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

Weigert, Cora; Hennige, Anita M.; Lehmann, Rainer; Brodbeck, Katrin; Baumgartner, Frank R.; Schäuble, Myriam; Häring, Hans Ulrich; Schleicher, Erwin

doi:10.1074/jbc.m509782200

Cited by 118 publications

(90 citation statements)

References 52 publications

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“…Serine phosphorylation of IRS-1 appears to be a major mechanism for the adverse effects of PKC-␦ on insulin action (32,41,47). Although in vitro at least 18 PKC-␦-dependent phosphorylation sites in IRS-1 have been identified (41), so far only two sites could be demonstrated to be phosphorylated in vivo and to be functional active, these are Ser 24 and Ser 318 (32,42,47). Neither of these sites were shown to be phosphorylated upon insulin stimulation by PKC-␦, although insulin could activate PKC-␦ and induce its association to IRS-1 (40).…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-δ on Insulin Action in Skeletal Muscle Cells

Waraich

Weigert

Kalbacher

et al. 2008

Journal of Biological Chemistry

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The activation of the protein kinase C (PKC) family of serine/ threonine kinases contributes to the modulation of insulin signaling, and the PKC-dependent phosphorylation of insulin receptor substrate (IRS)-1 has been implicated in the development of insulin resistance. Here we demonstrate Ser 357 of rat IRS-1 as a novel PKC-␦-dependent phosphorylation site in skeletal muscle cells upon stimulation with insulin and phorbol ester using Ser(P) 357 antibodies and active and kinase dead mutants of PKC-␦. Phosphorylation of this site was simulated using IRS-1 Glu 357 and shown to reduce insulin-induced tyrosine phosphorylation of IRS-1, to decrease activation of Akt, and to subsequently diminish phosphorylation of glycogen synthase kinase-3. When the phosphorylation was prevented by mutation of Ser 357 to alanine, these effects of insulin were enhanced. When the adjacent Ser To accomplish its fundamental role in maintaining in vivo metabolic homeostasis, insulin binds and activates insulin receptors, which in turn recruit insulin-receptor substrate (IRS) 2 proteins (1). By disruption of their respective genes in mice, IRS-1 and IRS-2 have been assigned a central role in mediating the normal actions of insulin. Defects at the level of the IRS proteins also comprise a major locus for the development of metabolic disorders, including insulin resistance and type 2 diabetes (2, 3). IRS proteins are regulated at several steps, including gene expression, protein degradation, and phosphorylation (4, 5). Although the phosphorylation of IRS-1 on tyrosine residues is mandatory for insulin-stimulated responses, serine/threonine phosphorylation appears to be the mechanism for the precise regulation and could either enhance or attenuate the insulin effects (6, 7). However, in most studies serine phosphorylation of IRS-1 has been implicated as a negative regulator of insulin signaling (8 -12). It can induce the dissociation of IRS-1 from its receptor and hinder the phosphorylation of tyrosine residues (8), release the IRS-1 from intracellular complexes that maintain them in close proximity to the receptor (13), or induce its protein degradation (14). These multiple effects suggest that the serine residues subjected to phosphorylation play a pivotal role in regulating IRS-1 function. Of note, the unbalanced chronic stimulation of IRS-1 serine kinases leads to hyperphosphorylation of IRS-1 and is a major pathophysiological mechanism in the development of insulin resistance. Among these IRS-1 kinases, members of the protein kinase C (PKC) family of serine/threonine kinases have received considerable attention for their regulatory role in insulin signaling. Although particularly the activation of atypical PKCs has been reported as positive modulation of insulin signaling (15, 16), the majority of studies has demonstrated that PKCs are implicated in impaired insulin signaling including classical (17-19), novel (20), and more recently also atypical PKC isoforms (21). Activation of PKC isoforms by insulin (11, 21, 22), hyperglycemia (1...

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Section: Discussionmentioning

confidence: 99%

“…34, and the murine PKC-␦ and dominant kinase-negative PKC-␦ expression vectors were described in Ref. 42.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-δ on Insulin Action in Skeletal Muscle Cells

Waraich

Weigert

Kalbacher

et al. 2008

Journal of Biological Chemistry

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“…Protein (250 µg) of total extracts was separated by SDS-PAGE (7.5%, vol./vol.) and western blot analysis was performed as described elsewhere [19].…”

Section: Methodsmentioning

confidence: 99%

IL-6 deficiency in mice neither impairs induction of metabolic genes in the liver nor affects blood glucose levels during fasting and moderately intense exercise

et al. 2010

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Aims/hypothesis Fasting and exercise are strong physiological stimuli for hepatic glucose production. IL-6 has been implicated in the regulation of gluconeogenic genes, but the results are contradictory and the relevance of IL-6 for fasting-and exercise-induced hepatic glucose production is not clear. Methods Investigations were performed in rat hepatoma cells, and on C57Bl6 and Il6 −/− mice under the following conditions: IL-6 stimulation/injection, non-exhaustive exercise (60 min run on a treadmill) and fasting for 16 h. Metabolite analysis, quantitative real-time PCR and immunoblotting were performed.

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“…Weigert et al (43) recently compared the relative fold induction of SOCS3 mRNA in skeletal muscle and liver from mice treated with IL-6 in vivo. While IL-6 increased SOCS3 twofold in muscle (comparable with our fold induction in SOCS3 protein expression in vitro), it was increased ϳ25-fold in liver, suggesting that capacity for IL-6 to induce SOCS3 is much greater in hepatic tissue.…”

Section: Il-6 and Muscle Metabolismmentioning

confidence: 99%

Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

Carey

Steinberg

Macaulay³

et al. 2006

Diabetes

722

648

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Although interleukin-6 (IL-6) has been associated with insulin resistance, little is known regarding the effects of IL-6 on insulin sensitivity in humans in vivo. Here, we show that IL-6 infusion increases glucose disposal without affecting the complete suppression of endogenous glucose production during a hyperinsulinemic-euglycemic clamp in healthy humans. Because skeletal muscle accounts for most of the insulin-stimulated glucose disposal in vivo, we examined the mechanism(s) by which IL-6 may affect muscle metabolism using L6 myotubes. IL-6 treatment increased fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increased AMP-activated protein kinase (AMPK). To determine whether the activation of AMPK mediated cellular metabolic events, we conducted experiments using L6 myotubes infected with dominant-negative AMPK ␣-subunit. The effects described above were abrogated in AMPK dominant-negative-infected cells. Our results demonstrate that acute IL-6 treatment enhances insulin-stimulated glucose disposal in humans in vivo, while the effects of IL-6 on glucose and fatty acid metabolism in vitro appear to be mediated by AMPK. Diabetes

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

Cited by 118 publications

References 52 publications

Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-δ on Insulin Action in Skeletal Muscle Cells

Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-δ on Insulin Action in Skeletal Muscle Cells

IL-6 deficiency in mice neither impairs induction of metabolic genes in the liver nor affects blood glucose levels during fasting and moderately intense exercise

Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

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