Insulin signalling: the role of insulin receptor substrate 1

1994 ◽  
Vol 4 (4) ◽  
pp. 115-119 ◽  
Author(s):  
Susanne R. Keller ◽  
Gustav E. Lienhard
Keyword(s):  
Insulin Receptor ◽  
Insulin Signalling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

scholarly journals Gly972Arg Variant of Insulin Receptor Substrate 1 Gene and Colorectal Cancer Risk in Overweight/Obese Subjects

2016 ◽  
Vol 31 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Touraj Mahmoudi ◽  
Keivan Majidzadeh-A ◽  
Khatoon Karimi ◽  
Hamid Farahani ◽  
Reza Dabiri ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Insulin Receptor ◽  
Case Control Study ◽  
Insulin Receptor Substrate ◽  
Protective Effects ◽  
Insulin Receptor Substrate 1 ◽  
Pcr Rflp ◽  
Obese Subjects ◽  
Control Study

Background Given the major role of obesity and insulin resistance (IR) in colorectal cancer (CRC), we investigated whether genetic variants in ghrelin ( GHRL), resistin ( RETN) and insulin receptor substrate 1 ( IRS1) were associated with CRC risk. Methods This study was conducted as a case-control study, and 750 subjects, including 438 controls and 312 patients with CRC, were enrolled and genotyped using the PCR-RFLP method. Results No significant differences were observed for GHRL (rs696217), RETN (rs3745367) and IRS1 (rs1801278, Gly972Arg or G972R) gene variants between the cases and controls. However, the IRS1 G972R R allele compared with the G allele and the G972R RR+GR genotype compared with the GG genotype appeared to be markers of decreased CRC susceptibility in the overweight/obese subjects (p = 0.024; odds ratio [OR] = 0.42, 95% confidence interval [95% CI], 0.20-0.91; and p = 0.048; OR = 0.42, 95% CI, 0.17-0.99, respectively). Furthermore, the R allele and RR+GR genotype were also associated with decreased risks for obesity in the patients with CRC (p = 0.007; OR = 0.35, 95% CI, 0.15-0.77; and p = 0.015; OR = 0.35, 95% CI, 0.15-0.72, respectively). Conclusions In accordance with previous studies, our findings suggest that the IRS1 G972R R allele and RR+GR genotype have protective effects for CRC in overweight/obese patients and for obesity in patients with CRC. Nevertheless, further studies are required to confirm these findings.

14-3-3 Facilitates Insulin-Stimulated Intracellular Trafficking of Insulin Receptor Substrate 1

2002 ◽  
Vol 16 (3) ◽  
pp. 552-562 ◽  
Author(s):  
Xiaoqin Xiang ◽  
Mingsheng Yuan ◽  
Ying Song ◽  
Neil Ruderman ◽  
Rong Wen ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Intracellular Trafficking ◽  
High Speed ◽  
Insulin Treatment ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Integral Role ◽  
Endogenous Proteins

Abstract The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. These findings strongly suggest that 14-3-3 participates in the intracellular trafficking of IRS-1 by promoting the displacement of serine-phosphorylated IRS-1 from particular structures. They also suggest that 14-3-3 proteins could play an integral role in the process of insulin desensitization.

scholarly journals A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration

2005 ◽  
Vol 392 (2) ◽  
pp. 345-352 ◽  
Author(s):  
Antonio J. Ruiz-Alcaraz ◽  
Hui-Kang Liu ◽  
Daniel J. Cuthbertson ◽  
Edward J. Mcmanus ◽  
Simeen Akhtar ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signalling ◽  
Insulin Injection ◽  
Underlying Mechanism ◽  
Type Ii Diabetes Mellitus ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Insulin Receptor Tyrosine Kinase ◽  
Cell Culture Systems ◽  
Or Gene

Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.

scholarly journals Role of the Insulin-Like Growth Factor I/Insulin Receptor Substrate 1 Axis in Rad51 Trafficking and DNA Repair by Homologous Recombination

2003 ◽  
Vol 23 (21) ◽  
pp. 7510-7524 ◽  
Author(s):  
Joanna Trojanek ◽  
Thu Ho ◽  
Luis Del Valle ◽  
Michal Nowicki ◽  
Jin Ying Wang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Growth Factor ◽  
Homologous Recombination ◽  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Insulin Like Growth Factor ◽  
Insulin Receptor Substrate 1 ◽  
Factor I ◽  
Igf I

ABSTRACT The receptor for insulin-like growth factor I (IGF-IR) controls normal and pathological growth of cells. DNA repair pathways represent an unexplored target through which the IGF-IR signaling system might support pathological growth leading to cellular transformation. However, this study demonstrates that IGF-I stimulation supports homologous recombination-directed DNA repair (HRR). This effect involves an interaction between Rad51 and the major IGF-IR signaling molecule, insulin receptor substrate 1 (IRS-1). The binding occurs within the cytoplasm, engages the N-terminal domain of IRS-1, and is attenuated by IGF-I-mediated IRS-1 tyrosine phosphorylation. In the absence of IGF-I stimulation, or if mutated IGF-IR fails to phosphorylate IRS-1, localization of Rad51 to the sites of damaged DNA is diminished. These results point to a direct role of IRS-1 in HRR and suggest a novel role for the IGF-IR/IRS-1 axis in supporting the stability of the genome.

scholarly journals Role of Insulin Receptor Substrate-1 and pp60 in the Regulation of Insulin-induced Glucose Transport and GLUT4 Translocation in Primary Adipocytes

1997 ◽  
Vol 272 (41) ◽  
pp. 25839-25844 ◽  
Author(s):  
Yasushi Kaburagi ◽  
Shinobu Satoh ◽  
Hiroyuki Tamemoto ◽  
Ritsuko Yamamoto-Honda ◽  
Kazuyuki Tobe ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Receptor Substrate ◽  
Glut4 Translocation ◽  
Insulin Receptor Substrate 1

scholarly journals Essential Role of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 in Adipocyte Differentiation

2001 ◽  
Vol 21 (7) ◽  
pp. 2521-2532 ◽  
Author(s):  
Hiroshi Miki ◽  
Toshimasa Yamauchi ◽  
Ryo Suzuki ◽  
Kajuro Komeda ◽  
Atsuko Tsuchida ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Adipocyte Differentiation ◽  
Kinase Inhibitor ◽  
Binding Protein ◽  
Insulin Receptor Substrate ◽  
Wild Type ◽  
Double Knockout ◽  
Insulin Receptor Substrate 1 ◽  
Fatty Acid Binding

ABSTRACT To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1−/−), IRS-2 deficient (IRS-2−/−), and IRS-1 IRS-2 double deficient (IRS-1−/−IRS-2−/−), from mouse embryos of the corresponding genotypes. The abilities of IRS-1−/− cells and IRS-2−/− cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1−/− IRS-2−/− cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) is severely decreased in IRS-1−/−IRS-2−/− cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1−/−IRS-2−/− cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1−/−IRS-2−/− cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPα and PPARγ, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1−/− IRS-2−/− double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPα and PPARγ expression and adipocyte differentiation.

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