blood levels were discovered at the control phase. CONCLUSIONS: The study brought a number of new information about the importance of the "non-classical" glucoregulatory hormones in impairment of glucose metabolism, during long-term administration of low prednisone doses. The results suggest, that without normalisation of low DHEA/S, SHBG and high FAI levels it would not be possible to correct glucose metabolism properly in patients with long-term glucocorticoid therapy.
- MeSH
- androgeny krev MeSH
- dospělí MeSH
- globulin vázající pohlavní hormony analýza MeSH
- glukokortikoidy aplikace a dávkování škodlivé účinky MeSH
- glukosa metabolismus MeSH
- hydrokortison krev MeSH
- hypoglykemika terapeutické užití MeSH
- IGFBP-3 analýza MeSH
- insulinu podobný růstový faktor I analýza MeSH
- inzulin farmakologie MeSH
- lidé MeSH
- metformin terapeutické užití MeSH
- mladiství MeSH
- nemoci pojiva farmakoterapie metabolismus MeSH
- prednison aplikace a dávkování škodlivé účinky MeSH
- růstový hormon krev MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- androgeny MeSH
- globulin vázající pohlavní hormony MeSH
- glukokortikoidy MeSH
- glukosa MeSH
- hydrokortison MeSH
- hypoglykemika MeSH
- IGFBP-3 MeSH
- insulinu podobný růstový faktor I MeSH
- inzulin MeSH
- metformin MeSH
- prednison MeSH
- růstový hormon MeSH
Autologous serum eye drops (ASEDs) are used as a treatment for severe dry eye disease. The concentration and stability of various growth factors in ASEDs is determinative for their efficiency. We therefore assessed the concentrations of transforming growth factor beta 1 (TGF-β1), epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) in ASEDs following storage at 4-8, -20, -80 and -156 °C. Twenty % and 100% sera from eight healthy volunteers were analysed by the sandwich enzyme immunoassay at different time intervals up to seven months. The mean levels of TGF-β1 and EGF in undiluted and 20% serum did not differ significantly from the baseline levels in fresh serum for any storage conditions after 7 days at 4-8 °C, as well as after 4- and 7-month preservation at sub-zero temperatures. In 20% serum, no IGF-1 concentration decrease was found following 7 days of preservation at 4-8 °C. However, a decrease to 78 % and 81 % (P < 0.01) of baseline values was found in 20% serum after 4-month storage at -20 °C and 7-month storage at -156 °C, respectively. A more pronounced decrease in IGF-1 was observed in undiluted serum. All assessed growth factors present in 20% frozen serum remained stable for up to 7 months. The highest stability was achieved at -80 °C. At -20 and -156 °C, some decrease in IGF-1 occurred. Our results indicate that 20% ASEDs can be stored frozen up to 7 months under proper conditions.
- MeSH
- epidermální růstový faktor * MeSH
- insulinu podobný růstový faktor I * metabolismus MeSH
- lidé MeSH
- oční roztoky MeSH
- sérum metabolismus MeSH
- teplota MeSH
- transformující růstový faktor beta1 MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- epidermální růstový faktor * MeSH
- insulinu podobný růstový faktor I * MeSH
- oční roztoky MeSH
- transformující růstový faktor beta1 MeSH
We tested the following hypothesis: when two pudu males share a single pen throughout the year, the dominant animal will have a higher level of IGF-1 than its subordinate pen mate, particularly during the period of increased social friction (e.g. rut and establishment of territories). To test this hypothesis, we used data from six adult males maintained at the University of Concepión, Chile (latitude 36.6 degrees S), and analysed them from the males' dominance point of view. Two males plus eight to ten females were kept in one pen and although we did not specifically measure dominance, the rank position was obvious from frequent encounters between the bucks. Three consecutive blood samples were taken monthly over the period of 1 year. In addition to IGF-1, we also analysed seasonal levels of testosterone, cortisol, prolactin, LH and FSH. The analysis revealed that IGF-1 levels of dominant males were significantly higher than those of subordinate males from September to November (the second part of the antler growing period and time of establishing territories). Testosterone levels were higher and FSH levels were lower in dominant males during the rut. Levels of prolactin were higher in dominant animals in November (summer). Cortisol and LH did not show any significant differences between dominant and subordinate males. This data provides the first evidence indicating the possible link between dominance and blood levels of IGF-1. The functional explanation of such links is discussed.
- MeSH
- hydrokortison krev MeSH
- insulinu podobný růstový faktor I metabolismus MeSH
- pohlavní steroidní hormony krev MeSH
- roční období * MeSH
- vysoká zvěř fyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- hydrokortison MeSH
- insulinu podobný růstový faktor I MeSH
- pohlavní steroidní hormony MeSH