IGF-I Receptor Gene Research Articles

A genetic investigation in five Chinese families with keratoconus.

This study investigated the genetic characteristics of five Chinese families with keratoconus (KC). In the five families affected by KC, medical records, clinical observations, and blood samples were collected from all individuals. All KC family members (n = 20) underwent both whole exome sequencing of genomic DNA and Sanger sequencing to confirm the variants. Online software was utilized to analyze all variants, and the online server I-TASSER was employed for in silico predictions of the three-dimensional protein structures of the variants. The newly discovered variants and single nucleotide polymorphisms were further examined in 322 sporadic KC patients. The Pentacam tomographic composite index in those affected first-degree family members of the probands showed a pathological change. Five new variants were detected in the five probands and other affected members in their families: a heterozygous missense variant g.19043832C>T (p.Ser145Asn) in the homer scaffolding protein 3 (HOMER3) gene; a heterozygous missense variant g.99452113G>A (p.Gly483Arg) in the insulin-like growth factor 1 receptor (IGF1R) gene; a heterozygous missense variant g.55118280G>T (p.Trp843Leu) in the echinoderm microtubule-associated protein like 6 (EML6) gene; a heterozygous frameshift variant c. 1226_1227del (p.Gln410Glufs*17) in the DOP1 leucine zipper-like protein B (DOP1B) gene; and a heterozygous splice-site variant c.7776+2T>A in the neurobeachin-like protein 2 (NBEAL2) gene. These variations were predicted to be potentially pathogenic and associated with KC. Five novel variants in HOMER3, IGF1R, EML6, DOP1B, and NBEAL2 genes were identified in this study and may be associated with the pathogenesis of KC. This study provides new information about the gene variants and their protein changes in KC patients. The findings should be explored further and could potentially be applied to the early diagnosis of KC before clinical onset.

In ovo betaine injection improves breast muscle growth in newly hatched goslings through FXR/IGF-2 pathway

Betaine has been shown to enhance growth performance and increase breast muscle yield in ducks and broilers through various mechanisms, including the modification of DNA methylation. However, the impact of in ovo betaine injection on muscle growth in newly hatched goslings remains unclear. In this study, fifty eggs were injected with saline or betaine at 7.5 mg/egg prior to incubation, and the subsequent effects on breast muscle growth in the newly hatched goslings were investigated. Betaine significantly increased (P < 0.05) the hatch weight, breast muscle weight, and breast muscle index, accompanied by an augmentation in muscle bundle cross-sectional area. Concurrently, betaine significantly upregulated (P < 0.05) the expression levels of myogenic regulatory factors, including myogenin (MyoG) and paired box 7 (Pax7) both mRNA and protein, while downregulating (P < 0.05) the mRNA and protein levels of myostatin (MSTN). Histological analysis revealed a higher abundance of proliferating cell nuclear antigen (PCNA) and Pax7 immune-positive cells in the breast muscle of the betaine group, consistent with elevated PCNA and Pax7 mRNA and protein levels. Additionally, significantly increased (P < 0.05) contents of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) were observed in the breast muscle of the betaine group, so was mRNA expression of IGF-1, IGF-2, and insulin-like growth factor 1 receptor (IGF-1R). Betaine also significantly in8creased (P < 0.05) global DNA methylation of the breast muscle, accompanied by enhanced mRNA and protein levels of methionine cycle and DNA methylation-related enzymes, Interestingly, the promoter regions of IGF-1, IGF-2, and IGF-1R genes were significantly hypomethylated (P < 0.05). Moreover, in ovo betaine injection significantly upregulated (P < 0.05) the protein level of farnesoid X receptor (FXR) in breast muscle and FXR binding to the promoter of IGF-2 gene. These findings suggest that in ovo betaine injection promotes breast muscle growth during embryonic development in goslings through the FXR-mediated IGF-2 pathway, ultimately improving hatch weight and breast muscle weight.

IGF-1R, E-cadherin, N-cadherin, and occludin gene expression and resistance to EGFR tyrosine-kinase inhibitors in patients with lung adenocarcinoma in Serbia.

8524 Background: Mutations in epidermal growth factor-receptor ( EGFR) are found in approximately 10% of patients with lung adenocarcinoma in Serbia. EGFR tyrosine-kinase inhibitors ( EGFR-TKIs) is a safe and effective targeted therapy. However, most patients develop resistance. Acquired resistance to EGFR-TKI is defined as disease progression after achieving response or stable disease and there is a possible molecular association with epithelial-mesenchymal transition (EMT), particularly N-cadherin, E-cadherin, occludin and insulin-like growth factor-1 receptor (IGF-1R). We assessed the gene expression levels of IGF-1R, E-cadherin, N-cadherin, and occludin as predictive factors of resistance to EGFR-TKIs and survival outcomes in patients with advanced EGFR mutation-positive lung adenocarcinoma in Serbia. Methods: 101 patients with stage IIIB/IV EGFR mutation positive lung adenocarcinoma treated with EGFR-TKIs were included in the study. Quantitative RT-PCR was performed to determine mutations in EGFR, and expression of N-cadherin, E-cadherin, occludin and IGF-1R. Kaplan-Meier method was employed to estimate overall-survival (OS) and progression-free survival (PFS), with significance set at p&lt;0.05. Results: Median age of patients was 61.7 (39 - 81) years, 65.3% were females and 91% were diagnosed with metastatic lung adenocarcinoma. EGFR mutations were more frequently detected in females (p &lt;0.001). Median overall survival (OS) was 21 months (15.2–26.7 CI 95%) and progression-free survival (PFS) was 10 months (7.4-12.5 CI 95%). Patients whose tumors had lower levels of IGF-1R, and N-cadherin expression had statistically significantly longer PFS (p &lt;0.001). Patients with lower levels of IGF-1R and higher levels of E-cadherin gene expression were more likely to have a complete or partial response to therapy (p = 0.04). There was a statistically significant association between elevated IGF-1R expression and the occurrence of EGFR-TKI resistance in patients (p &lt;0.001). There was a statistically significant association between increased N-cadherin expression and reduced E-cadherin expression with EGFR-TKI resistance in patients. Conclusions: The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin. In this group of patients, higher levels of IGF-1R and N-cadherin gene expression were associated with shorter PFS and resistance to EGFR TKI, compared to higher levels of expression of E-cadherin, which may indicate potential value of expression of these genes in predicting acquired resistance to EGFR-TKI. Therefore, more research is needed to prove the potential predictive value of E-cadherin, N-cadherin and IFG-1R in acquired resistance to EGFR-TKI and developing novel therapeutic options with anti-EMT properties that can overcome this problem.

Effect of β-hydroxybutyrate acid on gene expression levels of antioxidant biomarkers and growth hormone-related genes in liver cell culture.

In dairy cattle, oxidative stress is a predominant problem associated with diseases and reproductive health issues. This study aimed to detect the variation in the antioxidant biomarkers by adding different concentrations of β-hydroxybutyric acid (BHBA) and sought to elucidate its effects on the gene expression levels of growth hormone (GH) and antioxidant biomarkers in bovine hepatocytes. Four antioxidant biomarkers, namely malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH Px) were evaluated using commercially available bovine ELISA kits. The expression levels of the bovine GH, its receptor (GHR), insulin-like growth factor (IGF), IGF-1, IGF-1 receptor, CAT, SOD, GSH-Px and β-actin (as a reference) genes in liver cell culture were determined by reverse transcriptase-PCR assay. With the increase of BHBA concentration and culture time, the activities of SOD, CAT, and GSH Px biomarkers in hepatocytes decreased. However, the content of MDA in hepatocytes increased gradually with the increase of hepatocyte culture time and BHBA concentration. The qPCR results revealed that after adding BHBA, gene expression levels of GSH-Px, SOD and IGF biomarkers in hepatocytes began to differ in the culture groups at 12 h, whereas the gene expression level of the CAT and GHR biomarkers in hepatocytes began to differ at 6 h. Quantitative PCR results showed that the BHBA significantly downregulated the expression levels of the GHR gene and CAT, GSH Px and SOD antioxidant biomarker genes.

A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression

ObjectiveThe 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. MethodsWe 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. ResultsVILPs 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. ConclusionsThis 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.

Clinical characteristics of and growth hormone treatment effects on short stature with type 1 insulin-like growth factor receptor (IGF1R) gene alteration.

Short stature with IGF-1 receptor (IGF1R) gene alteration is known as small-for-gestational-age (SGA) short stature with elevated serum IGF1 levels. Its prevalence and clinical characteristics remain unclear. No adapted treatment is available for short stature related to IGF1R gene alteration in Japan, and genetic testing is not yet widely accessible. We investigated short stature with IGF1R gene alterations and analyzed the clinical data of 13 patients using the results of questionnaires issued to the Japanese Society for Pediatric Endocrinology. Four cases were caused by a deletion of chromosome 15q26.3, and eight were caused by heterozygous pathogenic variants in the IGF1R gene. Cases with deletions showed a more severe degree of growth impairment (-4.5 ± 0.43 SD) than those caused by pathological variants (-2.71 ± 0.15 SD) and were accompanied by neurodevelopmental delay. However, cases caused by pathological variants lacked distinctive features. Only three of the 12 cases demonstrated serum IGF1 values exceeding +2 SD, and the other three had values below 0 SD. Four patients did not meet the criteria for SGA at birth. Six patients received GH therapy for SGA short stature and showed improvement in growth rate without any side effects or elevated serum IGF1 levels during treatment. Elevated IGF1 levels (over +2 SD) after GH treatment should be considered a suspicious finding. Owing to the lack of distinctive features, there was a possibility of undiagnosed cases of this condition. Promoting genetic testing and clinical trials on GH administration for this condition is recommended.

FRI293 Phoenixin As A Novel Autocrine/Paracrine Factor Mediating Prolactin Regulation By Functional Interaction Of LH And IGF-I/-II In Carp Pituitary Cells

Abstract Disclosure: C. Ye: None. X. Qin: None. M. He: None. A.O. Wong: None. Phoenixin (PNX), a novel peptide identified by bioinformatics, is known to have pleiotropic functions mediated by its receptor GPR173. At present, very little is known for PNX regulation and the intracellular signaling for PNX expression is still unclear. Recently, PNX and GPR173 were cloned in grass carp and found to be co-expressed in carp lactotrophs. In carp pituitary cells, PNX was also confirmed to be a novel autocrine/paracrine factor maintaining/stimulating prolactin (PRL) synthesis &amp; secretion. To unveil the functional role of PNX in PRL regulation, a systematic screening of &amp;gt;40 neuroendocrine factors/local growth factors was conducted in the same cell model to look for regulators with modulatory functions for both PNX and PRL in carp pituitary. Based on our study, IGF-I &amp; -II were shown to elevate PNX mRNA level with parallel rise in PRL gene expression in carp pituitary cells whereas the opposite was true for the functional agonist of LH, namely hCG. In parallel experiment, PRL mRNA expression induced by IGF-I was negated by removing endogenous PNX using immunoneutralization with PNX antiserum. Besides, hCG inhibition on PNX &amp; PRL gene expression could be mimicked by parallel treatment of LH but not FSH, whereas removal of endogenous LH by LH antiserum immunoneutralization could lead to the opposite effects. Of note, hCG co-treatment not only attenuated the PNX and PRL responses induced by IGF-I but also triggered notable suppression of IGF-I receptor (IGF1R) gene expression at pituitary cell level. In our study, IGF1R &amp; insulin receptor (InsR) expressed in carp pituitary cells were both activated by IGF-I treatment, but IGF-I induced PNX and PRL mRNA expression could be blocked only by the inactivators for IGF1R but not InsR. Using a pharmacological approach, the gene expression of PNX and PRL induced by IGF-I was confirmed to be mediated through the PI3K/Akt and MEK1/2/ERK1/2 but not P38MAPK pathways. Our findings, as a whole, suggest that (i) IGF signals can induce PRL gene expression in carp pituitary via IGF1R coupled to PI3K/Akt &amp; MAPK cascades and this stimulatory effect is mediated via local production of PNX, and (ii) LH released in the pituitary can act locally to inhibit both basal &amp; IGF-induced PRL expression and these inhibitory actions are mediated by blocking pituitary expression of PNX &amp; IGF1R. Presentation: Friday, June 16, 2023

Research Note: Association of insulin-like growth factor 1 receptor gene polymorphism with production performance in Savimalt and French Giant meat-type quails

This study aimed to investigate the association of insulin-like growth factor 1 receptor (IGF-1R) gene single nucleotide polymorphisms (SNPs) with growth traits and carcass traits of quail by PCR amplification and direct sequencing technology. Genomic DNA was extracted from blood samples collected from 49 female French Giant (FG) quails and 36 female Savimalt (SV) quails as part of this study. Growth traits and carcass traits were measured and assessed for IGF-1R gene analysis in the 2 meat-type quail strains. The results showed that 2 SNPs (A57G and A72T) of the IGF-1R gene were detected in the 2 quail strains. The A57G (P=0.002) and A72T (P=0.026) were significantly associated with breastbone length (BBL) in FG. Whereas A57G was significantly associated with chest weight (CW, P=0.004), BBL (P=0.009), and body length (BL, P=0.009) in SV, while A72T was significantly associated with BBL (P=0.014) and BL (P=0.028) in SV. Haplotypes based on these 2 SNPs showed significant effects on BBL in FG strain (P=0.000), and they also had significant effects on CW (P=0.007), BBL (P=0.004), and BL (P=0.001) in SV strain. Additionally, A57G was significantly associated with liver rate (LR) in FG strain (P=0.017). A72T showed significant associations with dressed carcass weight (DCW, P=0.048) and breast muscle weight (BMW, P=0.018) in FG strain. A57G was significantly associated with DCW (P=0.048), whole net carcass weight (WNCW, P=0.048), BMW (P=0.036), and liver muscle rate (LMR, P=0.003) in SV strain. Haplotypes also displayed significant effects on BMW (P=0.029) and LMR (P=0.010) in FG strain. These findings indicated that the IGF-1R gene could serve as a valuable molecular genetic marker for enhancing growth traits and carcass traits in meat-type quails.

Association of IGF1R polymorphisms with kidney function-related traits.

Unimpaired kidney function is important for maintaining a healthy state of homeostasis in the body. A genome-wide association study (GWAS) conducted on kidney function-associated traits and novel loci of Japanese subjects found that insulin-like-growth factor 1 receptor (IGF1R) gene variants associated with replication were responsible for all three kinds of kidney functions and satisfied the Bonferroni significance level. This study aimed to investigate whether a comparable relationship exists in the Korean population. This study replicated three SNPs (rs28657002, rs10794486, and rs4966025) and conducted a linear regression analysis between 46 SNPs in the IGF1R gene and three kidney function-related traits, namely blood urea nitrogen (BUN), creatinine, and estimated glomerular filtration rate (eGFR) in Koreans. The IGF1R gene was found to be replicated with a significant correlation in Koreans and was extended to the entire gene region to confirm its association with kidney-related functions. Three SNPs in IGF1R were replicated (rs28657002, BUN, P = 3.39 × 10-4; rs10794486, creatinine, P = 5.79 × 10-6; rs4966025, eGFR, P = 1.57 × 10-5) and five SNPs (rs28657002, rs10794486, rs4966025, rs12439557, and rs11247372) showed common significance among the three traits. Additionally, two significant SNPs (rs11857366 and rs28657002) showed the potential to affect IGF1R expression. The results suggest that genetic polymorphisms in the IGF1R replicated previous studies and could affect kidney function. The results of this study will further enhance our understanding of how genetic differences in individuals affect kidney function-related traits.

Radio-immunotherapy by 188Re-antiCD20 and stable silencing of IGF-IR in Raji cells, new insight in treatment of lymphoma

Hematologic malignancies such as Non-Hodgkin’s lymphoma (NHL), remain a serious threat to human health due to their heterogeneity and complexity. The inherent genetic heterogeneity of NHL B-cells, as well as the instability of lymphoma cancer cells, results in drug resistance in lymphoma, posing a fundamental challenge to NHL treatment. Burkitt lymphoma (including Raji cell line) is a rare and highly aggressive form of B-cell NHL. Since overexpression of the insulin-like growth factor-1 receptor (IGF-1R) playing a prominent role in the development and transformation of different malignancies, especially lymphoma malignancies, we have explored the role of IGF-1R in the development and progression of Raji cells and the stable silencing of IGF-1R by lentivirus-mediated RNA interference (RNAi). We have shown that stable silencing of the IGF-1R gene in Raji cells using lentivirus-mediated-RNAi have resulted in a significant reduction in Raji cell proliferation. Moreover, the results of the cell viability assays indicatedhigh resistance of Raji cells to rituximab. However, coupling rituximab to 188Re potentially leads to specific targeting of Raji cells by 188Re, improving the therapeutic efficacy. We found that the synergistic effect of using a gene therapy-based system in combination with radioimmunotherapy could be a promising therapeutic strategy in the future. To the best of our knowledge, this is the first study that reports the knock down of IGF-1R via lentiviral-mediated shRNA in Raji cells.

RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer

The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.

The effect of insulin-like growth factor 1 receptor gene single nucleotide polymorphism on growth and milk production traits in two native Indian tropical goat breeds

Insulin like growth factor1(IGF-1) is an essential growth factor that mediates the growth-promoting functions of pituitary growth hormone. Insulin like growth factor 1 receptor (IGF1R) is a tyrosine kinase receptor that mediates the actions of IGF1. Therefore, IGF1R is a candidate gene for examining SNPs linked with growth and production traits. The objective of this study was to detect the c.546 + 179170A > T transversion in intron 2 of the gene encoding IGF1R in two goat breeds, Attappady Black and Malabari, and examine the association of this polymorphism with growth and milk production. For the identification of the SNP, the T-ARMS-PCR was utilized. All three genotypes were present in the two investigated breeds. The polymorphism was found to be significantly (p < 0.05) linked with growth traits. At birth, 3 and 6 months of age, Attappady goats with the AT genotype had significantly (p < 0.05) higher body weights than those with the AA and TT genotypes. Malabari goats with the AT genotype had significantly (p < 0.05) higher body weights at birth and at 3 months of age. The genotypes of the IGF1R gene had no effect on total or peak milk production. Therefore, this SNP could be used as a molecular marker in selection of meat-producing goat breeds. HIGHLIGHTS c.546 + 179170A > T IGF1R transversion was detected using T-ARMS-PCR in two indigenous goat breeds from Kerala. Attappady Black and Malabari goat breeds of Kerala possessed all the three genotypes In these breeds, there was a significant correlation between this SNP, c.546 + 179170A > T IGF1R, and body weight. In both the breeds, there was no association between this SNP and milk production traits.

Research Note: Association of IGF-1R gene polymorphism with egg quality and carcass traits of quail (Coturnix japonica)

Insulin-like growth factor 1 receptor (IGF-1R) gene is the main effector of insulin-like growth factor (IGF), which plays an important role in growth, development and reproduction of the animal organism. This study aimed to investigate the association of IGF-1R gene single nucleotide polymorphisms (SNPs) with egg quality and carcass traits of quail by direct sequencing. In this study, genomic DNA was extracted from quail blood samples of 46 Chinese yellow (CY) quail, 49 Beijing white (BW) quail and 48 Korean (KO) quail strains. Egg quality and carcass traits were measured and used for IGF-1R gene analysis in 3 quail strains. The results showed that 2 SNPs (A57G and A72T) of the IGF-1R gene were detected in 3 quail strains. The A57G was significantly associated with yolk width (YWI) in BW strain (P < 0.05). Whereas A72T was significantly associated with egg shell thickness (EST) in BW strain (P < 0.05), and significantly associated with egg weight (EW), egg long (EL), and egg short (ES) in KO strain (P < 0.05). Haplotypes based on 2 SNPs showed significant effect on EST in 3 quail strains (P < 0.05), it also has a significant effect on EW in KO strain (P < 0.05). Meanwhile, A72T was significantly associated with liver weight (LW) and dressing percentage (DP) in 3 strains (P < 0.05). Haplotypes showed significant effect on LW (P < 0.05). Therefore, the IGF-1R gene may be a molecular genetic marker to improve egg quality and carcass traits in quails.

MafA-positive insulin-producing cells derived from rat adipose stem cells are efficient in glucose hemostasis in vitro

Objective: MafA has been recognized as a specific pancreatic β-cells activator for Insulin expression. This study investigated the changes in glucose transport and consumption by MafA-positive Insulin-producing cells resulting from the differentiation of rat adipose tissue-derived mesenchymal stem cells. Methods: Adipose tissue-derived mesenchymal stem cells were differentiated into Insulin-producing cells in a 14-day protocol using nicotinamide and ITS. The ability to produce Insulin was confirmed by adipogenesis differentiation capacity and expression of Oct4, Nanog, and Sox2. Insulin and Glucagon concentrations in Insulin-producing cells were determined by ELISA. The ability of Insulin-producing cells for the presence of MafA, Glut2, ENO1, and IGF-I receptor genes was determined by Western blotting analysis. The amounts of Glucokinase and Pyruvate Carboxylase activities were measured by Fluorometric and Colorimetric methods, respectively. Results: The un-differentiated cells showed a promising capacity to differentiate toward adipocytes. The adipose tissue mesenchymal stem cells revealed significantly elevated levels of Oct4, Nanog, and Sox2 compared to differentiated adipocytes. The cells that differentiated into Insulin-producing cells secreted considerably more Insulin and Glucagon than undifferentiated cells.

The polymorphism of insulin-like growth factor-1 receptor (IGF-1R) gene in meat-type Lambs in Turkey: I. Effect on growth traits and body measurements

As an important tyrosine kinase activator, insulin-like growth factor-1 receptor (IGF-1R) is activated by IGF-1 and IGF-2 and is a cell surface protein that functionally regulates cell growth and proliferation. This study was conducted to investigate the association between the previously determined single nucleotide polymorphism (SNP; g 0.195C > T) in the IGF-1R gene with growth and skeletal development traits of meat-type lambs. Different sheep breeds and their crosses were involved in the study, and data were collected from a total of 159 lambs (62 males and 97 females). The selected region in IGF-1R was analyzed using PCR-RFLP and the SNP g 0.195C > T substitution was detected. Subsequently, three genotypes were determined for this genetic variation: AA (0.197), AB (0.493), and BB (0.310). The associations between the identified genotypes and growth traits were evaluated for the period from birth to PS (pre-slaughter). Statistical analysis showed that IGF-1R genotypes had a significant effect on birth weight (P < 0.01) and daily weight gain on day 90- PS (P < 0.05). Similarly, the effects of genotype on body measurements, withers height and back height were significant (P < 0.05). In ultrasound measurements, longissimus dorsi (LD) muscle depth, skin thickness, and fat thickness were not significant. The data obtained in this study show that the variation of IGF-1R gene has a significant effect on the growth characteristics of lambs. Therefore, the use of this gene as a genetic marker in the production of lambs for slaughter may lead to more profitable production.

Mutations in GHR and IGF1R Genes as a Potential Reason for the Lack of Catch-Up Growth in SGA Children.

The aim of this review was to describe all of the mutations in the growth hormone receptor (GHR) and insulin-like growth factor-1 receptor (IGF1R) genes that have been discovered so far, and their possible impact on final body height, as well as their relationship with catch-up growth in children born small for gestational age (SGA). Mutations in the GHR gene were found to cause a body height below −2 SD, from the mean for sex and age, whereas the mutations in the IGF1R gene were associated with low body height and intrauterine growth restriction (IUGR), and with being born SGA. After birth, when the child’s growth is not restricted by the intrauterine environment, the infant may develop its developmental potential and experience catch-up growth, which makes it possible to catch up with peers born appropriate for gestational age (AGA). Despite this, catch-up growth does not apply to all, but only to about 85% of SGA children, and its mechanism is unknown. It is possible that SGA children who did not experience catch-up growth are carriers of mutations in the GHR and/or IGF1R genes

Genetic Polymorphisms of IGF1 and IGF1R Genes and Their Effects on Growth Traits in Hulun Buir Sheep.

The identification of candidate genes and genetic variations associated with growth traits is important for sheep breeding. Insulin like growth factor 1 (IGF1) and insulin like growth factor 1 receptor (IGF1R) are well-accepted candidate genes that affect animal growth and development. The current study attempted to assess the association between IGF1 and IGF1R genetic polymorphisms and growth traits in Hulun Buir sheep. To achieve this goal, we first identified three and ten single nucleotide polymorphisms (SNPs) in exons of IGF1 and IGF1R in Hulun Buir sheep and then constructed six haplotypes of IGF1R based on linkage disequilibrium, respectively. Association studies were performed between SNPs and haplotypes of IGF1 and IGF1R with twelve growth traits in a population encompassing 229 Hulun Buir sheep using a general linear model. Our result indicated three SNPs in IGF1 were significantly associated with four growth traits (p < 0.05). In IGF1R, three SNPs and two haplotype blocks were significantly associated with twelve growth traits (p < 0.05). The combined haplotype H5H5 and H5H6 in IGF1R showed the strong association with 12 superior growth traits in Hulun Buir sheep (p < 0.05). In conclusion, we identified SNPs and haplotype combinations associated with the growth traits, which provided genetic resources for marker-assisted selection (MAS) in Hulun Buir sheep breeding.

The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling.

This study underscores the possibility of the pharmacologic modulation of the ARID1A factor to downregulate protumorigenic IGF-1 activity in patients with postmenopausal breast cancer undergoing aromatase inhibitor treatment.

Gamma-Aminobutyric Acid (GABA) Promotes Growth in Zebrafish Larvae by Inducing IGF-1 Expression via GABAA and GABAB Receptors.

Insulin-like growth factor-1 (IGF-1) primarily increases the release of gamma-aminobutyric acid (GABA) in neurons; moreover, it is responsible for the promotion of longitudinal growth in children and adolescents. Therefore, in this study, we investigated whether exogenous GABA supplementation activates IGF-mediated growth performance. Zebrafish larvae treated with GABA at three days post fertilization (dpf) showed a significant increase in the total body length from 6 to 12 dpf through upregulation of growth-stimulating genes, including IGF-1, growth hormone-1 (GH-1), growth hormone receptor-1 (GHR-1), and cholecystokinin A (CCKA). In particular, at 9 dpf, GABA increased total body length from 3.60 ± 0.02 to 3.79 ± 0.03, 3.89 ± 0.02, and 3.92 ± 0.04 mm at concentrations of 6.25, 12.5, and 25 mM, and the effect of GABA at 25 mM was comparable to 4 mM β-glycerophosphate (GP)-treated larvae (3.98 ± 0.02 mm). Additionally, the highest concentration of GABA (50 mM) -induced death in 50% zebrafish larvae at 12 dpf. GABA also enhanced IGF-1 expression and secretion in preosteoblast MC3T3-E1 cells, concomitant with high levels of the IGF-1 receptor gene (IGF-1R). In zebrafish larvae, the GABA-induced growth rate was remarkably decreased in the presence of an IGF-1R inhibitor, picropodophyllin (PPP), which indicates that GABA-induced IGF-1 enhances growth rate via IGF-1R. Furthermore, we investigated the effect of GABA receptors on growth performance along with IGF-1 activation. Inhibitors of GABAA and GABAB receptors, namely bicuculline and CGP 46381, respectively, considerably inhibited GABA-induced growth rate in zebrafish larvae accompanied by a marked decrease in the expression of growth-stimulating genes, including IGF-1, GH-1, GHR-1, and CCKA, but not with an inhibitor of GABAC receptor, TPMPA. Additionally, IGF-1 and IGF-1R expression was impaired in bicuculline and CGP 46381-treated MC3T3-E1 cells, but not in the cells treated with TPMPA. Furthermore, treatment with bicuculline and CGP 46381 significantly downregulated GABA-induced IGF-1 release in MC3T3-E1 cells. These data indicate that GABA stimulates IGF-1 release via GABAA and GABAB receptors and leads to growth promotion performance via IGF-1R.

+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren's Syndrome: Potential Clinical and Pathogenetic Implications.

Background: Alterations of the insulin-like growth factor (IGF) pathway along with genetic variations of the IGF1 receptor (IGF1R) gene have been linked to the development of systemic autoimmunity, possibly through apoptosis induction. This study aims to investigate whether genetic variations of the IGF1R contribute to Sjögren’s syndrome (SS) pathogenesis and explores potential functional implications. Methods: DNA extracted from whole peripheral blood derived from 277 primary SS patients, complicated or not by lymphoma, and 337 Healthy controls (HC) was genotyped for the rs2229765 IGF1R polymorphism using the RFLP-PCR assay. Gene expression of IGF1R and IGF1 isoforms, caspases 1, 4, and 5, and inflammasome components NLRP3, ASC, IL1β, IL18, IL33, IGFBP3, and IGFBP6 were quantitated by RT-PCR in total RNA extracted from minor salivary gland biopsies (MSGs) of 50 SS patients and 13 sicca controls (SCs). In addition, IGF1R immunohistochemical (IHC) expression was assessed in formalin-fixed, paraffin-embedded MSG tissue sections derived from 10 SS patients and 5 SCs. Results: The prevalence of the A/A genotype of the rs2229765 IGF1R polymorphism was significantly higher in the anti-Ro/SSA positive SS population compared to healthy controls (24.8% vs. 10.7%, p = 0.001). Moreover, IGF1Rs at both mRNA and protein levels were reduced in SS-derived MSGs compared to SCs and were negatively associated with caspase 1 transcripts. The latter were positively correlated with NLRP3, ASC, and IL1β at the salivary gland tissue level. IGF1R expression in peripheral blood was negatively correlated with ESR and IgG serum levels and positively correlated with urine-specific gravity values. Conclusions: The rs2229765 IGF1R variant confers increased susceptibility for seropositive primary SS. Dampened IGF1R mRNA and protein expression in salivary gland tissues could be related to increased apoptosis and subsequently to the activation of inflammasome pathways.