Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes

Shirakami, Atsuhisa; Toyonaga, Tetsushi; Tsuruzoe, Kaku; Shirotani, Tetsuya; Matsumoto, Kenshi; Yoshizato, Kazuaki; Kawashima, Junji; Hirashima, Yoshifumi; Miyamura, Nobuhiro; Kahn, C. Ronald; Araki, Eiichi

doi:10.1677/joe.0.1740309

Cited by 47 publications

(33 citation statements)

References 45 publications

(33 reference statements)

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“…3D and E). This is consistent with data for IRS-1 Ϫ/Ϫ mouse embryonic fibroblasts and for skeletal muscle of IRS-1 ϩ/Ϫ mice (47,52). A recent study using muscle-specific IRS-1-or IRS-2-knockout mice suggested that IRS-1 has a more important role than IRS-2 in skeletal muscle with respect to muscle mass and Akt signaling (53).…”

Section: Discussionsupporting

confidence: 89%

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C1-Ten Is a Protein Tyrosine Phosphatase of Insulin Receptor Substrate 1 (IRS-1), Regulating IRS-1 Stability and Muscle Atrophy

Koh

Lee

Yang

et al. 2013

Molecular and Cellular Biology

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f Muscle atrophy occurs under various catabolic conditions, including insulin deficiency, insulin resistance, or increased levels of glucocorticoids. This results from reduced levels of insulin receptor substrate 1 (IRS-1), leading to decreased phosphatidylinositol 3-kinase activity and thereby activation of FoxO transcription factors. However, the precise mechanism of reduced IRS-1 under a catabolic condition is unknown. Here, we report that C1-Ten is a novel protein tyrosine phosphatase (PTPase) of IRS-1 that acts as a mediator to reduce IRS-1 under a catabolic condition, resulting in muscle atrophy. C1-Ten preferentially dephosphorylated Y612 of IRS-1, which accelerated IRS-1 degradation. These findings suggest a novel type of IRS-1 degradation mechanism which is dependent on C1-Ten and extends our understanding of the molecular mechanism of muscle atrophy under catabolic conditions. C1-Ten expression is increased by catabolic glucocorticoid and decreased by anabolic insulin. Reflecting these hormonal regulations, the muscle C1-Ten is upregulated in atrophy but downregulated in hypertrophy. This reveals a previously unidentified role of C1-Ten as a relevant PTPase contributing to skeletal muscle atrophy.

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Section: Discussionsupporting

confidence: 89%

“…However, it is enough if there are other minor defects in insulin signaling (46,47). Thus, upregulation of C1-Ten in combination with the catabolic condition, such as an increase in glucocorticoids or insulin deficiency, exacerbates catabolic states through IRS-1 reduction.…”

Section: Discussionmentioning

confidence: 99%

C1-Ten Is a Protein Tyrosine Phosphatase of Insulin Receptor Substrate 1 (IRS-1), Regulating IRS-1 Stability and Muscle Atrophy

Koh

Lee

Yang

et al. 2013

Molecular and Cellular Biology

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“…More importantly, a high proportion of mice with a combined heterozygous defect in IR, IRS-1 and/or IRS-2 have diabetes, even though they have 50% of the normal concentrations of these molecules (Bruning et al 1997, Kido et al 2000. We also recently reported that the expression of IR, IRS-1 and IRS-2 was significantly decreased in obese IRS-1 heterozygous defective mice (Shirakami et al 2002). These results suggest that not only the absence but also a decrease in IRS-1 and IRS-2 protein may contribute to the pathogenesis or progression of diabetes.…”

Section: Introductionmentioning

confidence: 87%

Insulin down-regulates insulin receptor substrate-2 expression through the phosphatidylinositol 3-kinase/Akt pathway

Hirashima

Tsuruzoe

Kodama³

et al. 2003

Journal of Endocrinology

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Insulin receptor substrate (IRS)-1 and IRS-2 are the major substrates that mediate insulin action. Insulin itself regulates the expression of the IRS protein in the liver, but the underlying mechanisms of IRS-1 and IRS-2 regulation are not fully understood. Here we report that insulin suppressed the expression of both IRS-1 and IRS-2 proteins in Fao hepatoma cells. The decrease in IRS-1 protein occurred via proteasomal degradation without any change in IRS-1 mRNA, whereas the insulin-induced suppression of IRS-2 protein was associated with a parallel decrease in IRS-2 mRNA without changing IRS-2 mRNA half-life. The insulin-induced suppression of IRS-2 mRNA and protein was blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, LY294002, but not by the MAP kinase-ERK kinase (MEK) inhibitor, PD098059. Inhibition of Akt by overexpression of dominant-negative Akt also caused complete attenuation of the insulin-induced decrease in IRS-2 protein and partial attenuation of its mRNA down-regulation. Some nuclear proteins bound to the insulin response element (IRE) sequence on the IRS-2 gene in an insulindependent manner in vitro, and the binding was also blocked by the PI 3-kinase inhibitor. Reporter gene assay showed that insulin suppressed the activity of both human and rat IRS-2 gene promoters through the IRE in a PI 3-kinase-dependent manner. Our results indicate that insulin regulates IRS-1 and IRS-2 through different mechanisms and that insulin represses IRS-2 gene expression via a PI 3-kinase/Akt pathway.

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“…Inflammation causes deregulation of the IRS, as reviewed [7,8], with consequences in activation of the phosphatidylinositol 3-kinase/Akt pathway, which is essential for insulin-stimulated glucose transport [9]. However, partial inhibition of IRS function is not sufficient to have a major effect on insulin-induced glucose transport, since insulin action is normal in Irs1 +/− mice [10] or in mice with a partial knockdown of Irs1 in skeletal muscle [11]. In accordance, it has recently been established by studying various in vitro and in vivo insulinresistant models that the most deleterious defects in insulin action could also occur independently of IRS proteins [3].…”

Section: Introductionmentioning

confidence: 99%

Involvement of TNF-α in abnormal adipocyte and muscle sortilin expression in obese mice and humans

et al. 2009

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Aims/hypothesis Insulin resistance is caused by numerous factors including inflammation. It is characterised by defective insulin stimulation of adipocyte and muscle glucose transport, which requires the glucose transporter GLUT4 translocation towards the plasma membrane. Defects in insulin signalling can cause insulin resistance, but alterations in GLUT4 trafficking could also play a role. Our goal was to determine whether proteins controlling GLUT4 trafficking are altered in insulin resistance linked to obesity.Methods Using real-time RT-PCR, we searched for selected transcripts that were differentially expressed in adipose tissue and muscle in obese mice and humans. Using various adipocyte culture models and in vivo mice treatment, we searched for the involvement of TNF-α in these alterations in obesity.Results Sortilin mRNA and protein were downregulated in adipose tissue from obese db/db and ob/ob mice, and also in muscle. Importantly, sortilin mRNA was also decreased in morbidly obese human diabetic patients. Sortilin and TNF-α (also known as TNF) mRNA levels were inversely correlated in mice and human adipose tissues. TNF-α decreased sortilin mRNA and protein levels in cultured mouse and human adipocytes, an effect partly prevented by the peroxisome proliferator-activated receptor γ activator rosiglitazone. TNF-α also inhibited adipocyte and muscle sortilin mRNA when injected to mice. Conclusions/interpretation Sortilin, an essential player in adipocyte and muscle glucose metabolism through the control of GLUT4 localisation, is downregulated in obesity and TNF-α is likely to be involved in this defect. Chronic low-grade inflammation in obesity could thus contribute to insulin resistance by modulating proteins that control GLUT4 trafficking.

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Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes

Cited by 47 publications

References 45 publications

C1-Ten Is a Protein Tyrosine Phosphatase of Insulin Receptor Substrate 1 (IRS-1), Regulating IRS-1 Stability and Muscle Atrophy

C1-Ten Is a Protein Tyrosine Phosphatase of Insulin Receptor Substrate 1 (IRS-1), Regulating IRS-1 Stability and Muscle Atrophy

Insulin down-regulates insulin receptor substrate-2 expression through the phosphatidylinositol 3-kinase/Akt pathway

Involvement of TNF-α in abnormal adipocyte and muscle sortilin expression in obese mice and humans

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