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Receptor Substrate (receptor + substrate)

Distribution by Scientific Domains
Life Sciences58%
Medical Sciences41%

Kinds of Receptor Substrate

  • insulin receptor substrate
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    Selected Abstracts

    Exenatide prevents fat-induced insulin resistance and raises adiponectin expression and plasma levels

    DIABETES OBESITY & METABOLISM, Issue 10 2008
    L. Li
    Background:, Exenatide (exendin-4) can reduce blood glucose levels, increase insulin secretion and improve insulin sensitivity through mechanisms that are not completely understood. Methods:, In the present study, we examined the effects of exenatide treatment on glucose tolerance (intravenous glucose tolerance test), insulin sensitivity (euglycaemic,hyperinsulinaemic clamps), insulin signalling (insulin receptor substrate 1 tyrosine phosphorylation) and adipocytokine levels (visfatin and adiponectin) in high fat,fed rats. Results:, Administration of exenatide (0.5 or 2.0 ,g/kg twice daily × 6 weeks) prevented high-fat diet (HFD),induced increases in body weight, plasma free fatty acids, triglycerides and total cholesterol. Exenatide also prevented HFD-induced deterioration in peripheral and hepatic insulin sensitivity, insulin clearance, glucose tolerance and decreased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in fat and skeletal muscles. Interestingly, plasma visfatin levels decreased in exenatide-treated rats, whereas expression and plasma levels of adiponectin increased. Conclusions:, These results indicate that chronic exenatide treatment enhances insulin sensitivity and protects against high fat,induced insulin resistance. [source]

    Molecular mechanisms of insulin resistance

    DIABETIC MEDICINE, Issue 6 2005
    S. Schinner
    Abstract Currently, we observe an epidemic expansion of diabetes mellitus. In subjects with Type 2 diabetes the resistance of fat, muscle and liver to insulin is the central pathophysiological event in the development of this disease. Genetic and environmental factors play a major role in this process, although the precise pathogenesis of insulin resistance and Type 2 diabetes is still largely unknown. However, recent studies have contributed to a deeper understanding of the molecular mechanisms underlying this process. In this review we therefore summarize the current developments in understanding the pathophysiological process of insulin resistance and Type 2 diabetes. Among the many molecules involved in the intracellular processing of the signal provided by insulin, insulin receptor substrate (IRS)-2, the protein kinase B (PKB)-, isoform and the forkhead transcription factor Foxo1a (FKHR) are of particular interest in this context as recent data have provided strong evidence that dysfunction of these proteins results in insulin resistance in-vivo. Furthermore, we have now increasing evidence that the adipose tissue not only produces free fatty acids that contribute to insulin resistance, but also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. The identification of the molecular pathophysiological mechanisms of insulin resistance and Type 2 diabetes is essential for the development of novel and more effective therapies to better treat our patients with insulin resistance and Type 2 diabetes. [source]

    Molecular insights into insulin action and secretion

    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2002
    C. J. Rhodes
    Abstract Tightly co-ordinated control of both insulin action and secretion is required in order to maintain glucose homeostasis. Gene knockout experiments have helped to define key signalling molecules that affect insulin action, including insulin and insulin-like growth factor-1 (IGF-1) receptors, insulin receptor substrate (IRS) proteins and various downstream effector proteins. ,-cell function is also a tightly regulated process, with numerous factors (including certain signalling molecules) having an impact on insulin production, insulin secretion and ,-cell mass. While signalling molecules play important roles in insulin action and secretion under normal circumstances, abnormal insulin signalling in muscle, adipose tissue, liver and pancreas leads to insulin resistance and ,-cell dysfunction. In particular, the signalling protein IRS-2 may have a central role in linking these abnormalities, although other factors are likely to be involved. [source]

    Ternary complex formation of EphA4, FGFR and FRS2, plays an important role in the proliferation of embryonic neural stem/progenitor cells

    GENES TO CELLS, Issue 3 2010
    Takahiro Sawada
    EphA4 belongs to a superfamily of receptor tyrosine kinases and interacts with several molecules including fibroblast growth factor receptors (FGFRs) as we reported earlier. Several receptor tyrosine kinases, FGFRs, Trks, Alk and Ret, are currently known to transduce a signal through a docking protein, fibroblast growth factor receptor substrate 2, (FRS2,). However, nothing has been reported about the interaction of FRS2, with EphA4. Using the yeast two-hybrid system and the in vitro binding and kinase assays, we found that the mid-kinase region of EphA4 directly interacts with the FRS2, PTB domain upon tyrosine phosphorylation of the EphA4 juxtamembrane (JM) domain and EphA4 directly phosphorylates FRS2,. We also found that the FRS2, PTB domain and the amino-terminal region of EphA4 bind to the amino- and carboxy-terminal regions of the FGFR JM domain, respectively, suggesting that FRS2, and EphA4 interact with FGFR simultaneously. Furthermore, a kinase-dead EphA4 mutant that constitutively binds to FGFR functions as a dominant-negative molecule for signaling through both EphA4 and FGFR, and so does the truncated FRS2, lacking multiple tyrosine phosphorylation sites. These dominant-negative mutants similarly inhibit the ligand-dependent proliferation of the mouse embryonic neural stem/progenitor cells. These results suggest the formation of a ternary complex comprising EphA4, FGFR and FRS2,. The signaling complex appears to integrate the input from FGFR and EphA4, and release the output signal through FRS2,. [source]

    Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver

    HEPATOLOGY RESEARCH, Issue 9 2008
    Lisa Longato
    Aim:, Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression. Methods:, Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT),Frizzled (FZD) pathways, given their known roles in HCC. Results:, In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl,asparaginyl , hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC. Conclusion:, In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation. [source]

    Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology,

    JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2007
    Marianna Sadagurski
    Insulin receptor substrate (IRS) proteins play a central role in insulin signaling. Previously we have demonstrated that insulin is essential for normal skin development and function. In the present study we investigated the involvement of the IRS-1 and IRS-2 proteins in skin physiology and in mediating insulin action in skin. For this purpose we have investigated the effects of inactivation of each of the IRSs on skin, studying skin sections and primary skin cells derived from IRS-1 or IRS-2 null mice. We have demonstrated that while the skin of the IRS-2 null mice appeared normal, the skin of the IRS-1 null mice was thinner and translucent. Histological analysis revealed that the thinning of the IRS-1 null skin was a consequence of the thinning of the spinous compartment, consisting of fewer layers. Proliferation of the IRS-1 and IRS-2 null skin epidermal cells was normal. However, the differentiation process of the IRS-1 skin and skin cells was impaired. There was a marked decrease in the induction of the expression of K1, the marker of advanced stages of skin differentiation. In contrary, IRS-2 inactivation had no effects on skin differentiation. In conclusion, we have shown for the first time that IRS-1 but not IRS-2 has an effect on skin formation and development, being one of the main activators of the differentiation process in skin keratinocytes. Furthermore, we suggest that IRS-1 and IRS-2 have distinct roles in skin physiology. J. Cell. Physiol. 213: 519,527, 2007. © 2007 Wiley-Liss, Inc. [source]

    Acute physical exercise reverses S -nitrosation of the insulin receptor, insulin receptor substrate 1 and protein kinase B/Akt in diet-induced obese Wistar rats

    THE JOURNAL OF PHYSIOLOGY, Issue 2 2008
    José R. Pauli
    Early evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance. Here, we investigated whether this insulin resistance, mediated by S -nitrosation of proteins involved in early steps of the insulin signal transduction pathway, could be reversed by acute physical exercise. Rats on a high-fat diet were subjected to swimming for two 3 h-long bouts, separated by a 45 min rest period. Two or 16 h after the exercise protocol the rats were killed and proteins from the insulin signalling pathway were analysed by immunoprecipitation and immunoblotting. We demonstrated that a high-fat diet led to an increase in the iNOS protein level and S -nitrosation of insulin receptor , (IR,), insulin receptor substrate 1 (IRS1) and Akt. Interestingly, an acute bout of exercise reduced iNOS expression and S -nitrosation of proteins involved in the early steps of insulin action, and improved insulin sensitivity in diet-induced obesity rats. Furthermore, administration of GSNO (NO donor) prevents this improvement in insulin action and the use of an inhibitor of iNOS (l- N6 -(1-iminoethyl)lysine; l -NIL) simulates the effects of exercise on insulin action, insulin signalling and S -nitrosation of IR,, IRS1 and Akt. In summary, a single bout of exercise reverses insulin sensitivity in diet-induced obese rats by improving the insulin signalling pathway, in parallel with a decrease in iNOS expression and in the S -nitrosation of IR/IRS1/Akt. The decrease in iNOS protein expression in the muscle of diet-induced obese rats after an acute bout of exercise was accompanied by an increase in AMP-activated protein kinase (AMPK) activity. These results provide new insights into the mechanism by which exercise restores insulin sensitivity. [source]

    The isoflavonoid aglycone-rich fractions of Chungkookjang, fermented unsalted soybeans, enhance insulin signaling and peroxisome proliferator-activated receptor-, activity in vitro

    BIOFACTORS, Issue 4 2006
    Dae Young Kwon
    Abstract We investigated anti-diabetic candidates and their mechanisms from the fractions of Chungkookjang (CKJ), a traditional fermented unsalted soybean, by investigating insulin signaling, peroxisome proliferator-activated receptor (PPAR)-, activity and glucose-stimulated insulin secretion, in vitro. Cooked soybeans (CSB) and CKJ, fermented predominantly with Bacillus subtilis, were extracted by 70% EtOH followed by an XAD-4 column chromatography with a serial mixture of solvents comprised of MeOH and water. During fermentation, the contents of isoflavonoid aglycones were elevated, and the fractions enriched with aglycones enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. This increase in glucose uptake resulted from stimulating a translocation of the glucose transporter (GLUT)-4 into the plasma membrane through the phosphorylation of insulin receptor substrate (IRS)-1 and Akt. Especially, daidzein enriched fractions elevated insulin-stimulated glucose uptake by acting as PPAR-, agonist up to levels exhibited when 10 nM insulin is administered. Fractions containing small peptides with low polarity in CKJ slightly increased glucose-stimulated insulin secretion. The data suggest that an increase in isoflavonoid aglycones in CKJ, in comparison to CSB, enhances glucose utilization via activating insulin signaling and stimulates PPAR-, activity in adipocytes. In addition, CKJ contains small peptides improving glucose-stimulated insulin secretion in insulinoma cells. Overall, CKJ is superior to CSB in anti-diabetic action. [source]

    IMPLICATIONS OF CROSS-TALK BETWEEN TUMOUR NECROSIS FACTOR AND INSULIN-LIKE GROWTH FACTOR-1 SIGNALLING IN SKELETAL MUSCLE

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2008
    Miranda D Grounds
    SUMMARY 1Inflammation, particularly the pro-inflammatory cytokine tumour necrosis factor (TNF), increases necrosis of skeletal muscle. Depletion of inflammatory cells, such as neutrophils, cromolyn blockade of mast cell degranulation or pharmacological blockade of TNF reduces necrosis of dystrophic myofibres in the mdx mouse model of the lethal childhood disease Duchenne muscular dystrophy (DMD). 2Insulin-like growth factor-1 (IGF-1) is a very important cytokine for maintenance of skeletal muscle mass and the transgenic overexpression of IGF-1 within muscle cells reduces necrosis of dystrophic myofibres in mdx mice. Thus, IGF-1 usually has the opposite effect to TNF. 3Activation of TNF signalling via the c-Jun N-terminal kinase (JNK) can inhibit IGF-1 signalling by phosphorylation and conformational changes in insulin receptor substrate (IRS)-1 downstream of the IGF-1 receptor. Such silencing of IGF-1 signalling in situations where inflammatory cytokines are elevated has many implications for skeletal muscle in vivo. 4The basis for these interactions between TNF and IGF-1 is discussed with specific reference to clinical consequences for myofibre necrosis in DMD and also for the wasting (atrophy) of skeletal muscles that occurs in very old people and in cachexia associated with inflammatory disorders. [source]

    Phosphatidylinositol-3-OH kinase regulatory subunits are differentially expressed during development of the rat cerebellum

    DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2001
    José L. Trejo
    Abstract Recent evidence implicates a central role for PI3K signalling in mediating cell survival during the process of neuronal differentiation. Although PI3K activity is stimulated by a wide range of growth factors and cytokines in different cell lines and tissues, activation of this pathway by insulin-like growth factor I (IGF-I) most likely represents the main survival signal during neuronal differentiation. IGF-I is highly expressed during development of the central nervous system, and thus is a critical factor for the development and maturation of the cerebellum. Upon ligand binding, the IGF-I receptor phosphorylates tyrosine residues in SHC and insulin receptor substrates (IRSs) initiating two main signalling cascades, the MAP kinase and the phosphatidylinositol 3-kinase (PI3K) pathways. Activated PI3K is composed of a catalytic subunit (p110, or ,) associated with one of a large family of regulatory subunits (p85,, p85,, p55,, p55,, and p50,). To evaluate the contributions of these various regulatory subunits to neuronal differentiation, we have used antibodies specific for each of the PI3K subunits. Using these antisera, we now demonstrate that PI3K subunits are differentially regulated in cerebellar development, and that the expression level of the p55, regulatory subunit reaches a maximum during postnatal development, decreasing thereafter to low levels in the adult cerebellum. Furthermore, our studies reveal that the distribution of the various PI3K regulatory subunits varies during development of the cerebellum. Interestingly, p55, is expressed in both glial and neuronal cells; moreover, in Purkinje neurones, this subunit colocalises with the IGF-IR. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 39,50, 2001 [source]