Role of insulin receptor substrate-1 for diethylnitrosamine plus high-fat diet-induced hepatic tumorigenesis in mice

Metformin, an anti-type 2 diabetic agent that increases insulin sensitivity in target tissues, has been suggested having neuroprotective effects. Our previous data showed that metformin protects against high fat diet (HFD)-induced impairment in renal afferent nerves that express the transient receptor potential vanilloid 1 (TRPV1) channels, and prevents HFD-induced renal functional deterioration and hypertension. However, mechanisms of metformin-mediated neuroprotection are largely unknown. This study tests the hypothesis that HFD impairs insulin signaling in afferent renal nerves, which is prevented by metformin via the pathway of IRS-1-tyr, AMPK, and GLUT-1/3. Metformin (1 ng/kg, daily intrathecal injection via indwelled catheters to segments T8-L3 supplying the kidneys) or vehicle was given to rats fed a HFD or normal fat diet (Con) for 8 weeks. Immunohistochemical staining showed that insulin receptor substrate-1 phosphorylated with serine (p-IRS-1-ser), insulin receptor substrate-1 phosphorylated with tyrosine (p-IRS-1-tyr), phosphorylated AMP-activated protein kinase (p-AMPK), glucose transporter 1 (GLUT-1), and GLUT-3 were expressed in dorsal root ganglia (DRG). Levels of p-IRS-1-ser were increased by HFD but decreased by metformin in Con rats, and HFD-induced increases in p-IRS-1-ser were prevented by metformin. Levels of p-IRS-1-tyr, p-AMPK, and the trafficking of GLUT-1 and GLUT-3 from cytoplasma to cell membrane in DRG were decreased by HFD but increased by metformin in Con rats, and HFD-induced decreases in these parameters were prevented by metformin (p-IRS-1-tyr, Con: 0.23±0.02, Con+Met: 0.34±0.04, HFD: 0.14±0.02, HFD+Met: 0.22±0.03, p<0.05). Afferent renal nerve activity (ARNA) in response to insulin perfusion into the renal pelvis was decreased by HFD but enhanced by metformin in Con rats, and HFD-induced decreases in ARNA was prevented by metformin. Our data showed that HFD decreases insulin signaling in afferent renal nerves, which is prevented by metformin injected intrathecally to segments innervating kidneys. These data indicate that metformin may constitute neuroprotecitve effects via improving insulin signaling in afferent renal nerves via activation of the pathway of IRS-1-tyr, AMPK, and GLUT-1/3.

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Crucial role of insulin receptor substrate-2 in compensatory β-cell hyperplasia in response to high fat diet-induced insulin resistance

Diabetes Obesity and Metabolism ◽

10.1111/j.1463-1326.2008.00951.x ◽

2008 ◽

Vol 10 ◽

pp. 147-156 ◽

Cited By ~ 28

Author(s):

I. Takamoto ◽

Y. Terauchi ◽

N. Kubota ◽

M. Ohsugi ◽

K. Ueki ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

High Fat Diet ◽

Crucial Role ◽

Insulin Receptor Substrate ◽

High Fat ◽

Β Cell ◽

Cell Hyperplasia

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The role of glucokinase and insulin receptor substrate-2 in the proliferation of pancreatic beta cells induced by short-term high-fat diet feeding in mice

Metabolism ◽

10.1016/j.metabol.2018.03.010 ◽

2018 ◽

Vol 85 ◽

pp. 48-58 ◽

Cited By ~ 4

Author(s):

Naoyuki Kitao ◽

Akinobu Nakamura ◽

Hideaki Miyoshi ◽

Hiroshi Nomoto ◽

Kiyohiko Takahashi ◽

...

Keyword(s):

Insulin Receptor ◽

Beta Cells ◽

High Fat Diet ◽

Pancreatic Beta Cells ◽

Insulin Receptor Substrate ◽

High Fat ◽

Short Term

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

The International Journal of Biological Markers ◽

10.5301/jbm.5000159 ◽

2016 ◽

Vol 31 (1) ◽

pp. 68-72 ◽

Cited By ~ 3

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.

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The role of insulin receptor substrate 1 gene polymorphism Gly972Arg as a risk factor for ischemic stroke among Indonesian subjects

BMC Research Notes ◽

10.1186/s13104-018-3823-6 ◽

2018 ◽

Vol 11 (1) ◽

Author(s):

Syahrul ◽

Samekto Wibowo ◽

Sofia Mubarika Haryana ◽

Indwiani Astuti ◽

Fariz Nurwidya

Keyword(s):

Risk Factor ◽

Ischemic Stroke ◽

Gene Polymorphism ◽

Insulin Receptor ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1

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

Molecular Endocrinology ◽

10.1210/mend.16.3.0790 ◽

2002 ◽

Vol 16 (3) ◽

pp. 552-562 ◽

Cited By ~ 17

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.

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Role of p85 subunit of phosphatidylinositol-3-kinase as an adaptor molecule linking the insulin receptor to insulin receptor substrate 1

Molecular Endocrinology ◽

10.1210/me.9.4.435 ◽

1995 ◽

Vol 9 (4) ◽

pp. 435-442 ◽

Cited By ~ 6

Author(s):

V. Sanchez-Margalet

Keyword(s):

Insulin Receptor ◽

Insulin Receptor Substrate ◽

Phosphatidylinositol 3 Kinase ◽

Insulin Receptor Substrate 1 ◽

Adaptor Molecule ◽

Phosphatidylinositol 3

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

Molecular and Cellular Biology ◽

10.1128/mcb.23.21.7510-7524.2003 ◽

2003 ◽

Vol 23 (21) ◽

pp. 7510-7524 ◽

Cited By ~ 76

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.

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