Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1

Tamemoto, Hiroyuki; Kadowaki, Takashi; Tobe, Kazuyuki; Yagi, Takeshi; Sakura, Hiroshi; Hayakawa, Tadao; Terauchi, Yasuo; Ueki, Kohjiro; Kaburagi, Yasushi; Satoh, Shinobu; Sekihara, Hisahiko; Yoshioka, Shinji; Horikoshi, Hiroyoshi; Furuta, Yasuhide; Ikawa, Yoji; Kasuga, Masato; Yazaki, Yoshio; Aizawa, Shinichi

doi:10.1038/372182a0

Cited by 958 publications

(678 citation statements)

References 27 publications

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“…Thus, our result would not constitute a contradiction with the concept of that report, although it is not clear how much insulin treatment could be directly involved in acting on hepatic insulin signaling. We are currently investigating the effect of hepatic insulin signaling on the development of NASH and HCC in insulin receptor substrate‐1 knockout mice 28 on a high‐fat diet, which represents impaired insulin action in the liver and severe hyperinsulinemia, and are dramatically spared from liver steatosis (Nakamura A, Tajima K, Khadbaatar Z, Terauchi Y, unpublished observation, 2011). This mouse model should provide a clue to the associations between hyperinsulinemia, hepatic insulin actions and the development of NASH.…”

Section: Discussionmentioning

confidence: 99%

Impact of glucose tolerance on the severity of non-alcoholic steatohepatitis

Nakamura¹,

Yoneda

Fujita

et al. 2011

Journal of Diabetes Investigation

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Aims/Introduction: We investigated the relationship between non‐alcoholic steatohepatitis (NASH) and different stages of fasting plasma glucose (FPG) concentrations, and the association between factors related to glucose tolerance and severity of NASH.Materials and Methods: A total of 147 patients with non‐alcoholic fatty liver disease (NAFLD) who had undergone a liver biopsy were divided into three groups: a normal glucose tolerance (NGT) group, an impaired fasting glucose (IFG) group and a diabetes (DM) group. In addition, to investigate progression factors of NASH in the DM group, we divided the diabetic patients into two groups: a group with NASH (NASH group) and a group without NASH, the simple steatosis (SS) group. The relationship between the patients’ clinical parameters and the severity of NAFLD/NASH were analyzed.Results: In the patients with liver biopsies, the IFG group had the highest percentage of NASH. There was no correlation between FPG and either total NAFLD activity scores (NAS) or staging of NASH, but the fasting serum insulin was correlated significantly with both, even after adjusting for age, sex and body mass index. Among the diabetic patients, the fasting insulin values in the NASH group were significantly higher than in the SS group, but there were no differences in FPG or A1c values between the two groups. The fasting serum insulin correlated significantly with total NAS, but the FPG and A1c values did not.Conclusions: A high percentage of the IFG group developed NASH. Hyperinsulinemia, but not hyperglycemia, was associated with severity of NASH. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00134.x, 2011)

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Section: Discussionmentioning

confidence: 99%

Impact of glucose tolerance on the severity of non-alcoholic steatohepatitis

Nakamura¹,

Yoneda

Fujita

et al. 2011

Journal of Diabetes Investigation

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“…Mice null for IRS-1 and IRS-2 exhibit growth retardation and insulin resistance (Araki et al, 1994;Tamemoto et al, 1994;Withers et al, 1998), whereas IRS-4 knockouts have mild defects in growth, reproduction and glucose homoestasis (Liu et al, 1999;Fantin et al, 2000). IRS-4 expression increases cellular proliferation (White, 1998;Fantin et al, 1999), and may be implicated in cellular differentiation (Giovannone et al, 2000;Tseng et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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Using mass spectrometric analysis insulin receptor substrate 4 (IRS-4) has been identified as a novel adenovirus 5 early region 1A (Ad5E1A)-binding protein. IRS-4 interacts with both the transcriptional activation domain (conserved region 3) and the N-terminal region of Ad5E1A13S. Prolonged expression of Ad5E1A13S is required for the observed dramatic increase in the levels of IRS-4 mRNA and protein in Ad5E1-transformed human cell lines. Once expressed, as well as binding to E1A and the insulin receptor, IRS-4 remains tyrosine phosphorylated and constitutively associates with the regulatory p85 subunit of phosphoinositide 3 kinase, resulting in the phosphorylation of Akt (causing activation) and GSK-3b (causing inhibition). Reducing IRS-4 expression using small interfering RNA (siRNA) in established Ad5E1A-expressing cell lines decreases the activation of Akt and cellular proliferation. During Ad5 infection, IRS-4 is not expressed. However, Ad5E1A associates with IRS-1, increasing Akt and GSK-3b phosphorylation and tyrosine phosphorylation of IRS-1 itself. We conclude that the association and altered regulation of IRS proteins by Ad5E1A contribute to the adenovirus-transformed phenotype and modulates viral infection in an Akt-dependent manner.

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“…Although IRS-1 declines following the maturation of thymocytes into peripheral blood T cells (22), nothing is known about the expression of IRS-2 during myelopoiesis. IRS-1 knockout mice do not have major metabolic impairments (34,35), which suggested there was another high m.w. docking molecule that responds to insulin and IGF-I.…”

Section: Discussionmentioning

confidence: 99%

Developmental Expression of Insulin Receptor Substrate-2 During Dimethylsulfoxide-Induced Differentiation of Human HL-60 Cells

Schacher¹,

VanHoy²,

Liu

et al. 2000

The Journal of Immunology

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Insulin receptor substrate-2 (IRS-2) is phosphorylated on tyrosine by a number of cytokine receptors and is implicated in the activation of phosphatidylinositol 3′-kinase (PI3-kinase). Here, we demonstrate that induction of granulocytic differentiation of human promyeloid HL-60 cells leads to an increase in the amount of IRS-2 that is phosphorylated in response to insulin-like growth factor (IGF)-I. Although PI3-kinase is often activated following interaction with IRS-1, we could not detect IRS-1 protein, IRS-1 mRNA, or IRS-1-precipitable PI3-kinase enzymatic activity. However, PI3-kinase activity that was coimmunoprecipitated with either anti-phosphotyrosine or anti-IRS-2 following IGF-I stimulation was increased 100-fold. Heightened tyrosine phosphorylation of IRS-2 during granulocytic differentiation was not caused by an increase in expression of the tyrosine kinase IGF-I receptor, as measured by the amount of both the α- and β-subunits. Instead, immunoblotting experiments with an Ab to IRS-2 revealed that induction of granulocytic differentiation caused a large increase in IRS-2, and this occurred in the absence of detectable IRS-1 protein. These IRS-2-positive cells could not differentiate into more mature myeloid cells in serum-free medium unless IGF-I was added. These data are consistent with a model of granulocytic differentiation that requires at least two signals, the first of which leads to an increase in the cytoplasmic pool of IRS-2 protein and a second molecule that acts to tyrosine phosphorylate IRS-2 and enhance granulocytic differentiation.

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Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1

Cited by 958 publications

References 27 publications

Impact of glucose tolerance on the severity of non-alcoholic steatohepatitis

Impact of glucose tolerance on the severity of non-alcoholic steatohepatitis

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

Developmental Expression of Insulin Receptor Substrate-2 During Dimethylsulfoxide-Induced Differentiation of Human HL-60 Cells

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