scholarly journals Caffeine modulates phosphorylation of insulin receptor substrate-1 and impairs insulin signal transduction in rat skeletal muscle

2011 ◽  
Vol 111 (6) ◽  
pp. 1629-1636 ◽  
Author(s):  
Tatsuro Egawa ◽  
Satoshi Tsuda ◽  
Xiao Ma ◽  
Taku Hamada ◽  
Tatsuya Hayashi
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Dependent Manner ◽  
Insulin Signal Transduction ◽  
Physiological Dose

Caffeine decreases insulin sensitivity and insulin-stimulated glucose transport in skeletal muscle; however, the precise mechanism responsible for this deleterious effect is not understood fully. We investigated the effects of incubation with caffeine on insulin signaling in rat epitrochlearis muscle. Caffeine (≥1 mM, ≥15 min) suppressed insulin-stimulated insulin receptor substrate (IRS)-1 Tyr612 phosphorylation in a dose- and time-dependent manner. These responses were associated with inhibition of the insulin-stimulated phosphorylation of phosphatidylinositol 3-kinase (PI3K) Tyr458, Akt Ser473, and glycogen synthase kinase-3β Ser9 and with inhibition of insulin-stimulated 3- O-methyl-d-glucose (3MG) transport but not with inhibition of the phosphorylation of insulin receptor-β Tyr1158/62/63. Furthermore, caffeine enhanced phosphorylation of IRS-1 Ser307 and an IRS-1 Ser307 kinase, inhibitor-κB kinase (IKK)-α/β Ser176/180. Blockade of IKK/IRS-1 Ser307 by caffeic acid ameliorated the caffeine-induced downregulation of IRS-1 Tyr612 phosphorylation and 3MG transport. Caffeine also increased the phosphorylation of IRS-1 Ser789 and an IRS-1 Ser789 kinase, 5′-AMP-activated protein kinase (AMPK). However, inhibition of IRS-1 Ser789 and AMPK phosphorylation by dantrolene did not rescue the caffeine-induced downregulation of IRS-1 Tyr612 phosphorylation or 3MG transport. In addition, caffeine suppressed the phosphorylation of insulin-stimulated IRS-1 Ser636/639 and upstream kinases, including the mammalian target of rapamycin and p70S6 kinase. Intravenous injection of caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin-stimulated IRS-1 Tyr612 and Akt Ser473 in epitrochlearis muscle. Our results indicate that caffeine inhibits insulin signaling partly through the IKK/IRS-1 Ser307 pathway, via a Ca2+- and AMPK-independent mechanism in skeletal muscle.

scholarly journals PTEN Expression Causes Feedback Upregulation of Insulin Receptor Substrate 2

2001 ◽  
Vol 21 (12) ◽  
pp. 3947-3958 ◽  
Author(s):  
Laura Simpson ◽  
Jing Li ◽  
Danny Liaw ◽  
Ian Hennessy ◽  
Jonathan Oliner ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signaling ◽  
Specific Activity ◽  
Mammalian Target Of Rapamycin ◽  
Specific Inhibitor ◽  
Pi3k Pathway ◽  
Negative Regulator ◽  
Pten Expression ◽  
Insulin Receptor Substrate ◽  
Gene Encoding

ABSTRACT PTEN is a tumor suppressor that antagonizes phosphatidylinositol-3 kinase (PI3K) by dephosphorylating the D3 position of phosphatidylinositol (3,4,5)-triphosphate (PtdIns-3,4,5-P3). Given the importance of PTEN in regulating PtdIns-3,4,5-P3 levels, we used Affymetrix GeneChip arrays to identify genes regulated by PTEN. PTEN expression rapidly reduced the activity of Akt, which was followed by a G1 arrest and eventually apoptosis. The gene encoding insulin receptor substrate 2 (IRS-2), a mediator of insulin signaling, was found to be the most induced gene at all time points. A PI3K-specific inhibitor, LY294002, also upregulated IRS-2, providing evidence that it was the suppression of the PI3K pathway that was responsible for the message upregulation. In addition, PTEN, LY294002, and rapamycin, an inhibitor of mammalian target of rapamycin, caused a reduction in the molecular weight of IRS-2 and an increase in the association of IRS-2 with PI3K. Apparently, PTEN inhibits a negative regulator of IRS-2 to upregulate the IRS-2–PI3K interaction. These studies suggest that PtdIns-3,4,5-P3 levels regulate the specific activity and amount of IRS-2 available for insulin signaling.

Microcystin-LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase

2017 ◽  
Vol 33 (1) ◽  
pp. 16-22 ◽  
Author(s):  
Jinghui Liu ◽  
Chun Xu ◽  
Shaofeng Zhang ◽  
Haoyan Li ◽  
Kele Chen ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

Cellular depletion of atypical PKCλ is associated with enhanced insulin sensitivity and glucose uptake in L6 rat skeletal muscle cells

2010 ◽  
Vol 299 (3) ◽  
pp. E402-E412 ◽  
Author(s):  
Clare Stretton ◽  
Ashleigh Evans ◽  
Harinder S. Hundal
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Dominant Negative Mutant

Atypical protein kinase C (aPKC) isoforms (λ and ζ) have been implicated in the control of insulin-stimulated glucose uptake in adipose and skeletal muscle, but their precise role in this process remains unclear, especially in light of accumulating evidence showing that, in response to numerous stimuli, including insulin and lipids such as ceramide, activation of aPKCs acts to negatively regulate key insulin-signaling molecules, such as insulin receptor substrate-1 (IRS-1) and protein kinase B (PKB)/cAMP-dependent PKC (Akt). In this study, we have depleted PKCλ in L6 skeletal muscle cells using RNA interference and assessed the effect this has upon insulin action. Muscle cells did not express detectable amounts of PKCζ. Depletion of PKCλ (>95%) had no significant effect on the expression of proteins participating in insulin signaling [i.e., insulin receptor, IRS-1, phosphatidylinositol 3-kinase (PI 3-kinase), PKB, or phosphate and tensin homolog deleted on chromosome 10] or those involved in glucose transport [Akt substrate of 160 kDa, glucose transporter (GLUT)1, or GLUT4]. However, PKCλ-depleted muscle cells exhibited greater activation of PKB/Akt and phosphorylation of its downstream target glycogen synthase kinase 3, in the basal state and displayed greater responsiveness to submaximal doses of insulin with respect to p85-PI 3-kinase/IRS-1 association and PKB activation. The increase in basal and insulin-induced signaling resulted in an associated enhancement of basal and insulin-stimulated glucose transport, both of which were inhibited by the PI 3-kinase inhibitor wortmannin. Additionally, like RNAi-mediated depletion of PKCλ, overexpression of a dominant-negative mutant of PKCζ induced a similar insulin-sensitizing effect on PKB activation. Our findings indicate that aPKCs are likely to play an important role in restraining proximal insulin signaling events but appear dispensable with respect to insulin-stimulated glucose uptake in cultured L6 muscle cells.

scholarly journals Functional Studies of Akt Isoform Specificity in Skeletal Muscle in Vivo; Maintained Insulin Sensitivity Despite Reduced Insulin Receptor Substrate-1 Expression

2007 ◽  
Vol 21 (1) ◽  
pp. 215-228 ◽  
Author(s):  
Mark E. Cleasby ◽  
Tracie A. Reinten ◽  
Gregory J. Cooney ◽  
David E. James ◽  
Edward W. Kraegen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Short Hairpin

Abstract The phosphoinositide 3-kinase/Akt pathway is thought to be essential for normal insulin action and glucose metabolism in skeletal muscle and has been shown to be dysregulated in insulin resistance. However, the specific roles of and signaling pathways triggered by Akt isoforms have not been fully assessed in muscle in vivo. We overexpressed constitutively active (ca-) Akt-1 or Akt-2 constructs in muscle using in vivo electrotransfer and, after 1 wk, assessed the roles of each isoform on glucose metabolism and fiber growth. We achieved greater than 2.5-fold increases in total Ser473 phosphorylation in muscles expressing ca-Akt-1 and ca-Akt-2, respectively. Both isoforms caused hypertrophy of muscle fibers, consistent with increases in p70S6kinase phosphorylation, and a 60% increase in glycogen accumulation, although only Akt-1 increased glycogen synthase kinase-3β phosphorylation. Akt-2, but not Akt-1, increased basal glucose uptake (by 33%, P = 0.004) and incorporation into glycogen and lipids, suggesting a specific effect on glucose transport. Consistent with this, short hairpin RNA-mediated silencing of Akt-2 caused reductions in glycogen storage and glucose uptake. Consistent with Akt-mediated insulin receptor substrate 1 (IRS-1) degradation, we observed approximately 30% reductions in IRS-1 protein in muscle overexpressing ca-Akt-1 or ca-Akt-2. Despite this, we observed no decrease in insulin-stimulated glucose uptake. Furthermore, a 68% reduction in IRS-1 levels induced using short hairpin RNAs targeting IRS-1 also did not affect glucose disposal after a glucose load. These data indicate distinct roles for Akt-1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in the development of insulin resistance in skeletal muscle in vivo.

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

2003 ◽  
Vol 179 (2) ◽  
pp. 253-266 ◽  
Author(s):  
Y Hirashima ◽  
K Tsuruzoe ◽  
S Kodama ◽  
M Igata ◽  
T Toyonaga ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Kinase Inhibitor ◽  
Insulin Response ◽  
Dominant Negative ◽  
Akt Pathway ◽  
Insulin Receptor Substrate ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Gene Assay

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 insulin-dependent 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.

scholarly journals Direct Cross-talk of Interleukin-6 and Insulin Signal Transduction via Insulin Receptor Substrate-1 in Skeletal Muscle Cells

2006 ◽  
Vol 281 (11) ◽  
pp. 7060-7067 ◽  
Author(s):  
Cora Weigert ◽  
Anita M. Hennige ◽  
Rainer Lehmann ◽  
Katrin Brodbeck ◽  
Frank Baumgartner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signal Transduction ◽  
Insulin Receptor ◽  
Cross Talk ◽  
Interleukin 6 ◽  
Muscle Cells ◽  
Insulin Receptor Substrate ◽  
Insulin Signal Transduction ◽  
Insulin Signal ◽  
Direct Cross

scholarly journals MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle

2016 ◽  
Vol 291 (52) ◽  
pp. 26627-26635 ◽  
Author(s):  
Hyun Lee ◽  
Jung-Jin Park ◽  
Nga Nguyen ◽  
Jun Sub Park ◽  
Jin Hong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

Voluntary exercise training enhances glucose transport but not insulin signaling capacity in muscle of hypertensive TG(mREN2)27 rats

2005 ◽  
Vol 99 (1) ◽  
pp. 357-362 ◽  
Author(s):  
Andrew M. Lemieux ◽  
Cody J. Diehl ◽  
Julie A. Sloniger ◽  
Erik J. Henriksen
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Abdominal Fat ◽  
Voluntary Exercise ◽  
Phosphatidylinositol 3 Kinase ◽  
Muscle Glucose Transport

Male heterozygous TG(mREN2)27 rats (TGR) overexpress a murine renin transgene, display marked hypertension, and have insulin resistance of skeletal muscle glucose transport and insulin signaling. We have shown previously that voluntary exercise training by TGR improves insulin-mediated skeletal muscle glucose transport (Kinnick TR, Youngblood EB, O’Keefe MP, Saengsirisuwan V, Teachey MK, and Henriksen EJ. J Appl Physiol 93: 805–812, 2002). The present study evaluated whether this training-induced enhancement of muscle glucose transport is associated with upregulation of critical insulin signaling elements, including insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3. TGR remained sedentary or ran spontaneously in activity wheels for 6 wk, averaging 7.1 ± 0.8 km/day by the end of week 3 and 4.3 ± 0.5 km/day over the final week of training. Exercise training reduced total abdominal fat by 20% ( P < 0.05) in TGR runners (2.64 ± 0.01% of body weight) compared with sedentary TGR controls (3.28 ± 0.01%). Insulin-stimulated (2 mU/ml) glucose transport activity in soleus muscle was 36% greater in TGR runners compared with sedentary TGR controls. However, the protein expression and functionality of tyrosine phosphorylation of insulin receptor and IRS-1, IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase, and Ser473 phosphorylation of Akt were not altered by exercise training. Only insulin-stimulated glycogen synthase kinase-3β Ser9 phosphorylation was increased (22%) by exercise training. These results indicate that voluntary exercise training in TGR can enhance insulin-mediated glucose transport in skeletal muscle, as well as reduce total abdominal fat mass. However, this adaptive response in muscle occurs independently of modifications in the proximal elements of the insulin signaling cascade.

Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat

2005 ◽  
Vol 288 (6) ◽  
pp. E1074-E1081 ◽  
Author(s):  
Julie A. Sloniger ◽  
Vitoon Saengsirisuwan ◽  
Cody J. Diehl ◽  
Betsy B. Dokken ◽  
Narissara Lailerd ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Signaling Pathway ◽  
Whole Body

Essential hypertension is frequently associated with insulin resistance of skeletal muscle glucose transport, with a potential role of angiotensin II in the pathogenesis of both conditions. The male heterozygous TG(mREN2)27 rat harbors the mouse transgene for renin, exhibits local elevations in angiotensin II, and is an excellent model of both hypertension and insulin resistance. The present study was designed to investigate the potential cellular mechanisms for insulin resistance in this hypertensive animal model, including an assessment of elements of the insulin-signaling pathway. Compared with nontransgenic, normotensive Sprague-Dawley control rats, male heterozygous TG(mREN2)27 rats displayed elevated ( P < 0.05) fasting plasma insulin (74%), an exaggerated insulin response (108%) during an oral glucose tolerance test, and reduced whole body insulin sensitivity. TG(mREN2)27 rats also exhibited decreased insulin-mediated glucose transport and glycogen synthase activation in both the type IIb epitrochlearis (30 and 46%) and type I soleus (22 and 64%) muscles. Importantly, there were significant reductions (∼30–50%) in insulin stimulation of tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1), IRS-1 associated with the p85 subunit of phosphatidylinositol 3-kinase, Akt Ser473 phosphorylation, and Ser9 phosphorylation of glycogen synthase kinase-3β in epitrochlearis and soleus muscles of TG(mREN2)27 rats. Soleus muscle triglyceride concentration was 25% greater in the transgenic group compared with nontransgenic animals. Collectively, these data provide the first evidence that the insulin resistance of the hypertensive male heterozygous TG(mREN2)27 rat can be attributed to specific defects in the insulin-signaling pathway in skeletal muscle.

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